abstract-colorectal-set.txt

1. Virchows Arch. 2016 Aug;469(2):125-34. doi: 10.1007/s00428-016-1956-3. Epub 2016 
Jun 20.

Molecular pathological classification of colorectal cancer.

Müller MF(1), Ibrahim AE(2)(3), Arends MJ(4).

Author information:
(1)Division of Pathology, Centre for Comparative Pathology, Edinburgh Cancer 
Research Centre, Institute of Genetics & Molecular Medicine, Western General 
Hospital, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, UK.
(2)Department of Pathology, Addenbrooke's Hospital, University of Cambridge, 
Hills Road, Cambridge, CB2 0QQ, UK.
(3)Bedford Hospital NHS Trust, Viapath Cellular Pathology, Kempston Road, 
Bedford, MK42 9DJ, UK.
(4)Division of Pathology, Centre for Comparative Pathology, Edinburgh Cancer 
Research Centre, Institute of Genetics & Molecular Medicine, Western General 
Hospital, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, UK. 
M.Arends@ed.ac.uk.

Colorectal cancer (CRC) shows variable underlying molecular changes with two 
major mechanisms of genetic instability: chromosomal instability and 
microsatellite instability. This review aims to delineate the different pathways 
of colorectal carcinogenesis and provide an overview of the most recent advances 
in molecular pathological classification systems for colorectal cancer. Two 
molecular pathological classification systems for CRC have recently been 
proposed. Integrated molecular analysis by The Cancer Genome Atlas project is 
based on a wide-ranging genomic and transcriptomic characterisation study of CRC 
using array-based and sequencing technologies. This approach classified CRC into 
two major groups consistent with previous classification systems: (1) ∼16 % 
hypermutated cancers with either microsatellite instability (MSI) due to 
defective mismatch repair (∼13 %) or ultramutated cancers with DNA polymerase 
epsilon proofreading mutations (∼3 %); and (2) ∼84 % non-hypermutated, 
microsatellite stable (MSS) cancers with a high frequency of DNA somatic copy 
number alterations, which showed common mutations in APC, TP53, KRAS, SMAD4, and 
PIK3CA. The recent Consensus Molecular Subtypes (CMS) Consortium analysing CRC 
expression profiling data from multiple studies described four CMS groups: 
almost all hypermutated MSI cancers fell into the first category CMS1 
(MSI-immune, 14 %) with the remaining MSS cancers subcategorised into three 
groups of CMS2 (canonical, 37 %), CMS3 (metabolic, 13 %) and CMS4 (mesenchymal, 
23 %), with a residual unclassified group (mixed features, 13 %). Although 
further research is required to validate these two systems, they may be useful 
for clinical trial designs and future post-surgical adjuvant treatment 
decisions, particularly for tumours with aggressive features or predicted 
responsiveness to immune checkpoint blockade.

DOI: 10.1007/s00428-016-1956-3
PMCID: PMC4978761
PMID: 27325016 [Indexed for MEDLINE]


2. Ann Oncol. 2019 Nov 1;30(11):1796-1803. doi: 10.1093/annonc/mdz387.

Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line 
efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) 
trial.

Stintzing S(1), Wirapati P(2), Lenz HJ(3), Neureiter D(4), Fischer von 
Weikersthal L(5), Decker T(6), Kiani A(7), Kaiser F(8), Al-Batran S(9), Heintges 
T(10), Lerchenmüller C(11), Kahl C(12), Seipelt G(13), Kullmann F(14), Moehler 
M(15), Scheithauer W(16), Held S(17), Modest DP(18), Jung A(19), Kirchner T(19), 
Aderka D(20), Tejpar S(21), Heinemann V(18).

Author information:
(1)Department of Medicine, Division of Hematology, Oncology, and Tumor 
Immunology (CCM), Charité Universitaetsmedizin Berlin, Berlin, Germany. 
Electronic address: sebastian.stintzing@charite.de.
(2)SIB Swiss Institute of Bioinformatics, Bioinformatic Core Facility, Lausanne, 
Switzerland.
(3)USC Norris Comprehensive Cancer Center, Los Angeles, USA.
(4)Institute of Pathology, Paracelsus Medical University/Salzburger 
Landeskliniken (SALK), Salzburg, Austria.
(5)Gesundheitszentrum St. Marien, Amberg.
(6)Oncological Practice, Ravensburg.
(7)Medizinische Klinik IV, Klinikum Bayreuth, Bayreuth.
(8)VK&K Studien GbR, Landshut.
(9)Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt/Main.
(10)Department of Medicine II, Städtisches Klinikum Neuss, Neuss.
(11)Oncological Practice, Münster.
(12)Haematology and Oncology, Staedtisches Klinikum Magdeburg, Magdeburg.
(13)Oncological Practice, Bad Soden.
(14)Department of Medicine I, Klinikum Weiden, Weiden.
(15)University Hospital Mainz, Mainz, Germany.
(16)Department of Internal Medicine I & Comprehensive Cancer Center, Medical 
University Vienna, Vienna, Austria.
(17)ClinAssess GmbH, Leverkusen.
(18)Department of Medicine III, University Hospital, LMU Munich, Munich.
(19)Institute of Pathology University of Munich, Munich, Germany.
(20)Department of Gastrointestinal Oncology, Chaim Sheba Medical Center, Ramat 
Gan, Israel.
(21)Molecular Digestive Oncology, UZ Leuven, Belgium.

BACKGROUND: FIRE-3 compared first-line therapy with FOLFIRI plus either 
cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal 
cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC 
samples according to their gene-signature in four different subtypes. Relevance 
of CMS for the treatment of mCRC has yet to be defined.
PATIENTS AND METHODS: In this exploratory analysis, patients were grouped 
according to the previously published tumor CRC-CMSs. Objective response rates 
(ORR) were compared using chi-square test. Overall survival (OS) and 
progression-free survival (PFS) times were compared using Kaplan-Meier 
estimation, log-rank tests. Hazard ratios (HR) were estimated according to the 
Cox proportional hazard method.
RESULTS: CMS classification could be determined in 438 out of 514 specimens 
available from the intent-to-treat (ITT) population (n = 592). Frequencies for 
the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), 
CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 
(12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus 
(vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% 
versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the 
treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS 
(P < 0.001), and OS (P < 0.001). Within the RAS wild-type population, OS 
observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI 
bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS 
was comparable in CMS1 and CMS2, independent of targeted therapy.
CONCLUSIONS: CMS classification is prognostic for mCRC. Prolonged OS induced by 
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study 
appears to be driven by CMS3 and CMS4. CMS classification provides deeper 
insights into the biology to CRC, but at present time has no direct impact on 
clinical decision-making.The FIRE-3 (AIO KRK-0306) study had been registered at 
ClinicalTrials.gov: NCT00433927.

© The Author(s) 2019. Published by Oxford University Press on behalf of the 
European Society for Medical Oncology.

DOI: 10.1093/annonc/mdz387
PMCID: PMC6927316
PMID: 31868905 [Indexed for MEDLINE]


3. Nat Med. 2015 Nov;21(11):1350-6. doi: 10.1038/nm.3967. Epub 2015 Oct 12.

The consensus molecular subtypes of colorectal cancer.

Guinney J(1), Dienstmann R(1)(2), Wang X(3)(4), de Reyniès A(5), Schlicker A(6), 
Soneson C(7), Marisa L(5), Roepman P(8), Nyamundanda G(9), Angelino P(7), Bot 
BM(1), Morris JS(10), Simon IM(8), Gerster S(7), Fessler E(3), De Sousa E Melo 
F(3), Missiaglia E(7), Ramay H(7), Barras D(7), Homicsko K(11), Maru D(10), 
Manyam GC(10), Broom B(10), Boige V(12), Perez-Villamil B(13), Laderas T(1), 
Salazar R(14), Gray JW(15), Hanahan D(11), Tabernero J(2), Bernards R(6), Friend 
SH(1), Laurent-Puig P(16)(17), Medema JP(3), Sadanandam A(9), Wessels L(6), 
Delorenzi M(7)(18)(19), Kopetz S(10), Vermeulen L(3), Tejpar S(20).

Author information:
(1)Sage Bionetworks, Seattle, Washington, USA.
(2)Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de 
Barcelona, Barcelona, Spain.
(3)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 
University of Amsterdam, Amsterdam, the Netherlands.
(4)Department of Biomedical Sciences, City University of Hong Kong, Hong Kong.
(5)Ligue Nationale Contre le Cancer, Paris, France.
(6)Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands.
(7)Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
(8)Agendia NV, Amsterdam, the Netherlands.
(9)Institute of Cancer Research, London, UK.
(10)The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.
(11)École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
(12)Gustave Roussy, Villejuif, France.
(13)Laboratorio de Genomica y Microarrays, Instituto de Investigación Sanitaria 
San Carlos, Hospital Clinico San Carlos, Madrid, Spain.
(14)Institut Catala d'Oncologia, L'Institut d'Investigació Biomèdica de 
Bellvitge, Barcelona, Spain.
(15)Biomedical Engineering, Oregon Health Sciences University, Portland, Oregon, 
USA.
(16)Université Paris Descartes, Paris, France.
(17)Department of Biology, Hôpital Européen Georges-Pompidou, Assistance 
Publique - Hôpitaux de Paris, Paris, France.
(18)Ludwig Center for Cancer Research, University of Lausanne, Lausanne, 
Switzerland.
(19)Department of Oncology, University of Lausanne, Lausanne, Switzerland.
(20)Universitair ziekenhuis Leuven, Leuven, Belgium.

Comment in
    BMJ. 2015;351:h5433.
    Nat Rev Cancer. 2022 Feb;22(2):68-69.

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous 
outcomes and drug responses. To resolve inconsistencies among the reported gene 
expression-based CRC classifications and facilitate clinical translation, we 
formed an international consortium dedicated to large-scale data sharing and 
analytics across expert groups. We show marked interconnectivity between six 
independent classification systems coalescing into four consensus molecular 
subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability 
immune, 14%), hypermutated, microsatellite unstable and strong immune 
activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling 
activation; CMS3 (metabolic, 13%), epithelial and evident metabolic 
dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth 
factor-β activation, stromal invasion and angiogenesis. Samples with mixed 
features (13%) possibly represent a transition phenotype or intratumoral 
heterogeneity. We consider the CMS groups the most robust classification system 
currently available for CRC-with clear biological interpretability-and the basis 
for future clinical stratification and subtype-based targeted interventions.

DOI: 10.1038/nm.3967
PMCID: PMC4636487
PMID: 26457759 [Indexed for MEDLINE]


4. Cell. 2020 Sep 3;182(5):1341-1359.e19. doi: 10.1016/j.cell.2020.07.005. Epub 
2020 Aug 6.

Coordinated Cellular Neighborhoods Orchestrate Antitumoral Immunity at the 
Colorectal Cancer Invasive Front.

Schürch CM(1), Bhate SS(2), Barlow GL(3), Phillips DJ(4), Noti L(5), Zlobec 
I(5), Chu P(3), Black S(3), Demeter J(6), McIlwain DR(3), Kinoshita S(6), 
Samusik N(6), Goltsev Y(3), Nolan GP(7).

Author information:
(1)Department of Microbiology & Immunology, Stanford University School of 
Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University 
School of Medicine, Stanford, CA 94305, USA. Electronic address: 
christian.m.schuerch@gmail.com.
(2)Department of Microbiology & Immunology, Stanford University School of 
Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University 
School of Medicine, Stanford, CA 94305, USA; Department of Bioengineering, 
Stanford University School of Medicine, Stanford, CA 94305, USA.
(3)Department of Microbiology & Immunology, Stanford University School of 
Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University 
School of Medicine, Stanford, CA 94305, USA.
(4)Department of Microbiology & Immunology, Stanford University School of 
Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University 
School of Medicine, Stanford, CA 94305, USA; Department of Dermatology, Stanford 
University School of Medicine, Stanford, CA 94305, USA.
(5)Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
(6)Department of Microbiology & Immunology, Stanford University School of 
Medicine, Stanford, CA 94305, USA.
(7)Department of Microbiology & Immunology, Stanford University School of 
Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University 
School of Medicine, Stanford, CA 94305, USA. Electronic address: 
gnolan@stanford.edu.

Erratum in
    Cell. 2020 Oct 29;183(3):838.

Antitumoral immunity requires organized, spatially nuanced interactions between 
components of the immune tumor microenvironment (iTME). Understanding this 
coordinated behavior in effective versus ineffective tumor control will advance 
immunotherapies. We re-engineered co-detection by indexing (CODEX) for 
paraffin-embedded tissue microarrays, enabling simultaneous profiling of 140 
tissue regions from 35 advanced-stage colorectal cancer (CRC) patients with 56 
protein markers. We identified nine conserved, distinct cellular neighborhoods 
(CNs)-a collection of components characteristic of the CRC iTME. Enrichment of 
PD-1+CD4+ T cells only within a granulocyte CN positively correlated with 
survival in a high-risk patient subset. Coupling of tumor and immune CNs, 
fragmentation of T cell and macrophage CNs, and disruption of inter-CN 
communication was associated with inferior outcomes. This study provides a 
framework for interrogating how complex biological processes, such as 
antitumoral immunity, occur through concerted actions of cells and spatial 
domains.

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cell.2020.07.005
PMCID: PMC7479520
PMID: 32763154 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of Interests G.P.N. has received 
research grants from Pfizer, Vaxart, Celgene, and Juno Therapeutics during the 
course of this work. G.P.N., Y.G., and N.S. have equity in and are scientific 
advisory board members of Akoya Biosciences. C.M.S. is a scientific advisor to 
Enable Medicine. Akoya Biosciences makes reagents and instruments that are 
dependent on licenses from Stanford University. Stanford University has been 
granted US patent 9909167, which covers some aspects of the technology described 
in this paper.


5. Ther Adv Med Oncol. 2020 Jul 24;12:1758835920936089. doi: 
10.1177/1758835920936089. eCollection 2020.

Molecular subtypes and the evolution of treatment management in metastatic 
colorectal cancer.

Martini G(1), Dienstmann R(2), Ros J(3), Baraibar I(3), Cuadra-Urteaga JL(3), 
Salva F(3), Ciardiello D(1), Mulet N(3), Argiles G(4), Tabernero J(5), Elez 
E(6).

Author information:
(1)Università della Campania L. Vanvitelli, Naples.
(2)VHIO, Barcelona, Barcelona, Spain.
(3)Vall d'Hebron Hospital, Barcelona, Catalunya, Spain.
(4)Vall d'Hebron Hospital, Barcelona, Spain.
(5)Vall d'Hebron University Hospital, Barcelona, Spain.
(6)Vall D'Hebron Institute of Oncology P/Vall D'Hebron 119-121, Barcelona, 08035 
Spain.

Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic 
challenge, which is further complicated by the common occurrence of several 
molecular alterations that confer resistance to standard chemotherapy and 
targeted agents. Mechanisms of resistance have been identified at multiple 
levels in the epidermal growth factor receptor (EGFR) pathway, including 
mutations in KRAS, NRAS, and BRAF V600E, and in the HER2 and MET receptors. 
These alterations represent oncogenic drivers that may co-exist in the same 
tumor with other primary and acquired alterations via a clonal selection 
process. Other molecular alterations include DNA damage repair mechanisms and 
rare kinase fusions, potentially offering a rationale for new therapeutic 
strategies. In recent years, genomic analysis has been expanded by a more 
complex study of epigenomic, transcriptomic, and microenvironment features. The 
Consensus Molecular Subtype (CMS) classification describes four CRC subtypes 
with distinct biological characteristics that show prognostic and potential 
predictive value in the clinical setting. Here, we review the panorama of 
actionable targets in CRC, and the developments in more recent molecular tests, 
such as liquid biopsy analysis, which are increasingly offering clinicians a 
means of ensuring optimal tailored treatments for patients with metastatic CRC 
according to their evolving molecular profile and treatment history.

© The Author(s), 2020.

DOI: 10.1177/1758835920936089
PMCID: PMC7383645
PMID: 32782486

Conflict of interest statement: Conflict of interest statement: GM, IB, JR, CD, 
JC, FS, NM declare no conflict of interest. RD: advisory role for Roche; 
speaker’s fees from Roche, Symphogen, Ipsen, Amgen, Sanofi, MSD, Servier; and 
direct research funding from Merck. GA: personal financial interests, honoraria 
for advisory roles, travel grants, research grants (past 5 years) from Hoffman 
La-Roche, Bristol-Myers Squibb, Bayer, Servier, Amgen, Merck Serono, Menarini; 
institutional financial interests, honoraria due to investigator contributions 
to clinical trials from Hoffman La-Roche, Novartis, Boehringer Ingelheim, Boston 
Pharmaceuticals, Hoffman La Roche, Genentech. JT: personal financial interest in 
the form of scientific consultancy roles for Array Biopharma, AstraZeneca, 
Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, 
Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, 
Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, 
Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael 
Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, 
Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, 
HalioDX SAS and Roche Diagnostics; institutional financial interest in the form 
of financial support for clinical trials or contracted research for Agendia BV, 
Amgen SA, Debiopharm International SA, Janssen-Cilag SA, Mologen AG, Novartis 
Farmacéutica SA, Pharma Mar, Roche Farma SA, Laboratorios Servier SL and 
Symphogen A/S. EE: personal financial interests, honoraria for advisory roles, 
travel grants, research grants (past 5 years) from Hoffman La-Roche, Sanofi 
Aventis, Amgen, Merck Serono, Servier, MSD, Array Pharmaceuticals, Bristol-Myers 
Squibb; institutional financial interests, honoraria due to investigator 
contribution in clinical trials from Hoffman La-Roche, Sanofi Aventis, Amgen, 
Merck Serono, MSD, Boehringer Ingelheim, AbbVie, Array Pharmaceuticals, 
Pierre-Fabre, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, Medimmune.


6. Cancer. 2019 Jun 15;125(12):2002-2010. doi: 10.1002/cncr.31994. Epub 2019 Mar 
11.

Clinical and molecular characterization of early-onset colorectal cancer.

Willauer AN(1), Liu Y(2), Pereira AAL(1), Lam M(1), Morris JS(3), Raghav KPS(1), 
Morris VK(1), Menter D(1), Broaddus R(4), Meric-Bernstam F(5), Hayes-Jordan 
A(6), Huh W(7), Overman MJ(1), Kopetz S(1), Loree JM(1).

Author information:
(1)Department of Gastrointestinal Medical Oncology, The University of Texas MD 
Anderson Cancer Center, Houston, Texas.
(2)Department of Statistics, Rice University, Houston, Texas.
(3)Department of Biostatistics, The University of Texas MD Anderson Cancer 
Center, Houston, Texas.
(4)Department of Pathology, The University of Texas MD Anderson Cancer Center, 
Houston, Texas.
(5)Department of Investigational Cancer Therapeutics, The University of Texas MD 
Anderson Cancer Center, Houston, Texas.
(6)Department of Pediatric Surgical Oncology, The University of Texas MD 
Anderson Cancer Center, Houston, Texas.
(7)Department of Pediatrics, The University of Texas MD Anderson Cancer Center, 
Houston, Texas.

Comment in
    Cancer Discov. 2019 Jul;9(7):OF5.

BACKGROUND: Colorectal cancer (CRC) incidence is increasing in adults younger 
than 50 years. This study evaluated clinical and molecular features to identify 
those features unique to early-onset CRC that differentiate these patients from 
patients 50 years old or older.
METHODS: Baseline characteristics were evaluated according to the CRC onset age 
with 3 independent cohorts. A fourth cohort was used to describe the impact of 
age on the consensus molecular subtype (CMS) prevalence.
RESULTS: This retrospective review of more than 36,000 patients with CRC showed 
that early-onset patients were more likely to have microsatellite instability 
(P = .038), synchronous metastatic disease (P = .009), primary tumors in the 
distal colon or rectum (P < .0001), and fewer BRAF V600 mutations (P < .001) in 
comparison with patients 50 years old or older. Patients aged 18 to 29 years had 
fewer adenomatous polyposis coli (APC) mutations (odds ratio [OR], 0.56; 95% 
confidence interval [CI], 0.35-0.90; P = .015) and an increased prevalence of 
signet ring histology (OR, 4.89; 95% CI, 3.23-7.39; P < .0001) in comparison 
with other patients younger than 50 years. In patients younger than 40 years, 
CMS1 was the most common subtype, whereas CMS3 and CMS4 were uncommon 
(P = .003). CMS2 was relatively stable across age groups. Early-onset patients 
with inflammatory bowel disease were more likely to have mucinous or signet ring 
histology (OR, 5.54; 95% CI, 2.24-13.74; P = .0004) and less likely to have APC 
mutations (OR, 0.24; 95% CI, 0.07-0.75; P = .019) in comparison with early-onset 
patients without predisposing conditions.
CONCLUSIONS: Early-onset CRC is not only distinct from traditional CRC: special 
consideration should be given to and further investigations should be performed 
for both very young patients with CRC (18-29 years) and those with predisposing 
conditions. The etiology of the high rate of CMS1 in patients younger than 
40 years deserves further exploration.

© 2019 American Cancer Society.

DOI: 10.1002/cncr.31994
PMCID: PMC6583775
PMID: 30854646 [Indexed for MEDLINE]


7. Cancer Cell. 2019 Sep 16;36(3):319-336.e7. doi: 10.1016/j.ccell.2019.08.003.

Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal 
Cancer to Drive Poor-Prognosis Subtypes and Metastasis.

Jackstadt R(1), van Hooff SR(2), Leach JD(3), Cortes-Lavaud X(1), Lohuis JO(1), 
Ridgway RA(1), Wouters VM(2), Roper J(4), Kendall TJ(5), Roxburgh CS(6), Horgan 
PG(6), Nixon C(1), Nourse C(1), Gunzer M(7), Clark W(1), Hedley A(1), Yilmaz 
OH(8), Rashid M(9), Bailey P(10), Biankin AV(10), Campbell AD(1), Adams DJ(9), 
Barry ST(11), Steele CW(3), Medema JP(2), Sansom OJ(12).

Author information:
(1)Cancer Research UK Beatson Institute, Glasgow, UK.
(2)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 
University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, 
Amsterdam, the Netherlands.
(3)Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer 
Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.
(4)Department of Medicine, Division of Gastroenterology, Duke University, 
Durham, NC, USA.
(5)Division of Pathology/Centre for Inflammation Research, University of 
Edinburgh, UK.
(6)Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, 
UK.
(7)Institute for Experimental Immunology and Imaging, University Hospital, 
University Duisburg-Essen, Essen, Germany.
(8)Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA; 
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
(9)Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
(10)Institute of Cancer Sciences, University of Glasgow, Garscube Estate, 
Glasgow, UK.
(11)Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.
(12)Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer 
Sciences, University of Glasgow, Garscube Estate, Glasgow, UK. Electronic 
address: o.sansom@beatson.gla.ac.uk.

Comment in
    Cancer Cell. 2019 Sep 16;36(3):213-214.

The metastatic process of colorectal cancer (CRC) is not fully understood and 
effective therapies are lacking. We show that activation of NOTCH1 signaling in 
the murine intestinal epithelium leads to highly penetrant metastasis (100% 
metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. 
Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a 
tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes 
(CMS4 and CRIS-B), and drives metastasis through transforming growth factor 
(TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this 
recruitment with clinically relevant therapeutic agents blocks metastasis. We 
propose that NOTCH1 signaling is key to CRC progression and should be exploited 
clinically.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2019.08.003
PMCID: PMC6853173
PMID: 31526760 [Indexed for MEDLINE]

Conflict of interest statement: Simon T. Barry is an employee and shareholder of 
AstraZeneca.


8. Cancer Res. 2019 Aug 15;79(16):4227-4241. doi: 10.1158/0008-5472.CAN-18-3945. 
Epub 2019 Jun 25.

Transcriptomic Differences between Primary Colorectal Adenocarcinomas and 
Distant Metastases Reveal Metastatic Colorectal Cancer Subtypes.

Kamal Y(#)(1), Schmit SL(#)(2), Hoehn HJ(2), Amos CI(3)(4), Frost HR(3).

Author information:
(1)Department of Biomedical Data Sciences, Geisel School of Medicine at 
Dartmouth, Hanover, New Hampshire.
(2)Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research 
Institute, Tampa, Florida.
(3)Department of Biomedical Data Sciences, Geisel School of Medicine at 
Dartmouth, Hanover, New Hampshire. rob.frost@dartmouth.edu chris.amos@bcm.edu.
(4)Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine, 
Houston, Texas.
(#)Contributed equally

Approximately 20% of colorectal cancer patients with colorectal adenocarcinomas 
present with metastases at the time of diagnosis, and therapies that specially 
target these metastases are lacking. We present a novel approach for 
investigating transcriptomic differences between primary colorectal 
adenocarcinoma and distant metastases, which may help to identify primary tumors 
with high risk for future dissemination and to inform the development of 
metastasis-targeted therapies. To effectively compare the transcriptomes of 
primary colorectal adenocarcinoma and metastatic lesions at both the gene and 
pathway levels, we eliminated tissue specificity of the "host" organs where 
tumors are located and adjusted for confounders such as exposure to chemotherapy 
and radiation, and identified that metastases were characterized by reduced 
epithelial-mesenchymal transition (EMT) but increased MYC target and DNA-repair 
pathway activities. FBN2 and MMP3 were the most differentially expressed genes 
between primary tumors and metastases. The two subtypes of colorectal 
adenocarcinoma metastases that were identified, EMT inflammatory and 
proliferative, were distinct from the consensus molecular subtype (CMS) 3, 
suggesting subtype exclusivity. In summary, this study highlights transcriptomic 
differences between primary tumors and colorectal adenocarcinoma metastases and 
delineates pathways that are activated in metastases that could be targeted in 
colorectal adenocarcinoma patients with metastatic disease. SIGNIFICANCE: These 
findings identify a colorectal adenocarcinoma metastasis-specific 
gene-expression signature that is free from potentially confounding background 
signals coming from treatment exposure and the normal host tissue that the 
metastasis is now situated within.

©2019 American Association for Cancer Research.

DOI: 10.1158/0008-5472.CAN-18-3945
PMCID: PMC6697603
PMID: 31239274 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of Interest: There are no conflicts of 
interest for all authors


9. Clin Cancer Res. 2016 Aug 15;22(16):4057-66. doi: 10.1158/1078-0432.CCR-15-2879. 
Epub 2016 Mar 18.

Immune and Stromal Classification of Colorectal Cancer Is Associated with 
Molecular Subtypes and Relevant for Precision Immunotherapy.

Becht E(1), de Reyniès A(2), Giraldo NA(1), Pilati C(3), Buttard B(1), Lacroix 
L(1), Selves J(4), Sautès-Fridman C(1), Laurent-Puig P(3), Fridman WH(5).

Author information:
(1)INSERM UMR_S 1138, Cancer, Immune Control and Escape, Cordeliers Research 
Centre, Paris, France. Université Paris Descartes, Paris, France. Université 
Pierre et Marie Curie, Paris, France.
(2)Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, 
Paris, France.
(3)Université Paris Descartes, Paris, France. INSERM, UMR_S1147, Paris, France.
(4)Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche, 
1037 INSERM - Université Toulouse III, Toulouse, France. Department of 
Pathology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
(5)INSERM UMR_S 1138, Cancer, Immune Control and Escape, Cordeliers Research 
Centre, Paris, France. Université Paris Descartes, Paris, France. Université 
Pierre et Marie Curie, Paris, France. herve.fridman@crc.jussieu.fr.

PURPOSE: The tumor microenvironment is formed by many distinct and interacting 
cell populations, and its composition may predict patients' prognosis and 
response to therapies. Colorectal cancer is a heterogeneous disease in which 
immune classifications and four consensus molecular subgroups (CMS) have been 
described. Our aim was to integrate the composition of the tumor 
microenvironment with the consensus molecular classification of colorectal 
cancer.
EXPERIMENTAL DESIGN: We retrospectively analyzed the composition and the 
functional orientation of the immune, fibroblastic, and angiogenic 
microenvironment of 1,388 colorectal cancer tumors from three independent 
cohorts using transcriptomics. We validated our findings using 
immunohistochemistry.
RESULTS: We report that colorectal cancer molecular subgroups and 
microenvironmental signatures are highly correlated. Out of the four molecular 
subgroups, two highly express immune-specific genes. The good-prognosis 
microsatellite instable-enriched subgroup (CMS1) is characterized by 
overexpression of genes specific to cytotoxic lymphocytes. In contrast, the 
poor-prognosis mesenchymal subgroup (CMS4) expresses markers of lymphocytes and 
of cells of monocytic origin. The mesenchymal subgroup also displays an 
angiogenic, inflammatory, and immunosuppressive signature, a coordinated pattern 
that we also found in breast (n = 254), ovarian (n = 97), lung (n = 80), and 
kidney (n = 143) cancers. Pathologic examination revealed that the mesenchymal 
subtype is characterized by a high density of fibroblasts that likely produce 
the chemokines and cytokines that favor tumor-associated inflammation and 
support angiogenesis, resulting in a poor prognosis. In contrast, the canonical 
(CMS2) and metabolic (CMS3) subtypes with intermediate prognosis exhibit low 
immune and inflammatory signatures.
CONCLUSIONS: The distinct immune orientations of the colorectal cancer molecular 
subtypes pave the way for tailored immunotherapies. Clin Cancer Res; 22(16); 
4057-66. ©2016 AACR.

©2016 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-15-2879
PMID: 26994146 [Indexed for MEDLINE]


10. Eur J Cancer. 2019 Dec;123:118-129. doi: 10.1016/j.ejca.2019.09.008. Epub 2019 
Nov 1.

The correlation between immune subtypes and consensus molecular subtypes in 
colorectal cancer identifies novel tumour microenvironment profiles, with 
prognostic and therapeutic implications.

Soldevilla B(1), Carretero-Puche C(1), Gomez-Lopez G(2), Al-Shahrour F(2), 
Riesco MC(3), Gil-Calderon B(1), Alvarez-Vallina L(4), Espinosa-Olarte P(3), 
Gomez-Esteves G(1), Rubio-Cuesta B(1), Sarmentero J(1), La Salvia A(3), 
Garcia-Carbonero R(5).

Author information:
(1)Laboratorio de Oncología Clínico-Traslacional, Unidad de Investigación en 
Tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, 
28041, Madrid, Spain; Centro Nacional de Investigación Oncológica (CNIO), 28029, 
Madrid, Spain.
(2)Bioinformatics Unit, Centro Nacional de Investigación Oncológica (CNIO), 
28029, Madrid, Spain.
(3)Laboratorio de Oncología Clínico-Traslacional, Unidad de Investigación en 
Tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, 
28041, Madrid, Spain; Oncology Department, Hospital Universitario Doce de 
Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 
UCM, CNIO, CIBERONC, Madrid, Spain.
(4)Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital 
Universitario 12 de Octubre, 28041, Madrid, Spain; Immuno-Oncology and 
Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (i+12), 
28041, Madrid, Spain; Immunotherapy and Cell Engineering Laboratory, Department 
of Engineering, Aarhus University, 8000, C Aarhus, Denmark.
(5)Laboratorio de Oncología Clínico-Traslacional, Unidad de Investigación en 
Tumores Digestivos, Instituto de Investigación I+12, Hospital 12 de Octubre, 
28041, Madrid, Spain; Oncology Department, Hospital Universitario Doce de 
Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 
UCM, CNIO, CIBERONC, Madrid, Spain; Complutense University of Madrid, Madrid, 
Spain. Electronic address: rgcarbonero@gmail.com.

BACKGROUND: Solid tumour growth is the consequence of a complex interplay 
between cancer cells and their microenvironment. Recently, a new global 
transcriptomic immune classification of solid tumours has identified six immune 
subtypes (ISs) (C1-C6). Our aim was to specifically characterise ISs in 
colorectal cancer (CRC) and assess their interplay with the consensus molecular 
subtypes (CMSs).
METHODS: Clinical and molecular information, including CMSs and ISs, were 
obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, 
differential gene expression and gene set enrichment analysis were performed to 
characterise ISs in the global CRC population by using CMSs.
RESULTS: Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) 
and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), 
whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest 
representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), 
whereas all C6 TGF-β dominant cases belonged to CMS4 (2.3%). Prognostic 
relevance of ISs in CRC substantially differed from that reported for the global 
TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients 
than CMS classification. C2 had higher densities of CD8, CD4 activated, 
follicular helper T cells, regulatory T cells and neutrophils and the highest 
M1/M2 polarisation. C2 had a heightened activation of pathways related to the 
immune system, apoptosis and DNA repair, mTOR signalling and oxidative 
phosphorylation, whereas C1 was more dependent of metabolic pathways.
CONCLUSIONS: The correlation of IS and CMS allows a more precise categorisation 
of patients with relevant clinical and biological implications, which may be 
valuable tools to improve tailored therapeutic interventions in CRC patients.

Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/j.ejca.2019.09.008
PMID: 31678770 [Indexed for MEDLINE]


11. Clin Cancer Res. 2018 Mar 1;24(5):1062-1072. doi: 10.1158/1078-0432.CCR-17-2484. 
Epub 2017 Nov 27.

Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights 
a Continuum in Mutation Profiles and Consensus Molecular Subtypes.

Loree JM(1), Pereira AAL(1), Lam M(1), Willauer AN(1), Raghav K(1), Dasari A(1), 
Morris VK(1), Advani S(1), Menter DG(1), Eng C(1), Shaw K(2), Broaddus R(3), 
Routbort MJ(4), Liu Y(5), Morris JS(5), Luthra R(4), Meric-Bernstam F(6), 
Overman MJ(1), Maru D(3), Kopetz S(7).

Author information:
(1)Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer 
Center, Houston, Texas.
(2)Sheikh Khalifa Bin Zayed Al Nahyan Institute of Personalized Cancer Therapy, 
The University of Texas MD Anderson Cancer Center, Houston, Texas.
(3)Department of Pathology, The University of Texas MD Anderson Cancer Center, 
Houston, Texas.
(4)Department of Hematopathology, The University of Texas MD Anderson Cancer 
Center, Houston, Texas.
(5)Department of Biostatistics, The University of Texas MD Anderson Cancer 
Center, Houston, Texas.
(6)Investigational Cancer Therapeutics, The University of Texas MD Anderson 
Cancer Center, Houston, Texas.
(7)Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer 
Center, Houston, Texas. skopetz@mdanderson.org.

Comment in
    Clin Cancer Res. 2018 Mar 1;24(5):989-990.

Purpose: Colorectal cancers are classified as right/left-sided based on whether 
they occur before/after the splenic flexure, with established differences in 
molecular subtypes and outcomes. However, it is unclear if this division is 
optimal and whether precise tumor location provides further 
information.Experimental Design: In 1,876 patients with colorectal cancer, we 
compared mutation prevalence and overall survival (OS) according to side and 
location. Consensus molecular subtype (CMS) was compared in a separate cohort of 
608 patients.Results: Mutation prevalence differed by side and location for 
TP53, KRAS, BRAFV600, PIK3CA, SMAD4, CTNNB1, GNAS, and PTEN Within left- and 
right-sided tumors, there remained substantial variations in mutation rates. For 
example, within right-sided tumors, RAS mutations decreased from 70% for cecal, 
to 43% for hepatic flexure location (P = 0.0001), while BRAFV600 mutations 
increased from 10% to 22% between the same locations (P < 0.0001). Within 
left-sided tumors, the sigmoid and rectal region had more TP53 mutations (P = 
0.027), less PIK3CA (P = 0.0009), BRAF (P = 0.0033), or CTNNB1 mutations (P < 
0.0001), and less MSI (P < 0.0001) than other left-sided locations. Despite 
this, a left/right division preceding the transverse colon maximized prognostic 
differences by side and transverse colon tumors had K-modes mutation clustering 
that appeared more left than right sided. CMS profiles showed a decline in CMS1 
and CMS3 and rise in CMS2 prevalence moving distally.Conclusions: Current 
right/left classifications may not fully recapitulate regional variations in 
tumor biology. Specifically, the sigmoid-rectal region appears unique and the 
transverse colon is distinct from other right-sided locations. Clin Cancer Res; 
24(5); 1062-72. ©2017 AACRSee related commentary by Dienstmann, p. 989.

©2017 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-17-2484
PMCID: PMC5844818
PMID: 29180604 [Indexed for MEDLINE]

Conflict of interest statement: Disclosures: All authors report no conflicts of 
interest to declare.


12. Curr Gastroenterol Rep. 2019 Jan 30;21(2):5. doi: 10.1007/s11894-019-0674-9.

Back to the Colorectal Cancer Consensus Molecular Subtype Future.

Menter DG(1), Davis JS(2), Broom BM(3), Overman MJ(4), Morris J(2), Kopetz S(4).

Author information:
(1)Department of Gastrointestinal Medical Oncology, The University of Texas MD 
Anderson Cancer Center, 1515 Holcombe Boulevard--Unit 0426, Houston, TX, 77030, 
USA. dmenter@mdanderson.org.
(2)Department of Biostatistics, The University of Texas MD Anderson Cancer 
Center, Houston, TX, 77030, USA.
(3)Department of Bioinformatics and Computational Biology, The University of 
Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
(4)Department of Gastrointestinal Medical Oncology, The University of Texas MD 
Anderson Cancer Center, 1515 Holcombe Boulevard--Unit 0426, Houston, TX, 77030, 
USA.

PURPOSE OF REVIEW: This review seeks to provide an informed prospective on the 
advances in molecular profiling and analysis of colorectal cancer (CRC). The 
goal is to provide a historical context and current summary on how advances in 
gene and protein sequencing technology along with computer capabilities led to 
our current bioinformatic advances in the field.
RECENT FINDINGS: An explosion of knowledge has occurred regarding genetic, 
epigenetic, and biochemical alterations associated with the evolution of 
colorectal cancer. This has led to the realization that CRC is a heterogeneous 
disease with molecular alterations often dictating natural history, response to 
treatment, and outcome. The consensus molecular subtypes (CMS) classification 
classifies CRC into four molecular subtypes with distinct biological 
characteristics, which may form the basis for clinical stratification and 
subtype-based targeted intervention. This review summarizes new developments of 
a field moving "Back to the Future." CRC molecular subtyping will better 
identify key subtype specific therapeutic targets and responses to therapy.

DOI: 10.1007/s11894-019-0674-9
PMCID: PMC6622456
PMID: 30701321 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of Interest The authors declare that 
they have no conflict of interest.


13. Sci Transl Med. 2014 Feb 19;6(224):224ra24. doi: 10.1126/scitranslmed.3007094.

Detection of circulating tumor DNA in early- and late-stage human malignancies.

Bettegowda C(1), Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, 
Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron 
JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty 
MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, 
Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson 
L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih lM, Oba-Shinjo SM, Siena S, 
Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, 
Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, 
Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr.

Author information:
(1)Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical 
Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 
Baltimore, MD 21231, USA.

Comment in
    Nat Biotechnol. 2014 May;32(5):441-3.

The development of noninvasive methods to detect and monitor tumors continues to 
be a major challenge in oncology. We used digital polymerase chain 
reaction-based technologies to evaluate the ability of circulating tumor DNA 
(ctDNA) to detect tumors in 640 patients with various cancer types. We found 
that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, 
colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and 
head and neck cancers, but in less than 50% of primary brain, renal, prostate, 
or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 
57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, 
pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often 
present in patients without detectable circulating tumor cells, suggesting that 
these two biomarkers are distinct entities. In a separate panel of 206 patients 
with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for 
detection of clinically relevant KRAS gene mutations was 87.2% and its 
specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues 
into the mechanisms underlying resistance to epidermal growth factor receptor 
blockade in 24 patients who objectively responded to therapy but subsequently 
relapsed. Twenty-three (96%) of these patients developed one or more mutations 
in genes involved in the mitogen-activated protein kinase pathway. Together, 
these data suggest that ctDNA is a broadly applicable, sensitive, and specific 
biomarker that can be used for a variety of clinical and research purposes in 
patients with multiple different types of cancer.

DOI: 10.1126/scitranslmed.3007094
PMCID: PMC4017867
PMID: 24553385 [Indexed for MEDLINE]

Conflict of interest statement: Competing interests: K.W.K. and B.V. are 
consultants for Inostics. L.A.D. is a consultant for Amgen and Anaeropharma. 
L.A.D. and V.E.V. are co-founders and on the board of directors of Personal 
Genome Diagnostics. K.W.K., B.V., L.A.D., N.P., and V.E.V. all own Personal 
Genome Diagnostics stock, which is subject to certain restrictions under 
University policy. L.D.W. works as a paid consultant for Personal Genome 
Diagnostics. Johns Hopkins University has several patents related to the work 
presented in this paper. The terms of all these arrangements are managed by the 
Johns Hopkins University in accordance with its conflict-of-interest policies. 
A.B. is a shareholder and advisory board member of Horizon Discovery, and an 
advisory board member or Biocartis. L.A.F. is an advisory board member of 
Genentech-Roche. C.M.S. is a scientific advisor to Asuragen Inc. and a 
consultant to Redpath Inc.


14. Clin Cancer Res. 2018 Feb 15;24(4):794-806. doi: 10.1158/1078-0432.CCR-17-1234. 
Epub 2017 Dec 14.

Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models 
Uncover Potentially Targetable Cancer Cell Dependencies.

Sveen A(1)(2), Bruun J(1)(2)(3), Eide PW(1)(2), Eilertsen IA(1)(2), Ramirez 
L(4), Murumägi A(3), Arjama M(3), Danielsen SA(1)(2), Kryeziu K(1)(2), Elez 
E(4), Tabernero J(4), Guinney J(5), Palmer HG(4), Nesbakken A(2)(6)(7), 
Kallioniemi O(3), Dienstmann R(4)(5), Lothe RA(8)(2)(7).

Author information:
(1)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, Oslo, Norway.
(2)K.G.Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, 
Norway.
(3)Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 
Helsinki, Finland.
(4)Vall d'Hebron University Hospital and Institute of Oncology (VHIO), 
Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain.
(5)SAGE Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, 
Washington.
(6)Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, 
Norway.
(7)Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
(8)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, Oslo, Norway. rlothe@rr-research.no.

Purpose: Response to standard oncologic treatment is limited in colorectal 
cancer. The gene expression-based consensus molecular subtypes (CMS) provide a 
new paradigm for stratified treatment and drug repurposing; however, drug 
discovery is currently limited by the lack of translation of CMS to preclinical 
models.Experimental Design: We analyzed CMS in primary colorectal cancers, cell 
lines, and patient-derived xenografts (PDX). For classification of preclinical 
models, we developed an optimized classifier enriched for cancer cell-intrinsic 
gene expression signals, and performed high-throughput in vitro drug screening 
(n = 459 drugs) to analyze subtype-specific drug sensitivities.Results: The 
distinct molecular and clinicopathologic characteristics of each CMS group were 
validated in a single-hospital series of 409 primary colorectal cancers. The 
new, cancer cell-adapted classifier was found to perform well in primary tumors, 
and applied to a panel of 148 cell lines and 32 PDXs, these colorectal cancer 
models were shown to recapitulate the biology of the CMS groups. Drug screening 
of 33 cell lines demonstrated subtype-dependent response profiles, confirming 
strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical 
group, and revealing strong sensitivity to HSP90 inhibitors in cells with the 
CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This 
association was validated in vitro in additional CMS-predicted cell lines. 
Combination treatment with 5-fluorouracil and luminespib showed potential to 
alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a 
chemosensitive CMS2 PDX model.Conclusions: We provide translation of CMS 
classification to preclinical models and uncover a potential for targeted 
treatment repurposing in the chemoresistant CMS4 group. Clin Cancer Res; 24(4); 
794-806. ©2017 AACR.

©2017 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-17-1234
PMID: 29242316 [Indexed for MEDLINE]


15. Gut. 2021 Mar;70(3):544-554. doi: 10.1136/gutjnl-2019-319866. Epub 2020 Jul 20.

Image-based consensus molecular subtype (imCMS) classification of colorectal 
cancer using deep learning.

Sirinukunwattana K(1)(2)(3), Domingo E(4), Richman SD(5), Redmond KL(6), Blake 
A(7), Verrill C(3)(8)(9), Leedham SJ(10)(11), Chatzipli A(12), Hardy C(12), 
Whalley CM(13), Wu CH(14), Beggs AD(15), McDermott U(12), Dunne PD(16), Meade 
A(17), Walker SM(18), Murray GI(19), Samuel L(20), Seymour M(21), Tomlinson 
I(13)(22), Quirke P(5), Maughan T(23), Rittscher J(#)(24)(2)(3)(25), Koelzer 
VH(#)(4)(26)(27); S:CORT consortium.

Author information:
(1)Institute of Biomedical Engineering (IBME), Department of Engineering 
Science, University of Oxford, Oxford, UK.
(2)Big Data Institute, University of Oxford, Li Ka Shing Centre for Health 
Information and Discovery, Oxford, UK.
(3)Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, 
Oxford, UK.
(4)Department of Oncology, University of Oxford, Oxford, UK 
viktor.koelzer@usz.ch jens.rittscher@eng.ox.ac.uk 
enric.domingo@oncology.ox.ac.uk.
(5)Department of Pathology and Tumour Biology, Leeds Institute of Cancer and 
Pathology, Leeds, UK.
(6)Centre for Cancer Research and Cell Biology, Faculty of Medicine, Health and 
Life Sciences, Queen's University Belfast, Belfast, UK.
(7)Department of Oncology, University of Oxford, Oxford, UK.
(8)Department of Cellular Pathology, Oxford University Hospitals NHS Foundation 
Trust, Oxford, UK.
(9)Nuffield Department of Surgical Sciences and NIHR Oxford Biomedical Research 
Centre, University of Oxford, Oxford, UK.
(10)Gastrointestinal Stem-cell Biology Laboratory, Oxford Centre for Cancer Gene 
Research, Wellcome Trust Centre for Human Genetics, Oxford, UK.
(11)Translational Gastroenterology Unit, Experimental Medicine Division, 
Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of 
Oxford, Oxford, UK.
(12)Wellcome Trust Sanger Institute, Hinxton, UK.
(13)Institute of Cancer and Genomic Sciences, University of Birmingham, 
Birmingham, UK.
(14)Department of Statistics, University of Oxford, Oxford, UK.
(15)School of Cancer Sciences, University of Birmingham, Birmingham, UK.
(16)Centre for Cancer Research and Cell Biology, Queen's University Belfast, 
Belfast, UK.
(17)MRC Clinical Trials Unit at University College London, London, UK.
(18)Almac Diagnostics Ltd, Craigavon, UK.
(19)Department of Pathology, School of Medicine, Medical Sciences and Nutrition, 
University of Aberdeen, Aberdeen, UK.
(20)Department of Clinical Oncology, Aberdeen Royal Infirmary, Aberdeen, UK.
(21)Department of Oncology, Leeds Institute of Cancer and Pathology, Leeds, UK.
(22)Edinburgh Cancer Centre, MRC Institute of Genetics and Molecular Medicine, 
University of Edinburgh, Edinburgh, UK.
(23)CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, 
Oxford, UK.
(24)Institute of Biomedical Engineering (IBME), Department of Engineering 
Science, University of Oxford, Oxford, UK viktor.koelzer@usz.ch 
jens.rittscher@eng.ox.ac.uk enric.domingo@oncology.ox.ac.uk.
(25)Ludwig Institute for Cancer Research, Nuffield Department of Clinical 
Medicine, University of Oxford, Oxford, UK.
(26)Nuffield Department of Medicine, University of Oxford, Oxford, UK.
(27)Department of Pathology and Molecular Pathology, University of Zurich, 
Zurich, Switzerland.
(#)Contributed equally

OBJECTIVE: Complex phenotypes captured on histological slides represent the 
biological processes at play in individual cancers, but the link to underlying 
molecular classification has not been clarified or systematised. In colorectal 
cancer (CRC), histological grading is a poor predictor of disease progression, 
and consensus molecular subtypes (CMSs) cannot be distinguished without gene 
expression profiling. We hypothesise that image analysis is a cost-effective 
tool to associate complex features of tissue organisation with molecular and 
outcome data and to resolve unclassifiable or heterogeneous cases. In this 
study, we present an image-based approach to predict CRC CMS from standard H&E 
sections using deep learning.
DESIGN: Training and evaluation of a neural network were performed using a total 
of n=1206 tissue sections with comprehensive multi-omic data from three 
independent datasets (training on FOCUS trial, n=278 patients; test on rectal 
cancer biopsies, GRAMPIAN cohort, n=144 patients; and The Cancer Genome Atlas 
(TCGA), n=430 patients). Ground truth CMS calls were ascertained by matching 
random forest and single sample predictions from CMS classifier.
RESULTS: Image-based CMS (imCMS) accurately classified slides in unseen datasets 
from TCGA (n=431 slides, AUC)=0.84) and rectal cancer biopsies (n=265 slides, 
AUC=0.85). imCMS spatially resolved intratumoural heterogeneity and provided 
secondary calls correlating with bioinformatic prediction from molecular data. 
imCMS classified samples previously unclassifiable by RNA expression profiling, 
reproduced the expected correlations with genomic and epigenetic alterations and 
showed similar prognostic associations as transcriptomic CMS.
CONCLUSION: This study shows that a prediction of RNA expression classifiers can 
be made from H&E images, opening the door to simple, cheap and reliable 
biological stratification within routine workflows.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published 
by BMJ.

DOI: 10.1136/gutjnl-2019-319866
PMCID: PMC7873419
PMID: 32690604 [Indexed for MEDLINE]

Conflict of interest statement: Competing interests: KS and JR are co-founders 
of University of Oxford spinout Ground Truth Labs


16. Cancer Res. 2020 Nov 1;80(21):4668-4680. doi: 10.1158/0008-5472.CAN-19-4028. 
Epub 2020 Aug 19.

ERK1/2 Signaling Induces Upregulation of ANGPT2 and CXCR4 to Mediate Liver 
Metastasis in Colon Cancer.

Urosevic J(#)(1)(2), Blasco MT(#)(1)(2), Llorente A(#)(1), Bellmunt A(#)(1), 
Berenguer-Llergo A(3), Guiu M(1), Cañellas A(1)(2), Fernandez E(1), Burkov I(1), 
Clapés M(1), Cartanà M(1), Figueras-Puig C(1), Batlle E(1)(2)(4), Nebreda 
AR(1)(4), Gomis RR(5)(2)(4)(6).

Author information:
(1)Cancer Science Program, Institute for Research in Biomedicine (IRB 
Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
(2)CIBERONC, Spain.
(3)Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine 
(IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 
Spain.
(4)ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
(5)Cancer Science Program, Institute for Research in Biomedicine (IRB 
Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. 
roger.gomis@irbbarcelona.org.
(6)School of Medicine, Universitat de Barcelona, Barcelona, Spain.
(#)Contributed equally

Carcinoma development in colorectal cancer is driven by genetic alterations in 
numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are 
associated with the shortest overall survival for patients after diagnosis of 
colorectal cancer metastatic disease, yet how RAS-ERK signaling regulates 
colorectal cancer metastasis remains unknown. In this study, we used an unbiased 
screening approach based on selection of highly liver metastatic colorectal 
cancer cells in vivo to determine genes associated with metastasis. From this, 
an ERK1/2-controlled metastatic gene set (EMGS) was defined. EMGS was associated 
with increased recurrence and reduced survival in patients with colorectal 
cancer tumors. Higher levels of EMGS expression were detected in the colorectal 
cancer subsets consensus molecular subtype (CMS)1 and CMS4. ANGPT2 and CXCR4, 
two genes within the EMGS, were subjected to gain-of-function and 
loss-of-function studies in several colorectal cancer cell lines and then tested 
in clinical samples. The RAS-ERK1/2 axis controlled expression of the cytokine 
ANGPT2 and the cytokine receptor CXCR4 in colorectal cancer cells, which 
facilitated development of liver but not lung metastases, suggesting that ANGPT2 
and CXCR4 are important for metastatic outgrowth in the liver. CXCR4 controlled 
the expression of cytokines IL10 and CXCL1, providing evidence for a causal role 
of IL10 in supporting liver colonization. In summary, these studies demonstrate 
that amplification of ERK1/2 signaling in KRAS-mutated colorectal cancer cells 
affects the cytokine milieu of the tumors, possibly affecting tumor-stroma 
interactions and favoring liver metastasis formation. SIGNIFICANCE: These 
findings identify amplified ERK1/2 signaling in KRAS-mutated colorectal cancer 
cells as a driver of tumor-stroma interactions that favor formation of 
metastases in the liver.

©2020 American Association for Cancer Research.

DOI: 10.1158/0008-5472.CAN-19-4028
PMID: 32816905 [Indexed for MEDLINE]


17. Curr Colorectal Cancer Rep. 2018 Dec;14(6):217-225. doi: 
10.1007/s11888-018-0416-7. Epub 2018 Oct 11.

Microbiome and Colorectal Cancer.

Ahmed I(1), Umar S(1).

Author information:
(1)Department of Surgery and University of Kansas Cancer Center, University of 
Kansas Medical Center, Kansas City KS, USA.

PURPOSE OF REVIEW: The trillions of microbes collectively referred to as the 
human microbiota, inhabit the human body and establish a beneficial relationship 
with the host. It is clear however that dysbiosis impacting microbial diversity 
in the gut, may lead to development of inflammatory and malignant 
gastrointestinal diseases including colorectal cancer (CRC). We provide a 
literature review of the recent influx of information related to the alterations 
in gut microbiota composition that influences CRC incidence and progression.
RECENT FINDINGS: A growing body of evidence implicates altered gut microbiota in 
the development of CRC. Profiles of CRC associated microbiota have been shown to 
differ from those in healthy subjects and bacterial phylotypes vary depending on 
the primary tumor location. The compositional variation in the microbial profile 
is not restricted to cancerous tissue however and is different between cancers 
of the proximal and distal colons, respectively. More recently, studies have 
shed light on the "driver-passenger" model for CRC wherein, driver bacteria 
cause inflammation, increased cell proliferation and production of genotoxic 
substances to contribute towards mutational acquisition associated with 
adenoma-carcinoma sequence. These changes facilitate gradual replacement of 
driver bacteria by passengers that either promote or suppress tumor progression. 
Significant advances have also been made in associating individual bacterial 
species to consensus molecular subtypes (CMS) of CRC and this remarkable 
development is expected to galvanize scientific community into advancing 
therapeutic strategies for CRC.
SUMMARY: Increasing evidence suggests a link between the intestinal microbiota 
and CRC development although the mechanisms through which the bacterial 
constituents of the microbiome contribute towards CRC are complex and yet to be 
fully fathomed. Thus, more exhaustive and mechanistic studies are needed to 
identify key interactions amongst diet, microbial community and metabolites that 
help facilitate the adenoma-carcinoma sequence evolution in CRC. It is expected 
that development of therapeutics based on microbial association with CMS will 
likely facilitate the translation of molecular subtypes into the clinic for CRCs 
and potentially other malignancies.

DOI: 10.1007/s11888-018-0416-7
PMCID: PMC7808211
PMID: 33456404

Conflict of interest statement: Conflict of Interest Ishfaq Ahmed and Shahid 
Umar declare they have no conflict of interest.


18. Ann Oncol. 2018 May 1;29(5):1227-1234. doi: 10.1093/annonc/mdy085.

CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary 
colorectal cancer.

Smeby J(1), Sveen A(2), Merok MA(3), Danielsen SA(2), Eilertsen IA(2), Guren 
MG(4), Dienstmann R(5), Nesbakken A(6), Lothe RA(7).

Author information:
(1)Department of Molecular Oncology, Institute for Cancer Research; Division of 
Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre; Department of 
Oncology, Oslo University Hospital, Oslo; Institute of Clinical Medicine, 
Faculty of Medicine, University of Oslo, Oslo.
(2)Department of Molecular Oncology, Institute for Cancer Research; Division of 
Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre.
(3)Department of Molecular Oncology, Institute for Cancer Research; Department 
of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway.
(4)Division of Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre; 
Department of Oncology, Oslo University Hospital, Oslo.
(5)Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona; 
Vall d'Hebron University Hospital, Barcelona; Universitat Autonoma de Barcelona, 
Barcelona, Spain; Computational Oncology, Sage Bionetworks, Seattle, USA.
(6)Division of Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre; 
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo; 
Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, 
Norway.
(7)Department of Molecular Oncology, Institute for Cancer Research; Division of 
Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre; Institute of 
Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo. Electronic 
address: ragnhild.a.lothe@rr-research.no.

BACKGROUND: The prognostic impact of KRAS and BRAFV600E mutations in primary 
colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The 
gene expression-based consensus molecular subtypes (CMSs) of CRC define 
molecularly and clinically distinct subgroups, and represent a novel 
stratification framework in biomarker analysis. We investigated the prognostic 
value of these mutations within the CMS groups.
PATIENTS AND METHODS: Totally 1197 primary tumors from a Norwegian series of CRC 
stage I-IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 
12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression 
and confident CMS classification was obtained for 317 samples. This cohort was 
expanded with clinical and molecular data, including CMS classification, from 
514 patients in the publically available dataset GSE39582. Gene expression 
signatures associated with KRAS and BRAFV600E mutations were used to evaluate 
differential impact of mutations on gene expression among the CMS groups.
RESULTS: BRAFV600E and KRAS mutations were both associated with inferior 5-year 
overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus 
KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P < 0.001; KRAS mutation versus 
KRAS/BRAF wild-type: HR 1.30, P = 0.013). BRAFV600E-mutated MSS tumors were 
strongly enriched and associated with metastatic disease in CMS1, leading to 
negative prognostic impact in this subtype (OS: BRAFV600E mutation versus 
wild-type: HR 7.73, P = 0.001). In contrast, the poor prognosis of KRAS 
mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene 
expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P = 0.011). 
The subtype-specific prognostic associations were substantiated by differential 
effects of BRAFV600E and KRAS mutations on gene expression signatures according 
to the MSI status and CMS group.
CONCLUSIONS: BRAFV600E mutations are enriched and associated with metastatic 
disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS 
mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS 
tumors.

DOI: 10.1093/annonc/mdy085
PMCID: PMC5961317
PMID: 29518181 [Indexed for MEDLINE]


19. Ann Intern Med. 2020 Nov 3;173(9):704-713. doi: 10.7326/M20-1868. Epub 2020 Sep 
1.

Deep Learning Using Chest Radiographs to Identify High-Risk Smokers for Lung 
Cancer Screening Computed Tomography: Development and Validation of a Prediction 
Model.

Lu MT(1), Raghu VK(1), Mayrhofer T(2), Aerts HJWL(3), Hoffmann U(1).

Author information:
(1)Massachusetts General Hospital Cardiovascular Imaging Research Center, 
Brigham and Women's Hospital Program for Artificial Intelligence in Medicine, 
and Harvard Medical School, Boston, Massachusetts (M.T.L., V.K.R., U.H.).
(2)Harvard Medical School, Boston, Massachusetts,and Stralsund University of 
Applied Sciences, Stralsund, Germany (T.M.).
(3)Brigham and Women's Hospital Program for Artificial Intelligence in Medicine, 
Massachusetts General Hospital Cardiovascular Imaging Research Center, and 
Harvard Medical School, Boston, Massachusetts (H.J.A.).

Comment in
    Ann Intern Med. 2020 Nov 3;173(9):760-761.
    AJR Am J Roentgenol. 2021 Aug;217(2):521.

BACKGROUND: Lung cancer screening with chest computed tomography (CT) reduces 
lung cancer death. Centers for Medicare & Medicaid Services (CMS) eligibility 
criteria for lung cancer screening with CT require detailed smoking information 
and miss many incident lung cancers. An automated deep-learning approach based 
on chest radiograph images may identify more smokers at high risk for lung 
cancer who could benefit from screening with CT.
OBJECTIVE: To develop and validate a convolutional neural network (CXR-LC) that 
predicts long-term incident lung cancer using data commonly available in the 
electronic medical record (EMR) (chest radiograph, age, sex, and whether 
currently smoking).
DESIGN: Risk prediction study.
SETTING: U.S. lung cancer screening trials.
PARTICIPANTS: The CXR-LC model was developed in the PLCO (Prostate, Lung, 
Colorectal, and Ovarian) Cancer Screening Trial (n = 41 856). The final CXR-LC 
model was validated in additional PLCO smokers (n = 5615, 12-year follow-up) and 
NLST (National Lung Screening Trial) heavy smokers (n = 5493, 6-year follow-up). 
Results are reported for validation data sets only.
MEASUREMENTS: Up to 12-year lung cancer incidence predicted by CXR-LC.
RESULTS: The CXR-LC model had better discrimination (area under the 
receiver-operating characteristic curve [AUC]) for incident lung cancer than CMS 
eligibility (PLCO AUC, 0.755 vs. 0.634; P < 0.001). The CXR-LC model's 
performance was similar to that of PLCOM2012, a state-of-the-art risk score with 
11 inputs, in both the PLCO data set (CXR-LC AUC of 0.755 vs. PLCOM2012 AUC of 
0.751) and the NLST data set (0.659 vs. 0.650). When compared in equal-sized 
screening populations, CXR-LC was more sensitive than CMS eligibility in the 
PLCO data set (74.9% vs. 63.8%; P = 0.012) and missed 30.7% fewer incident lung 
cancers. On decision curve analysis, CXR-LC had higher net benefit than CMS 
eligibility and similar benefit to PLCOM2012.
LIMITATION: Validation in lung cancer screening trials and not a clinical 
setting.
CONCLUSION: The CXR-LC model identified smokers at high risk for incident lung 
cancer, beyond CMS eligibility and using information commonly available in the 
EMR.
PRIMARY FUNDING SOURCE: None.

DOI: 10.7326/M20-1868
PMID: 32866413 [Indexed for MEDLINE]


20. J Clin Oncol. 2019 Aug 1;37(22):1876-1885. doi: 10.1200/JCO.18.02258. Epub 2019 
May 1.

Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic 
Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance).

Lenz HJ(1), Ou FS(2), Venook AP(3), Hochster HS(4), Niedzwiecki D(5), Goldberg 
RM(6), Mayer RJ(7), Bertagnolli MM(8), Blanke CD(9), Zemla T(2), Qu X(10), 
Wirapati P(11), Tejpar S(12), Innocenti F(13), Kabbarah O(10).

Author information:
(1)1University of Southern California Norris Comprehensive Cancer Center, Los 
Angeles, CA.
(2)Mayo Clinic Cancer Center, Rochester, MN.
(3)3University of California, San Francisco, San Francisco, CA.
(4)4Yale Cancer Center, New Haven, CT.
(5)5Duke University Medical Center, Durham, NC.
(6)6West Virginia University Cancer Institute, Morgantown, WV.
(7)7Dana-Farber Cancer Institute, Boston, MA.
(8)8Brigham and Women's Hospital, Boston, MA.
(9)9Oregon Health & Science University, Portland, OR.
(10)10Genentech, San Francisco, CA.
(11)11Swiss Institute of Bioinformatics, Lausanne, Switzerland.
(12)12Universitair Ziekenhuis Leuven, Leuven, Belgium.
(13)13The University of North Carolina at Chapel Hill, Chapel Hill, NC.

Erratum in
    J Clin Oncol. 2020 Feb 20;38(6):656.

Comment in
    J Clin Oncol. 2019 Aug 1;37(22):1847-1850.

PURPOSE: To determine the predictive and prognostic value of the consensus 
molecular subtypes (CMSs) of colorectal cancer (CRC) that represent a merging of 
gene expression-based features largely in primary tumors from six independent 
classification systems and provide a framework for capturing the intrinsic 
heterogeneity of CRC in patients enrolled in CALGB/SWOG 80405.
PATIENTS AND METHODS: CALGB/SWOG 80405 is a phase III trial that compared the 
addition of bevacizumab or cetuximab to infusional fluorouracil, leucovorin, and 
oxaliplatin or fluorouracil, leucovorin, and irinotecan as first-line treatment 
of advanced CRC. We characterized the CMS classification using a novel 
NanoString gene expression panel on primary CRCs from 581 patients enrolled in 
this study to assess the prognostic and predictive value of CMSs in these 
patients.
RESULTS: The CMSs are highly prognostic for overall survival (OS; P < .001) and 
progression-free survival (PFS; P < .001). Furthermore, CMSs were predictive for 
both OS (P for interaction < .001) and PFS (P for interaction = .0032). In the 
CMS1 cohort, patients treated with bevacizumab had a significantly longer OS 
than those treated with cetuximab (P < .001). In the CMS2 cohort, patients 
treated with cetuximab had a significantly longer OS than patients treated with 
bevacizumab (P = .0046).
CONCLUSION: These findings highlight the possible clinical utility of CMSs and 
suggests that refinement of the CMS classification may provide a path toward 
identifying patients with metastatic CRC who are most likely to benefit from 
specific targeted therapy as part of the initial treatment.

DOI: 10.1200/JCO.18.02258
PMCID: PMC6675593
PMID: 31042420 [Indexed for MEDLINE]


21. Cancer Lett. 2020 Mar 31;473:186-197. doi: 10.1016/j.canlet.2019.09.009. Epub 
2019 Sep 24.

The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway 
gene expression in gastrointestinal cancer models.

Tam BY(1), Chiu K(2), Chung H(2), Bossard C(2), Nguyen JD(1), Creger E(2), 
Eastman BW(2), Mak CC(2), Ibanez M(2), Ghias A(2), Cahiwat J(2), Do L(2), Cho 
S(2), Nguyen J(2), Deshmukh V(2), Stewart J(2), Chen CW(2), Barroga C(2), 
Dellamary L(1), Kc SK(2), Phalen TJ(2), Hood J(1), Cha S(2), Yazici Y(3).

Author information:
(1)Formerly Samumed, LLC, CA, USA.
(2)Samumed, LLC, San Diego, CA, USA.
(3)Samumed, LLC, San Diego, CA, USA. Electronic address: yusuf@samumed.com.

The Wnt/β-catenin signaling pathway is aberrantly activated in colorectal (CRC) 
and many other cancers, and novel strategies for effectively targeting it may be 
needed due to its complexity. In this report, SM08502, a novel small molecule in 
clinical development for the treatment of solid tumors, was shown to reduce Wnt 
pathway signaling and gene expression through potent inhibition of CDC-like 
kinase (CLK) activity. SM08502 inhibited serine and arginine rich splicing 
factor (SRSF) phosphorylation and disrupted spliceosome activity, which was 
associated with inhibition of Wnt pathway-related gene and protein expression. 
Additionally, SM08502 induced the generation of splicing variants of Wnt pathway 
genes, suggesting that its mechanism for inhibition of gene expression includes 
effects on alternative splicing. Orally administered SM08502 significantly 
inhibited growth of gastrointestinal tumors and decreased SRSF phosphorylation 
and Wnt pathway gene expression in xenograft mouse models. These data implicate 
CLKs in the regulation of Wnt signaling and represent a novel strategy for 
inhibiting Wnt pathway gene expression in cancers. SM08502 is a first-in-class 
CLK inhibitor being investigated in a Phase 1 clinical trial for subjects with 
advanced solid tumors (NCT03355066).

Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.

DOI: 10.1016/j.canlet.2019.09.009
PMID: 31560935 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of competing interest Samumed LLC 
salary and equity: B.Y.T., K.C., H.C., C.B., E.C., M.I., A.G., J.C., L.D., 
S.Cho, J.N., V.D., J.S., C.W.C., C.Ba., L.D., B.W.E., C.C.M., S.K.K.C., J.H., 
T.J.P., S.Cha, Y.Y. Patent # WO2017189829 was filed related to results in this 
paper.


22. Int J Mol Sci. 2017 Oct 24;18(10):2229. doi: 10.3390/ijms18102229.

Immunogenomic Classification of Colorectal Cancer and Therapeutic Implications.

Roelands J(1)(2), Kuppen PJK(3), Vermeulen L(4), Maccalli C(5), Decock J(6), 
Wang E(7), Marincola FM(8), Bedognetti D(9), Hendrickx W(10).

Author information:
(1)Tumor Biology, Immunology, and Therapy Section, Immunology, Inflammation, and 
Metabolism Department, Division of Translational Medicine, Sidra Medical and 
Research Center, PO Box 26999 Doha, Qatar. jroelands@sidra.org.
(2)Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The 
Netherlands. jroelands@sidra.org.
(3)Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The 
Netherlands. P.J.K.Kuppen@lumc.nl.
(4)Academic Medical Center Amsterdam, Center for Experimental Molecular 
Medicine, 1105AZ Amsterdam, The Netherlands. l.vermeulen@amc.uva.nl.
(5)Tumor Biology, Immunology, and Therapy Section, Immunology, Inflammation, and 
Metabolism Department, Division of Translational Medicine, Sidra Medical and 
Research Center, PO Box 26999 Doha, Qatar. cmaccalli@sidra.org.
(6)Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar 
Foundation, PO Box 5825 Doha, Qatar. jdecock@hbku.edu.qa.
(7)Office of the Chief Research Officer (CRO), Sidra Medical and Research 
Center, PO Box 26999 Doha, Qatar. ewang@sidra.org.
(8)Office of the Chief Research Officer (CRO), Sidra Medical and Research 
Center, PO Box 26999 Doha, Qatar. francesco.marincola@abbvie.com.
(9)Tumor Biology, Immunology, and Therapy Section, Immunology, Inflammation, and 
Metabolism Department, Division of Translational Medicine, Sidra Medical and 
Research Center, PO Box 26999 Doha, Qatar. dbedognetti@sidra.org.
(10)Tumor Biology, Immunology, and Therapy Section, Immunology, Inflammation, 
and Metabolism Department, Division of Translational Medicine, Sidra Medical and 
Research Center, PO Box 26999 Doha, Qatar. whendrickx@sidra.org.

The immune system has a substantial effect on colorectal cancer (CRC) 
progression. Additionally, the response to immunotherapeutics and conventional 
treatment options (e.g., chemotherapy, radiotherapy and targeted therapies) is 
influenced by the immune system. The molecular characterization of colorectal 
cancer (CRC) has led to the identification of favorable and unfavorable 
immunological attributes linked to clinical outcome. With the definition of 
consensus molecular subtypes (CMSs) based on transcriptomic profiles, multiple 
characteristics have been proposed to be responsible for the development of the 
tumor immune microenvironment and corresponding mechanisms of immune escape. In 
this review, a detailed description of proposed immune phenotypes as well as 
their interaction with different therapeutic modalities will be provided. 
Finally, possible strategies to shift the CRC immune phenotype towards a 
reactive, anti-tumor orientation are proposed per CMS.

DOI: 10.3390/ijms18102229
PMCID: PMC5666908
PMID: 29064420 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflict of interest.


23. J Exp Med. 2020 Oct 5;217(10):e20201017. doi: 10.1084/jem.20201017.

A third Notch in colorectal cancer progression and metastasis.

Koch U(1), Radtke F(1).

Author information:
(1)Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss 
Institute for Experimental Cancer Research, Lausanne, Switzerland.

Comment on
    J Exp Med. 2020 Oct 5;217(10):

In this issue of JEM, Varga et al. (https://doi.org/10.1084/jem.20191515) 
describe a mouse model of invasive and metastatic colorectal cancer (CRC) 
closely resembling the human consensus molecular subtype (CMS) 4 associated with 
the poorest overall survival of the four CMSs. Transcriptomic and bioinformatic 
analysis combined with pharmacological and genetic studies identified Notch3 as 
a promoter of tumor progression and metastasis. NOTCH3 expression was 
up-regulated in CMS4 CRC patients and associated with tumor staging, lymph node 
and distant metastasis. These findings feature NOTCH3 as putative therapeutic 
target for advanced CMS4 CRC patients.

© 2020 Koch and Radtke.

DOI: 10.1084/jem.20201017
PMCID: PMC7537388
PMID: 32852523 [Indexed for MEDLINE]


24. Trends Cancer. 2016 Sep;2(9):505-518. doi: 10.1016/j.trecan.2016.07.008. Epub 
2016 Sep 3.

Colorectal Cancer Subtypes: Developmental Origin and Microenvironmental 
Regulation.

Fessler E(1), Medema JP(2).

Author information:
(1)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental and Molecular Medicine (CEMM), Academic Medical Center (AMC), 
Amsterdam 1105 AZ, The Netherlands; Cancer Center Amsterdam (CCA), Amsterdam, 
The Netherlands; Cancer Genomics Center, Utrecht, The Netherlands.
(2)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental and Molecular Medicine (CEMM), Academic Medical Center (AMC), 
Amsterdam 1105 AZ, The Netherlands; Cancer Center Amsterdam (CCA), Amsterdam, 
The Netherlands; Cancer Genomics Center, Utrecht, The Netherlands. Electronic 
address: j.p.medema@amc.nl.

Cancer is a heterogeneous disease and many cancer types do not represent a 
single entity, but are composed of biologically and clinically diverse subtypes. 
The subtype affiliation can influence prognosis and response to therapy. 
Recently, a multicenter colorectal cancer (CRC) subtyping consortium introduced 
a consensus molecular classification system for CRC. This will be of great 
benefit for future basic and clinical research since it enables uniform 
categorization of CRC specimens across different institutes and studies. The 
biological conformity observed within each consensus molecular subtype (CMS) 
holds promise for the design of subtype-specific treatment regimens. Herein, we 
review the CMSs of CRC with a focus on how multiple parameters, such as the 
origin, developmental route, and microenvironmental regulation shape distinct 
subtypes.

Copyright © 2016 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.trecan.2016.07.008
PMID: 28741479 [Indexed for MEDLINE]


25. Br J Surg. 2018 Jan;105(2):e204-e211. doi: 10.1002/bjs.10788.

Histopathological and molecular classification of colorectal cancer and 
corresponding peritoneal metastases.

Ubink I(1), van Eden WJ(2), Snaebjornsson P(3), Kok NFM(2), van Kuik J(4), van 
Grevenstein WMU(1), Laclé MM(4), Sanders J(3), Fijneman RJA(3), Elias SG(5), 
Borel Rinkes IHM(1), Aalbers AGJ(2), Kranenburg O(1)(6).

Author information:
(1)Department of Surgical Oncology, Cancer Centre, University Medical Centre 
Utrecht, Utrecht, The Netherlands.
(2)Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, 
The Netherlands.
(3)Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The 
Netherlands.
(4)Department of Pathology, University Medical Centre Utrecht, Utrecht, The 
Netherlands.
(5)Julius Centre for Health Sciences and Primary Care, University Medical Centre 
Utrecht, Utrecht, The Netherlands.
(6)Division of Biomedical Genetics, University Medical Centre Utrecht, Utrecht, 
The Netherlands.

BACKGROUND: Patients with colorectal peritoneal carcinomatosis have a very poor 
prognosis. The recently developed consensus molecular subtype (CMS) 
classification of primary colorectal cancer categorizes tumours into four robust 
subtypes, which could guide subtype-targeted therapy. CMS4, also known as the 
mesenchymal subtype, has the greatest propensity to form distant metastases. 
CMS4 status and histopathological features of colorectal peritoneal 
carcinomatosis were investigated in this study.
METHODS: Fresh-frozen tissue samples from primary colorectal cancer and paired 
peritoneal metastases from patients who underwent cytoreductive surgery combined 
with hyperthermic intraperitoneal chemotherapy were collected. Histopathological 
features were analysed, and a reverse transcriptase-quantitative PCR test was 
used to assess CMS4 status of all collected lesions.
RESULTS: Colorectal peritoneal carcinomatosis was associated with adverse 
histopathological characteristics, including a high percentage of stroma in both 
primary tumours and metastases, and poor differentiation grade and high-grade 
tumour budding in primary tumours. Furthermore, CMS4 was significantly enriched 
in primary tumours with peritoneal metastases, compared with unselected stage 
I-IV tumours (60 per cent (12 of 20) versus 23 per cent; P = 0.002). The 
majority of peritoneal metastases (75 per cent, 21 of 28) were also classified 
as CMS4. Considerable intrapatient subtype heterogeneity was observed. Notably, 
15 of 16 patients with paired tumours had at least one CMS4-positive tumour 
location.
CONCLUSION: Significant enrichment for CMS4 was observed in colorectal 
peritoneal carcinomatosis. Surgical relevance Cytoreductive surgery combined 
with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) improves survival of 
selected patients with colorectal peritoneal carcinomatosis, but recurrence is 
common. Histopathological and molecular analysis of colorectal peritoneal 
carcinomatosis could provide clues for development of novel therapies. In this 
study, colorectal peritoneal carcinomatosis was found to be enriched for tumours 
with high stromal content and CMS4-positive status. To further improve prognosis 
for patients with colorectal peritoneal carcinomatosis, therapies that target 
tumour-stroma interaction could be added to CRS-HIPEC.

© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.

DOI: 10.1002/bjs.10788
PMID: 29341165 [Indexed for MEDLINE]


26. Genes (Basel). 2019 Oct 11;10(10):788. doi: 10.3390/genes10100788.

Human Colorectal Cancer from the Perspective of Mouse Models.

Stastna M(1), Janeckova L(2), Hrckulak D(3), Kriz V(4), Korinek V(5).

Author information:
(1)Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 
1083, 142 20 Prague, Czech Republic. monika.stastna@img.cas.cz.
(2)Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 
1083, 142 20 Prague, Czech Republic. lucie.janeckova@img.cas.cz.
(3)Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 
1083, 142 20 Prague, Czech Republic. dusan.hrckulak@img.cas.cz.
(4)Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 
1083, 142 20 Prague, Czech Republic. vitezslav.kriz@img.cas.cz.
(5)Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 
1083, 142 20 Prague, Czech Republic. korinek@img.cas.cz.

Colorectal cancer (CRC) is a heterogeneous disease that includes both hereditary 
and sporadic types of tumors. Tumor initiation and growth is driven by 
mutational or epigenetic changes that alter the function or expression of 
multiple genes. The genes predominantly encode components of various 
intracellular signaling cascades. In this review, we present mouse intestinal 
cancer models that include alterations in the Wnt, Hippo, p53, epidermal growth 
factor (EGF), and transforming growth factor β (TGFβ) pathways; models of 
impaired DNA mismatch repair and chemically induced tumorigenesis are included. 
Based on their molecular biology characteristics and mutational and epigenetic 
status, human colorectal carcinomas were divided into four so-called consensus 
molecular subtype (CMS) groups. It was shown subsequently that the CMS 
classification system could be applied to various cell lines derived from 
intestinal tumors and tumor-derived organoids. Although the CMS system 
facilitates characterization of human CRC, individual mouse models were not 
assigned to some of the CMS groups. Thus, we also indicate the possible 
assignment of described animal models to the CMS group. This might be helpful 
for selection of a suitable mouse strain to study a particular type of CRC.

DOI: 10.3390/genes10100788
PMCID: PMC6826908
PMID: 31614493 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflicts of interest.


27. J Pathol. 2018 Nov;246(3):266-276. doi: 10.1002/path.5129. Epub 2018 Aug 31.

Consensus molecular subtype classification of colorectal adenomas.

Komor MA(1)(2), Bosch LJ(1), Bounova G(3), Bolijn AS(1), Delis-van Diemen PM(1), 
Rausch C(1), Hoogstrate Y(4), Stubbs AP(5), de Jong M(6), Jenster G(4), van 
Grieken NC(7), Carvalho B(1), Wessels LF(3)(8), Jimenez CR(2), Fijneman RJ(1), 
Meijer GA(1); NGS-ProToCol Consortium:.

Collaborators: Dits N, Bottcher R, Hiemstra AC, Ylstra B, Sie D, van den Broek 
E, van der Meer D, Pepers F, Caldenhoven E, Janssen B, van Workum W, van 
Lieshout S, Bangma CH, van Leenders G, van de Werken H.

Author information:
(1)Translational Gastrointestinal Oncology, Department of Pathology, Netherlands 
Cancer Institute, Amsterdam, The Netherlands.
(2)Oncoproteomics Laboratory, Department of Medical Oncology, VU University 
Medical Centre, Amsterdam, The Netherlands.
(3)Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 
Amsterdam, The Netherlands.
(4)Department of Urology, Erasmus Medical Centre Rotterdam, Rotterdam, The 
Netherlands.
(5)Department of Bioinformatics, Erasmus Medical Centre Rotterdam, Rotterdam, 
The Netherlands.
(6)GenomeScan, Leiden, The Netherlands.
(7)Department of Pathology, VU University Medical Centre, Amsterdam, The 
Netherlands.
(8)Department of Electrical Engineering, Mathematics and Computer Science, Delft 
University of Technology, Delft, The Netherlands.

Consensus molecular subtyping is an RNA expression-based classification system 
for colorectal cancer (CRC). Genomic alterations accumulate during CRC 
pathogenesis, including the premalignant adenoma stage, leading to changes in 
RNA expression. Only a minority of adenomas progress to malignancies, a 
transition that is associated with specific DNA copy number aberrations or 
microsatellite instability (MSI). We aimed to investigate whether colorectal 
adenomas can already be stratified into consensus molecular subtype (CMS) 
classes, and whether specific CMS classes are related to the presence of 
specific DNA copy number aberrations associated with progression to malignancy. 
RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was 
determined with polymerase chain reaction-based methodology. DNA copy number was 
assessed by low-coverage DNA sequencing (n = 30) or array-comparative genomic 
hybridisation (n = 32). Adenomas were classified into CMS classes together with 
CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), by use of 
the established CMS classifier. As a result, 54 of 62 (87%) adenomas were 
classified according to the CMS. The CMS3 'metabolic subtype', which was least 
common among CRCs, was most prevalent among adenomas (n = 45; 73%). One of the 
two adenomas showing MSI was classified as CMS1 (2%), the 'MSI immune' subtype. 
Eight adenomas (13%) were classified as the 'canonical' CMS2. No adenomas were 
classified as the 'mesenchymal' CMS4, consistent with the fact that adenomas 
lack invasion-associated stroma. The distribution of the CMS classes among 
adenomas was confirmed in an independent series. CMS3 was enriched with adenomas 
at low risk of progressing to CRC, whereas relatively more high-risk adenomas 
were observed in CMS2. We conclude that adenomas can be stratified into the CMS 
classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas 
at increased risk of progression, the distribution of the CMS classes among 
adenomas is consistent with the proportion of adenomas expected to progress to 
CRC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons 
Ltd on behalf of Pathological Society of Great Britain and Ireland.

© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd 
on behalf of Pathological Society of Great Britain and Ireland.

DOI: 10.1002/path.5129
PMCID: PMC6221003
PMID: 29968252 [Indexed for MEDLINE]


28. Ann Intern Med. 2019 Dec 3;171(11):796-804. doi: 10.7326/M19-0322. Epub 2019 Nov 
5.

Cost-Effectiveness Analysis of Lung Cancer Screening in the United States: A 
Comparative Modeling Study.

Criss SD(1), Cao P(2), Bastani M(3), Ten Haaf K(4), Chen Y(1), Sheehan DF(5), 
Blom EF(4), Toumazis I(3), Jeon J(2), de Koning HJ(4), Plevritis SK(3), Meza 
R(2), Kong CY(6).

Author information:
(1)Massachusetts General Hospital, Boston, Massachusetts (S.D.C., Y.C.).
(2)University of Michigan, Ann Arbor, Michigan (P.C., J.J., R.M.).
(3)Stanford University School of Medicine, Stanford, California (M.B., I.T., 
S.K.P.).
(4)Erasmus University Medical Center, Rotterdam, the Netherlands (K.T., E.F.B., 
H.J.D.).
(5)Massachusetts General Hospital, Boston, Massachusetts, and Broad Institute, 
Cambridge, Massachusetts (D.F.S.).
(6)Massachusetts General Hospital and Harvard Medical School, Boston, 
Massachusetts (C.Y.K.).

Comment in
    Ann Intern Med. 2020 May 19;172(10):706-707.
    Ann Intern Med. 2020 May 19;172(10):705-706.

BACKGROUND: Recommendations vary regarding the maximum age at which to stop lung 
cancer screening: 80 years according to the U.S. Preventive Services Task Force 
(USPSTF), 77 years according to the Centers for Medicare & Medicaid Services 
(CMS), and 74 years according to the National Lung Screening Trial (NLST).
OBJECTIVE: To compare the cost-effectiveness of different stopping ages for lung 
cancer screening.
DESIGN: By using shared inputs for smoking behavior, costs, and quality of life, 
4 independently developed microsimulation models evaluated the health and cost 
outcomes of annual lung cancer screening with low-dose computed tomography 
(LDCT).
DATA SOURCES: The NLST; Prostate, Lung, Colorectal, and Ovarian Cancer Screening 
Trial; SEER (Surveillance, Epidemiology, and End Results) program; Nurses' 
Health Study and Health Professionals Follow-up Study; and U.S. Smoking History 
Generator.
TARGET POPULATION: Current, former, and never-smokers aged 45 years from the 
1960 U.S. birth cohort.
TIME HORIZON: 45 years.
PERSPECTIVE: Health care sector.
INTERVENTION: Annual LDCT according to NLST, CMS, and USPSTF criteria.
OUTCOME MEASURES: Incremental cost-effectiveness ratios (ICERs) with a 
willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY).
RESULTS OF BASE-CASE ANALYSIS: The 4 models showed that the NLST, CMS, and 
USPSTF screening strategies were cost-effective, with ICERs averaging $49 200, 
$68 600, and $96 700 per QALY, respectively. Increasing the age at which to stop 
screening resulted in a greater reduction in mortality but also led to higher 
costs and overdiagnosis rates.
RESULTS OF SENSITIVITY ANALYSIS: Probabilistic sensitivity analysis showed that 
the NLST and CMS strategies had higher probabilities of being cost-effective 
(98% and 77%, respectively) than the USPSTF strategy (52%).
LIMITATION: Scenarios assumed 100% screening adherence, and models extrapolated 
beyond clinical trial data.
CONCLUSION: All 3 sets of lung cancer screening criteria represent 
cost-effective programs. Despite underlying uncertainty, the NLST and CMS 
screening strategies have high probabilities of being cost-effective.
PRIMARY FUNDING SOURCE: CISNET (Cancer Intervention and Surveillance Modeling 
Network) Lung Group, National Cancer Institute.

DOI: 10.7326/M19-0322
PMID: 31683314 [Indexed for MEDLINE]


29. ESMO Open. 2021 Aug;6(4):100211. doi: 10.1016/j.esmoop.2021.100211. Epub 2021 
Jul 13.

Intratumor morphologic and transcriptomic heterogeneity in (V600E)BRAF-mutated 
metastatic colorectal adenocarcinomas.

Angerilli V(1), Fontana E(2), Lonardi S(3), Sbaraglia M(1), Borelli B(4), Munari 
G(5), Salmaso R(1), Guzzardo V(1), Spolverato G(6), Pucciarelli S(6), Pilati 
P(7), Hahne JC(2), Bergamo F(8), Zagonel V(8), Dei Tos AP(1), Sadanandam A(2), 
Loupakis F(6), Valeri N(9), Fassan M(10).

Author information:
(1)Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, 
Padua, Italy.
(2)Division of Molecular Pathology, Institute of Cancer Research, London, UK.
(3)Medical Oncology Unit 3, Department of Oncology, Veneto Institute of Oncology 
IOV-IRCCS, Castelfranco Veneto, Italy.
(4)Department of Translational Research and New Technologies in Medicine and 
Surgery, Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, 
University of Pisa, Pisa, Italy.
(5)Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
(6)Department of Surgery, Oncology & Gastroenterology, 1st Surgery Unit, 
University of Padua, Padua, Italy.
(7)Surgery Unit, Veneto Institute of Oncology IOV-IRCCS, Castelfranco Veneto, 
Italy.
(8)Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology 
IOV-IRCCS, Padua, Italy.
(9)Division of Molecular Pathology, Institute of Cancer Research, London, UK; 
Division of Surgery and Cancer, Imperial College London, London, UK.
(10)Department of Medicine (DIMED), Surgical Pathology Unit, University of 
Padua, Padua, Italy; Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. 
Electronic address: matteo.fassan@unipd.it.

BACKGROUND: Intratumor heterogeneity (ITH) is described as the presence of 
various clones within one tumor, each with their own unique features in terms of 
morphology, inflammation, genetics or transcriptomics. Heterogeneity provides 
the fuel for drug resistance; therefore, an accurate assessment of tumor 
heterogeneity is essential for the development of effective therapies. The 
purpose of this study was to dissect morphologic and molecular ITH in colorectal 
adenocarcinoma.
MATERIALS AND METHODS: A series of 120 V600EBRAF-mutated (V600EBRAFmt) 
consecutive metastatic colorectal adenocarcinomas was assessed for morphologic 
heterogeneity. The two heterogeneous components of each specimen underwent a 
histopathological, immunohistochemical and molecular characterization to 
evaluate: histologic variant, grading, tumor-infiltrating lymphocytes (TILs), 
mismatch repair proteins' expression, KRAS/BRAF/NRAS mutations, microsatellite 
instability (MSI) status and consensus molecular subtype (CMS).
RESULTS: Thirty-one out of 120 (25.8%) V600EBRAFmt primary colorectal 
adenocarcinomas presented a heterogeneous morphology. Among these, eight cases 
had adequate material for molecular profiling. Five out of the eight (62.5%) 
cases resulted instable at MSI testing. The majority (62.5%) of the samples 
showed a CMS4 phenotype based on gene expression profiling. Heterogeneity in CMS 
classification was observed in four out of eight cases. One out of eight cases 
presented significant heterogeneity in the number of TILs between the two 
components of the tumor.
CONCLUSIONS: Although the distribution of the immune infiltrate appears 
relatively conserved among heterogeneous areas of the same tumor, changes in 
gene expression profile and CMS occur in 50% of V600EBRAFmt adenocarcinoma cases 
in our small series and might contribute to variability in response to 
anticancer therapy and clinical outcomes. Assessment of morphological and 
molecular ITH is needed to improve colorectal cancer classification and to 
tailor anticancer treatments and should be included in the pathology report.

Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/j.esmoop.2021.100211
PMCID: PMC8282957
PMID: 34271310 [Indexed for MEDLINE]

Conflict of interest statement: Disclosure NV received honoraria from Merck 
Serono, Pfizer, Bayer, Eli-Lilly and Menarini Silicon Biosystems. FL had roles 
as consultant or advisor for Roche, Bayer, Amgen and Genentech. SL had roles as 
consultant or advisor for Amgen, Bayer, Merck Serono and Lilly; she received 
research funding from Amgen and Merck Serono and is part of speakers' bureau of 
Lilly and BMS. VZ received honoraria and had roles as consultant or advisor for 
Bristol-Myers Squibb, Bayer, Roche, Pfizer, Janssen, Novartis, Astellas and 
Servier; he had roles as consultant or advisor for Celgene and Merck. MF 
received research funding from Astellas Pharma, Macrophage Pharma and QED 
Therapeutics and had roles as consultant or advisor for Astellas Pharma, Roche, 
GSK-Tesaro and Diaceutics. All other authors have declared no conflicts of 
interest.


30. Clin Cancer Res. 2021 Sep 1;27(17):4768-4780. doi: 
10.1158/1078-0432.CCR-21-0529. Epub 2021 Jun 24.

Intratumor CMS Heterogeneity Impacts Patient Prognosis in Localized Colon 
Cancer.

Marisa L(1), Blum Y(#)(1), Taieb J(#)(2)(3), Ayadi M(1), Pilati C(3), Le Malicot 
K(4), Lepage C(4)(5), Salazar R(6), Aust D(7), Duval A(8), Blons H(2)(3), Taly 
V(3), Gentien D(9), Rapinat A(9), Selves J(10), Mouillet-Richard S(3), Boige 
V(3)(11), Emile JF(12), de Reyniès A(#)(13), Laurent-Puig P(#)(14)(3).

Author information:
(1)Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, 
Paris, France.
(2)Institut du cancer Paris CARPEM, AP-HP, European Georges Pompidou Hospital, 
Paris, France.
(3)Centre de Recherche des Cordeliers, INSERM, CNRS SNC 5096, Sorbonne 
Université, Université de Paris, Paris, France.
(4)Fédération Francophone de Cancérologie Digestive, INSERM, Université de 
Bourgogne et Franche Comté, Dijon, France.
(5)Hepatogastroenterology and Digestive Oncology department, CHU Dijon, Dijon, 
France.
(6)Catalan Institute of Oncology (IDIBELL), Universitat de Barcelona, CIBERONC, 
Spanish Gastrointestinal Tumors TTD Group, Barcelona, Spain.
(7)Institute for Pathology, University Hospital Carl Gustav Carus, Dresden, 
Germany.
(8)Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, Equipe 
Instabilité des Microsatellites et Cancer, équipe labellisé par la Ligue 
Nationale contre le Cancer, Paris, France.
(9)Curie Institute, PSL Research University, Translational Research Department, 
Genomics Platform, Paris, France.
(10)Centre de Recherche en Cancérologie de Toulouse, INSERM, Université Toulouse 
III, Department of Pathology, CHU Toulouse, Toulouse, France.
(11)Department of Cancer Medicine, Gustave Roussy, Université Paris-Saclay, 
Villejuif, France.
(12)Department of Pathology, AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, 
France.
(13)Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, 
Paris, France. pierre.laurent-puig@parisdescartes.fr 
aurelien.dereynies@ligue-cancer.net.
(14)Institut du cancer Paris CARPEM, AP-HP, European Georges Pompidou Hospital, 
Paris, France. pierre.laurent-puig@parisdescartes.fr 
aurelien.dereynies@ligue-cancer.net.
(#)Contributed equally

PURPOSE: The consensus molecular subtypes (CMS) represent a significant advance 
in the understanding of intertumor heterogeneity in colon cancer. Intratumor 
heterogeneity (ITH) is the new frontier for refining prognostication and 
understanding treatment resistance. This study aims at deciphering the 
transcriptomic ITH of colon cancer and understanding its potential prognostic 
implications.
EXPERIMENTAL DESIGN: We deconvoluted the transcriptomic profiles of 1,779 tumors 
from the PETACC8 trial and 155 colon cancer cell lines as weighted sums of the 
four CMSs, using the Weighted In Silico Pathology (WISP) algorithm. We assigned 
to each tumor and cell line a combination of up to three CMS subtypes with a 
threshold above 20%.
RESULTS: Over 55% of tumors corresponded to mixtures of at least two CMSs, 
demonstrating pervasive ITH in colon cancer. Of note, ITH was associated with 
shorter disease-free survival (DFS) and overall survival, [HR, 1.34; 95% 
confidence interval (CI; 1.12-1.59), 1.40, 95% CI (1.14-1.71), respectively]. 
Moreover, we uncovered specific combinations of CMS associated with dismal 
prognosis. In multivariate analysis, ITH represents the third parameter 
explaining DFS variance, after T and N stages. At a cellular level, combined 
WISP and single-cell transcriptomic analysis revealed that most colon cancer 
cell lines are a mixture of cells falling into different CMSs, indicating that 
ITH may correspond to distinct functional statuses of colon cancer cells.
CONCLUSIONS: This study shows that CMS-based transcriptomic ITH is frequent in 
colon cancer and impacts its prognosis. CMS-based transcriptomic ITH may 
correspond to distinct functional statuses of colon cancer cells, suggesting 
plasticity between CMS-related cell populations. Transcriptomic ITH deserves 
further assessment in the context of personalized medicine.

©2021 The Authors; Published by the American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-21-0529
PMID: 34168047 [Indexed for MEDLINE]


31. Cancers (Basel). 2020 Jun 14;12(6):1571. doi: 10.3390/cancers12061571.

BRAF Mutated Colorectal Cancer: New Treatment Approaches.

Molina-Cerrillo J(1)(2)(3), San Román M(1), Pozas J(1), Alonso-Gordoa 
T(1)(2)(3), Pozas M(1), Conde E(4), Rosas M(5), Grande E(6), García-Bermejo 
ML(4), Carrato A(1)(2)(3).

Author information:
(1)Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, 
Spain.
(2)CIBERONC, The Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, 
Spain.
(3)Medicine School, Alcalá University, 28805 Madrid, Spain.
(4)Biomarkers and Therapeutic Targets Group and Core Facility, The Ramón y Cajal 
Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain.
(5)Pathology department, University Hospital Ramon y Cajal, 28034 Madrid, Spain.
(6)Department of Medical Oncology, MD Anderson Cancer Center, 28033 Madrid, 
Spain.

Colon cancer is one of the most frequently diagnosed malignancies in adults, 
considering both its incidence and prevalence. Anatomically, the right colon is 
considered as being from the cecum to the splenic flexure, and the left colon is 
from the splenic flexure to the rectum. Sidedness is a surrogate of a wide 
spectrum of colorectal cancer (CRC) biology features (embryology, microbiome, 
methylation, microsatellite instability (MSI), BRAF, aging, KRAS, consensus 
molecular subtypes (CMS), etc.), which result in prognostic factors. Different 
molecular subtypes have been identified, according to genomic and transcriptomic 
criteria. A subgroup harboring a BRAF mutation has been described, and 
represents approximately 10% of the patients diagnosed with colon cancer. This 
subgroup has morphological, clinical, and therapeutic characteristics that 
differ substantially from patients who do not carry this genetic alteration. 
Unfortunately, there is no established standard of care for this particular 
cohort of patients. This manuscript aims to study the biology of this subgroup 
of colon cancer, to understand the current approach in clinical research.

DOI: 10.3390/cancers12061571
PMCID: PMC7353017
PMID: 32545884

Conflict of interest statement: Teresa Alonso-Gordoa: Pfizer, Ipsen, 
Bristol-Myers Squibb, Roche, Eusa Pharma, MerckSharp&Dohme (C/A, SAB), Roche 
(RF). Enrique Grande: Pfizer, Bristol-Myers Squibb, Ipsen, Roche, Eisai, Eusa 
Pharma, MerckSharp&Dohme, Sanofi-Genzyme, Adacap, Novartis, PierreFabre, 
Lexicon, Celgene (C/A, SAB), Pfizer, AstraZeneca, MTEM/Threshold, Roche, Ipsen, 
Lexicon (RF). The rest of authors declares no conflict of interest. (C/A): 
Consulting/Advisory relationship; (RF) Research Funding; (SAB) Scientific 
Advisory Board.


32. J Clin Oncol. 2021 Sep 1;39(25):2779-2790. doi: 10.1200/JCO.20.02636. Epub 2021 
May 4.

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency 
Undergoing Surveillance.

Durno C(1)(2), Ercan AB(3)(4), Bianchi V(3), Edwards M(3), Aronson M(2), Galati 
M(3)(4), Atenafu EG(5), Abebe-Campino G(6), Al-Battashi A(7), Alharbi M(8), Azad 
VF(9), Baris HN(10), Basel D(11), Bedgood R(12), Bendel A(13), Ben-Shachar 
S(14), Blumenthal DT(15), Blundell M(16), Bornhorst M(17), Bronsema A(18), 
Cairney E(19), Rhode S(20), Caspi S(21), Chamdin A(22), Chiaravalli S(23), 
Constantini S(24), Crooks B(25), Das A(26), Dvir R(27), Farah R(28), Foulkes 
WD(29), Frenkel Z(30), Gallinger B(31), Gardner S(32), Gass D(33), Ghalibafian 
M(9), Gilpin C(34), Goldberg Y(35), Goudie C(36), Hamid SA(37), Hampel H(38), 
Hansford JR(39), Harlos C(40), Hijiya N(41), Hsu S(42), Kamihara J(43), Kebudi 
R(44), Knipstein J(45), Koschmann C(46), Kratz C(47), Larouche V(48), Lassaletta 
A(49), Lindhorst S(50), Ling SC(1), Link MP(51), Loret De Mola R(52), Luiten 
R(53), Lurye M(30), Maciaszek JL(54), MagimairajanIssai V(55), Maher OM(56), 
Massimino M(23), McGee RB(54), Mushtaq N(57), Mason G(58), Newmark M(59), 
Nicholas G(60), Nichols KE(61), Nicolaides T(32), Opocher E(62), Osborn M(63), 
Oshrine B(64), Pearlman R(65), Pettee D(66), Rapp J(67), Rashid M(68), Reddy 
A(69), Reichman L(70), Remke M(71), Robbins G(32), Roy S(72), Sabel M(73), 
Samuel D(74), Scheers I(75), Schneider KW(76), Sen S(77), Stearns D(78), 
Sumerauer D(79), Swallow C(80), Taylor L(54), Thomas G(81), Toledano H(82), 
Tomboc P(83), Van Damme A(84), Winer I(72), Yalon M(6), Yen LY(85), Zapotocky 
M(86), Zelcer S(19), Ziegler DS(87), Zimmermann S(88), Hawkins C(89), Malkin 
D(26), Bouffet E(26), Villani A(26), Tabori U(26).

Author information:
(1)Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick 
Children, Toronto, ON, Canada.
(2)Mount Sinai Hospital, The Familial Gastrointestinal Cancer Registry at the 
Zane Cohen Centre for Digestive Disease, Toronto, ON, Canada.
(3)The Hospital for Sick Children, The Arthur and Sonia Labatt Brain Tumour 
Research Centre, Toronto, ON, Canada.
(4)University of Toronto, Institute of Medical Science, Toronto, ON, Canada.
(5)Department of Biostatistics, Princess Margaret Cancer Centre, University of 
Toronto, Toronto, ON, Canada.
(6)Department of Pediatric Hematology-Oncology, Sheba Medical Center, Tel 
Hashomer, Israel.
(7)Ministry of Health Oman, Child Health Specialist Muscat, Muscat, Oman.
(8)Department of Pediatric Hematology Oncology, King Fahad Medical City, Riyadh, 
Saudi Arabia.
(9)MAHAK Pediatric Cancer Treatment and Research Center (MPCTRC), Tehran, Iran.
(10)Rambam Health Care Campus, The Genetics Institute, Haifa, Israel.
(11)Medical College of Wisconsin, Pediatrics, Milwaukee, WI.
(12)Coliseum Medical Centers, Macon, GA.
(13)Department of Pediatric Hematology-Oncology, Children's Hospitals and 
Clinics of Minnesota, Minneapolis, MN.
(14)Tel Aviv Sourasky Medical Center, Genetic Institute, Tel Aviv, Israel.
(15)Oncology Division, Tel Aviv University Sackler Faculty of Medicine, Tel 
Aviv, Israel.
(16)Sutter Health, Cancer Risk Program, Sacramento, CA.
(17)Children's National Medical Center, Brain Tumor Institute, Washington, DC.
(18)Department of Pediatric Hematology and Oncology, University Medical Center 
Hamburg-Eppendorf, Hamburg, Germany.
(19)Department of Pediatrics, London Health Sciences Centre, London, ON, Canada.
(20)Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH.
(21)Sheba Medical Center, Cancer Research Center, Tel Hashomer, Israel.
(22)Michigan State University, College of Human Medicine, Center for Bleeding 
and Clotting Disorders, East Lansing, MI.
(23)Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, 
Lombardia, Italy.
(24)Department of Pediatric Neurosurgery, Tel Aviv Sourasky Medical Center, Tel 
Aviv, Israel.
(25)Division of Hematology-Oncology, IWK Health Centre, Halifax, NS, Canada.
(26)Division of Hematology and Oncology, The Hospital for Sick Children, 
Toronto, ON, Canada.
(27)Department of Pediatric Hemato-Oncology, Tel Aviv Sourasky Medical Center, 
Tel Aviv, Israel.
(28)Lebanese American University Medical Center-Rizk, Beirut, Lebanon.
(29)Deparments of Oncology and Human Genetics, McGill University Health Centre, 
Cancer Genetics Program, Montreal, QC, Canada.
(30)Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel.
(31)Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 
Toronto, ON, Canada.
(32)Department of Pediatric Hematology-Oncology, NYU Langone Health, New York, 
NY.
(33)Department of Pediatric Hematology and Oncology, Atrium Health, Charlotte, 
NC.
(34)Children's Hospital of Eastern Ontario, Genetics, Ottawa, ON, Canada.
(35)Department of Oncology, Hadassah Medical Center, Jerusalem, Israel.
(36)Division of Oncology, McGill University Health Centre, Montreal, QC, Canada.
(37)The Indus Hospital, Karachi, Sindh, Pakistan.
(38)The Ohio State University Comprehensive Cancer Center, Internal Medicine, 
Columbus, OH.
(39)The Royal Children's Hospital Melbourne, Children's Cancer Centre, 
Parkville, Victoria, Australia.
(40)Department of Medical Oncology and Hematology, CancerCare Manitoba, 
Winnipeg, MB, Canada.
(41)Pediatric Hematology Oncology and Stem Cell Transplant, Columbia University 
Irving Medical Center, New York, NY.
(42)Department of Pediatric Hematology-Oncology, Sutter Health, Sacramento, CA.
(43)Dana-Farber Children's Hospital Cancer Center, Pediatric Oncology, Boston, 
MA.
(44)Department of Pediatric Hematology-Oncology, Istanbul University, Fatih, 
Istanbul, Turkey.
(45)Department of Pediatric Neurology, Medical College of Wisconsin, Milwaukee, 
WI.
(46)Department of Pediatric Hematology-Oncology, University of Michigan Medical 
School, Ann Arbor, MI.
(47)Department of Pediatric Haematology and Oncology, Hospital of the Goethe 
University Frankfurt, Frankfurt am Main, Hessen, Germany.
(48)Department of Hematology-Oncology, CHU de Quebec-Universite Laval, Quebec, 
QC, Canada.
(49)Department of Pediatric Hematology-Oncology, Hospital Infantil Universitario 
Nino Jesus, Madrid, Spain.
(50)Department of Hematology-Medical Oncology, Medical University of South 
Carolina, Charleston, SC.
(51)Department of Pediatrics, Stanford Medicine, Stanford, CA.
(52)Department of Pediatrics, Oregon Health & Science University, Portland, OR.
(53)Department of Clinical Cancer Genetics, Banner MD Anderson Cancer Center, 
Gilbert, AZ.
(54)Saint Jude Children's Research Hospital, Memphis, TN.
(55)Department of Pediatric Hematology-Oncology, CancerCare Manitoba, Winnipeg, 
MB, Canada.
(56)Department of Pediatric Hematology-Oncology, Nicklaus Children's Hospital, 
Miami, FL.
(57)Aga Khan University Hospital, Karachi, Pakistan.
(58)Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA.
(59)Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL.
(60)Division of Medical Oncology, University of Ottawa, Ottawa, ON, Canada.
(61)Department of Oncology, Saint Jude Children's Research Hospital, Memphis, 
TN.
(62)Department of Pediatrics, University of Padua, Padova, Veneto, Italy.
(63)Paediatric Haematology, Womens and Childrens Hospital (WCH), North Adelaide, 
South Australia, Australia.
(64)Johns Hopkins All Children's Hospital, Cancer and Blood Disorders Institute, 
Saint Petersburg, FL.
(65)Department of Internal Medicine, The Ohio State University Comprehensive 
Cancer Center, Columbus, OH.
(66)Akron Children's Hospital, Akron, OH.
(67)West Virginia University Cancer Institute, Morgantown, WV.
(68)IWK Health Centre, Halifax, NS, Canada.
(69)University of California San Francisco, San Francisco, CA.
(70)McGill University Health Centre, Montreal, QC, Canada.
(71)University Hospital Dusseldorf, Dusseldorf, Nordrhein-Westfalen, Germany.
(72)Wayne State University, Detroit, MI.
(73)Department of Pediatrics, University of Gothenburg Sahlgrenska Academy, 
Goteborg, Sweden.
(74)Valley Children's Hospital, Madera, CA.
(75)Universite Catholique de Louvain La Faculte de Medecine, Bruxelles, Belgium.
(76)Department of Pediatric Hematology-Oncology, Children's Hospital Colorado, 
Aurora, CO.
(77)Department of Pediatrics, Kokilaben Dhirubhai Ambani Hospital and Medical 
Research Institute, Mumbai, Maharashtra, India.
(78)UH Rainbow Babies and Children's Hospital Division of Pediatrics, Pediatric 
Neuro-oncology, Cleveland, OH.
(79)Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, 
University Hospital Motol, Charles University, Prague, Czechia.
(80)Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada.
(81)Oregon Health & Science University, Portland, OR.
(82)Department of Pediatric Hematology Oncology, Schneider Children's Medical 
Center of Israel, Petah Tikva, Israel.
(83)Department of Pediatrics, West Virginia University, Morgantown, WV.
(84)Department of Pediatric Hematology and Oncology, Universite Catholique de 
Louvain, Louvain-la-Neuve, Walloon Brabant, Belgium.
(85)Department of Neurosurgery, Taipei Veterans General Hospital, Taipei, 
Taiwan.
(86)Motol University Hospital, Praha, Czechia.
(87)Sydney Children's Hospital Randwick, Kids Cancer Centre, Randwick, New South 
Wales, Australia.
(88)Department of Pediatric Hematology and Oncology, Hannover Medical School, 
Hannover, Niedersachsen, Germany.
(89)Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, 
Toronto, ON, Canada.

PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal 
cancer predisposition syndrome characterized by early-onset synchronous and 
metachronous multiorgan tumors. We designed a surveillance protocol for early 
tumor detection in these individuals.
PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who 
were registered in the International Replication Repair Deficiency Consortium. 
Tumor spectrum, efficacy of the surveillance protocol, and malignant 
transformation of low-grade lesions were examined for the entire cohort. 
Survival outcomes were analyzed for patients followed prospectively from the 
time of surveillance implementation.
RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median 
age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For 
patients undergoing surveillance, all GI and other solid tumors, and 75% of 
brain cancers were detected asymptomatically. By contrast, only 16% of 
hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine 
patients were followed prospectively and used for survival analysis. Five-year 
overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 
63.7) when cancer was detected asymptomatically and symptomatically, 
respectively (P = .001). Patient outcome measured by adherence to the 
surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for 
patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial 
surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P 
< .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of 
transformation from low-to high-grade was 81% for GI cancers within 8 years and 
100% for gliomas in 6 years.
CONCLUSION: Surveillance and early cancer detection are associated with improved 
OS for individuals with CMMRD.

DOI: 10.1200/JCO.20.02636
PMCID: PMC8407605
PMID: 33945292 [Indexed for MEDLINE]

Conflict of interest statement: Hagit N. BarisConsulting or Advisory Role: 
Sanofi, Igentify LtdSpeakers' Bureau: Sanofi, Takeda, Pfizer Donald 
BaselHonoraria: BioMarinConsulting or Advisory Role: iQvia Deborah T. 
BlumenthalConsulting or Advisory Role: AstraZeneca, Novocure, Takeda Miriam 
BornhorstConsulting or Advisory Role: AstraZeneca/MedImmune Sara RhodeHonoraria: 
Myriad GeneticsSpeakers' Bureau: Myriad GeneticsTravel, Accommodations, 
Expenses: Myriad Genetics Roula FarahHonoraria: Novo NordiskConsulting or 
Advisory Role: Novo Nordisk William D. FoulkesResearch Funding: AstraZeneca 
David GassEmployment: X4 PharmaceuticalsHonoraria: X4 PharmaceuticalsSpeakers' 
Bureau: Precisionscientia Heather HampelStock and Other Ownership Interests: 
Genome MedicalConsulting or Advisory Role: InVitae, Genome Medical, Promega, 
23andMe Jordan R. HansfordConsulting or Advisory Role: Bayer Craig HarlosTravel, 
Accommodations, Expenses: GlaxoSmithKline Nobuko HijiyaHonoraria: 
NovartisConsulting or Advisory Role: Novartis, IncyteResearch Funding: Pfizer 
Junne KamiharaStock and Other Ownership Interests: PanTher Therapeutics, ROME 
Therapeutics, TellBioHonoraria: Pfizer, NanoString Technologies, Third Rock 
Ventures, Foundation MedicineConsulting or Advisory Role: ROME Therapeutics, 
Third Rock VenturesResearch Funding: PureTech, Ribon Therapeutics, ACD 
BiotechnePatents, Royalties, Other Intellectual Property: Patent on drug 
delivery device licensed to PanTher Therapeutics, Patents on Repeat RNA 
biomarkers and therapeutics licensed to Rome Therapeutics, Patents on 
Circulating Tumor Cell Biomarkers Licensed to TellBio Inc Jeffrey 
KnipsteinEmployment: PRA Health SciencesConsulting or Advisory Role: Atheneum 
Alvaro LassalettaStock and Other Ownership Interests: Gilead SciencesConsulting 
or Advisory Role: Shire, Jazz Pharmaceuticals, Roche, ServierTravel, 
Accommodations, Expenses: Shire, Gilead Sciences Simon C. LingHonoraria: 
AbbvieResearch Funding: Abbvie, Gilead Sciences Michael P. LinkConsulting or 
Advisory Role: Incyte, ADC Therapeutics, Lilly, Steba Biotech, Mesoblast, 
GlaxoSmithKline, SyndaxResearch Funding: Seattle Genetics, Janssen Oncology 
Rebecca Loret de MolaEmployment: Huron Consulting Maura MassiminoConsulting or 
Advisory Role: Oncoscience, Novartis Gary MasonEmployment: Janssen Research & 
Development, MerckStock and Other Ownership Interests: Johnson & Johnson, 
MerckTravel, Accommodations, Expenses: Janssen Research & Development Kim E. 
NicholsStock and Other Ownership Interests: IncyteResearch Funding: 
Incyte/Novartis, Alpine Immune Sciences Enrico OpocherConsulting or Advisory 
Role: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca Michael 
OsbornTravel, Accommodations, Expenses: Amgen, Pfizer Benjamin OshrineHonoraria: 
Mesoblast Alyssa ReddyConsulting or Advisory Role: Novartis, AstraZeneca Lara 
ReichmanResearch Funding: Illumina Marc RemkeStock and Other Ownership 
Interests: Bayer, BB Biotech Ventures, BioNTech AG, InVitae, IDEXX Laboratories 
Kami Wolfe SchneiderOther Relationship: Journal of Genetic Counseling Duncan 
StearnsConsulting or Advisory Role: AstraZenecaOpen Payments Link: 
https://openpaymentsdata.cms.gov/physician/792397 Patrick TombocHonoraria: 
Unicare Health PlanConsulting or Advisory Role: UniCare Health Plan An Van 
DammeConsulting or Advisory Role: Octapharm, Pfizer, BayerResearch Funding: 
Johnson & JohnsonTravel, Accommodations, Expenses: Pfizer, Sobi, Shire, Roche 
Ira WinerResearch Funding: Oncoceutics David S. ZieglerConsulting or Advisory 
Role: Bayer, AmgenTravel, Accommodations, Expenses: Bayer Cynthia 
HawkinsConsulting or Advisory Role: BayerPatents, Royalties, Other Intellectual 
Property: IP for low-grade glioma and sarcoma fusion panels as well as 
medulloblastoma subgrouping panel David MalkinConsulting or Advisory Role: Bayer 
Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche, 
Bristol Myers SquibbNo other potential conflicts of interest were reported.


33. Cancers (Basel). 2021 Sep 30;13(19):4923. doi: 10.3390/cancers13194923.

Implications of Intratumor Heterogeneity on Consensus Molecular Subtype (CMS) in 
Colorectal Cancer.

Chowdhury S(1), Hofree M(2)(3), Lin K(1), Maru D(4), Kopetz S(1), Shen JP(1).

Author information:
(1)Department of Gastrointestinal Medical Oncology, The University of Texas MD 
Anderson Cancer Center, Houston, TX 77030, USA.
(2)Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
02142, USA.
(3)Department of Biological Regulation, Weizmann Institute of Science, Rehovot 
76100, Israel.
(4)Department of Pathology, The University of Texas MD Anderson Cancer Center, 
Houston, TX 77030, USA.

The implications of intratumor heterogeneity on the four consensus molecular 
subtypes (CMS) of colorectal cancer (CRC) are not well known. Here, we use 
single-cell RNA sequencing (scRNASeq) to build an algorithm to assign CMS 
classification to individual cells, which we use to explore the distributions of 
CMSs in tumor and non-tumor cells. A dataset of colorectal tumors with bulk 
RNAseq (n = 3232) was used to identify CMS specific-marker gene sets. These gene 
sets were then applied to a discovery dataset of scRNASeq profiles (n = 10) to 
develop an algorithm for single-cell CMS (scCMS) assignment, which recapitulated 
the intrinsic biology of all four CMSs. The single-cell CMS assignment algorithm 
was used to explore the scRNASeq profiles of two prospective CRC tumors with 
mixed CMS via bulk sequencing. We find that every CRC tumor contains individual 
cells of each scCMS, as well as many individual cells that have enrichment for 
features of more than one scCMS (called mixed cells). scCMS4 and scCMS1 cells 
dominate stroma and immune cell clusters, respectively, but account for less 
than 3% epithelial cells. These data imply that CMS1 and CMS4 are driven by the 
transcriptomic contribution of immune and stromal cells, respectively, not tumor 
cells.

DOI: 10.3390/cancers13194923
PMCID: PMC8507736
PMID: 34638407

Conflict of interest statement: The authors declare no conflict of interest. The 
funders had no role in the design of the study; in the collection, analyses, or 
interpretation of data, in the writing of the manuscript, or in the decision to 
publish the results.


34. Ann Gastroenterol Surg. 2020 Jul 21;4(5):528-539. doi: 10.1002/ags3.12362. 
eCollection 2020 Sep.

Investigation of colorectal cancer in accordance with consensus molecular 
subtype classification.

Sawayama H(1), Miyamoto Y(1), Ogawa K(1), Yoshida N(1), Baba H(1).

Author information:
(1)Department of Gastroenterological Surgery Graduate School of Medical Sciences 
Kumamoto University Honjo Japan.

The classification of colorectal cancer (CRC) plays a pivotal role in predicting 
a patient's prognosis and determining treatment strategies. The consensus 
molecular subtype (CMS) classification system was constructed by analyzing 
genetic information from 18 CRC data sets, containing 4151 CRC samples. CRC was 
classified into four subtypes with distinct molecular and biological 
characteristics: CMS1 (microsatellite instability immune), CMS2 (canonical), 
CMS3 (metabolic), and CMS4 (mesenchymal). Since their designation in 2015, these 
classifications have been applied to basic and translational research of CRC, 
with the hope that understanding these subsets will influence a clinician's 
approach to therapeutic treatment and improve clinical outcomes. We reviewed CRC 
investigations in accordance with CMSs published in the last 5 years to further 
explore the clinical significance of these subtypes and identify underlying 
trends that may direct relevant future research. We determined that CMSs linked 
common features of CRC cell lines and PDX models in various studies. 
Furthermore, associations between prognosis and clinicopathological findings, 
including pathological grade and the stage of carcinogenesis, tumor budding, and 
tumor location, were correlated with CMS classification. Novel prognostic 
factors were identified, and the relationship between chemotherapeutic drug 
resistance and CMS has been fortified by our compilation of research; thus, 
indicating that this review provides advanced insight into clinical questions 
and treatment strategies for CRC.

© 2020 The Authors. Annals of Gastroenterological Surgery published by John 
Wiley & Sons Australia, Ltd on behalf of The Japanese Society of 
Gastroenterology.

DOI: 10.1002/ags3.12362
PMCID: PMC7511559
PMID: 33005848

Conflict of interest statement: Authors declare no conflict of interests for 
this article.


35. Radiol Oncol. 2020 May 28;54(3):272-277. doi: 10.2478/raon-2020-0031.

Consensus molecular subtypes (CMS) in metastatic colorectal cancer - 
personalized medicine decision.

Rebersek M(1)(2).

Author information:
(1)Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, 
Slovenia.
(2)Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

Background Colorectal cancer (CRC) is one of the most common types of cancer in 
the world. Metastatic disease is still incurable in most of these patients, but 
the survival rate has improved by treatment with novel systemic chemotherapy and 
targeted therapy in combination with surgery. New knowledge of its complex 
heterogeneity in terms of genetics, epigenetics, transcriptomics and 
microenvironment, including prognostic and clinical characteristics, led to its 
classification into various molecular subtypes of metastatic CRC, called 
consensus molecular subtypes (CMS). The CMS classification thus enables the 
medical oncologists to adjust the treatment from case to case. They can 
determine which type of systemic chemotherapy or targeted therapy is best suited 
to a specific patient, what dosages are needed and in what order. Conclusions 
CMS in metastatic CRC are the new tool to include the knowledge of molecular 
factors, tumour stroma and signalling pathways for personalized, 
patient-orientated systemic treatment in precision medicine.

DOI: 10.2478/raon-2020-0031
PMCID: PMC7409603
PMID: 32463385 [Indexed for MEDLINE]


36. JAMA Netw Open. 2021 Mar 1;4(3):e212474. doi: 10.1001/jamanetworkopen.2021.2474.

Evaluation of Reliability and Correlations of Quality Measures in Cancer Care.

Keating NL(1)(2), Cleveland JLF(3), Wright AA(4)(5), Brooks GA(6), Meneades 
L(1), Riedel L(1), Zubizarreta JR(1)(7)(8), Landrum MB(1).

Author information:
(1)Department of Health Care Policy, Harvard Medical School, Boston, 
Massachusetts.
(2)Division of General Internal Medicine, Brigham and Women's Hospital, Boston, 
Massachusetts.
(3)Department of Informatics and Analytics, Dana-Farber Cancer Institute, 
Boston, Massachusetts.
(4)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
Massachusetts.
(5)Division of Population Sciences, Dana-Farber Cancer Institute, Boston, 
Massachusetts.
(6)Section of Medical Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, New 
Hampshire.
(7)Department of Biostatistics, Harvard T.H. Chan School of Public Health, 
Boston, Massachusetts.
(8)Department of Statistics, Harvard Faculty of Arts and Sciences, Cambridge, 
Massachusetts.

IMPORTANCE: Measurement of the quality of care is important for alternative 
payment models in oncology, yet the ability to distinguish high-quality from 
low-quality care across oncology practices remains uncertain.
OBJECTIVE: To assess the reliability of cancer care quality measures across 
oncology practices using registry and claims-based measures of process, 
utilization, end-of-life (EOL) care, and survival, and to assess the 
correlations of practice-level performance across measure and cancer types.
DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used the 
Surveillance, Epidemiology, and End Results (SEER) Program registry linked to 
Medicare administrative data to identify individuals with lung cancer, breast 
cancer, or colorectal cancer (CRC) that was newly diagnosed between January 1, 
2011, and December 31, 2015, and who were treated in oncology practices with 20 
or more patients. Data were analyzed from January 2018 to December 2020.
MAIN OUTCOMES AND MEASURES: Receipt of guideline-recommended treatment and 
surveillance, hospitalizations or emergency department visits during 6-month 
chemotherapy episodes, care intensity in the last month of life, and 12-month 
survival were measured. Summary measures for each domain in each cohort were 
calculated. Practice-level rates for each measure were estimated from 
hierarchical linear models with practice-level random effects; practice-level 
reliability (reproducibility) for each measure based on the between-measure 
variance, within-measure variance, and distribution of patients treated in each 
practice; and correlations of measures across measure and cancer types.
RESULTS: In this study of SEER registry data linked to Medicare administrative 
data from 49 715 patients with lung cancer treated in 502 oncology practices, 21 
692 with CRC treated in 347 practices, and 52 901 with breast cancer treated in 
492 practices, few practices had 20 or more patients who were eligible for most 
process measures during the 5-year study period. Patients were 65 years or 
older; approximately 50% of the patients with lung cancer and CRC and all of the 
patients with breast cancer were women. Most measures had limited variability 
across practices. Among process measures, 0 of 6 for lung cancer, 0 of 6 for 
CRC, and 3 of 11 for breast cancer had a practice-level reliability of 0.75 or 
higher for the median-sized practice. No utilization, EOL care, or survival 
measure had reliability across practices of 0.75 or higher. Correlations across 
measure types were low (r ≤ 0.20 for all) except for a correlation between the 
CRC process and 1-year survival summary measures (r = 0.35; P < .001). Summary 
process measures had limited or no correlation across lung cancer, breast 
cancer, and CRC (r ≤ 0.16 for all).
CONCLUSIONS AND RELEVANCE: This study found that quality measures were limited 
by the small numbers of Medicare patients with newly diagnosed cancer treated in 
oncology practices, even after pooling 5 years of data. Measures had low 
reliability and had limited to no correlation across measure and cancer types, 
suggesting the need for research to identify reliable quality measures for 
practice-level quality assessments.

DOI: 10.1001/jamanetworkopen.2021.2474
PMCID: PMC7985722
PMID: 33749769 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of Interest Disclosures: Dr Keating 
reported receiving grants from Arnold Ventures during the conduct of the study 
and grants from the Centers for Medicare & Medicaid Services (CMS) contract 
evaluation team for the Oncology Care Model outside the submitted work. Dr 
Wright reported receiving grants from Arnold Ventures during the conduct of the 
study. Dr Riedel reported receiving grants from Arnold Ventures during the 
conduct of the study. Dr Landrum reported receiving grants from Arnold Ventures 
during the conduct of the study. No other disclosures were reported.


37. Cancers (Basel). 2020 Oct 28;12(11):3160. doi: 10.3390/cancers12113160.

YAP/TAZ Signalling in Colorectal Cancer: Lessons from Consensus Molecular 
Subtypes.

Mouillet-Richard S(1), Laurent-Puig P(1)(2).

Author information:
(1)Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université 
de Paris, F-75006 Paris, France.
(2)Institut du Cancer Paris CARPEM, APHP, Department of Biology, Hôpital 
Européen Georges Pompidou, F-75015 Paris, France.

Recent advance in the characterization of the heterogeneity of colorectal cancer 
has led to the definition of a consensus molecular classification within four 
CMS subgroups, each associated with specific molecular and clinical features. 
Investigating the signalling pathways that drive colorectal cancer progression 
in relation to the CMS classification may help design therapeutic strategies 
tailored for each CMS subtype. The two main effectors of the Hippo pathway YAP 
and its paralogue TAZ have been intensively scrutinized for their contribution 
to colon carcinogenesis. Here, we review the knowledge of YAP/TAZ implication in 
colorectal cancer from the perspective of the CMS framework. We identify gaps in 
our current understanding and delineate research avenues for future work.

DOI: 10.3390/cancers12113160
PMCID: PMC7692643
PMID: 33126419

Conflict of interest statement: The authors declare no conflict of interest.


38. BMC Cancer. 2020 Sep 4;20(1):850. doi: 10.1186/s12885-020-07316-z.

Interconnectivity between molecular subtypes and tumor stage in colorectal 
cancer.

Coebergh van den Braak RRJ(1), Ten Hoorn S(2)(3), Sieuwerts AM(4)(5), Tuynman 
JB(6), Smid M(4), Wilting SM(4), Martens JWM(4)(5), Punt CJA(7)(8), Foekens 
JA(4), Medema JP(2)(3), IJzermans JNM(1), Vermeulen L(9)(10).

Author information:
(1)Department of Surgery, Erasmus MC University Medical Center, 's Gravendijkwal 
230, 3015 CE, Rotterdam, The Netherlands.
(2)Laboratory for Experimental Oncology and Radiobiology, Amsterdam UMC, 
University of Amsterdam and Cancer Center Amsterdam, Meibergdreef 9, 1105AZ, 
Amsterdam, The Netherlands.
(3)Oncode Institute, Amsterdam UMC, Meibergdreef 9, 1105AZ, Amsterdam, The 
Netherlands.
(4)Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC 
University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
(5)Cancer Genomics Center Netherlands, Amsterdam, The Netherlands.
(6)Department of Surgery, Amsterdam UMC, Boelelaan 1117, 1081 HV, Amsterdam, The 
Netherlands.
(7)Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, 
Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.
(8)Julius Center for Health Sciences and Primary Care, University Medical Center 
Utrecht, Universiteitsweg 100, 3584 CX, Utrecht, The Netherlands.
(9)Laboratory for Experimental Oncology and Radiobiology, Amsterdam UMC, 
University of Amsterdam and Cancer Center Amsterdam, Meibergdreef 9, 1105AZ, 
Amsterdam, The Netherlands. l.vermeulen@amsterdamumc.nl.
(10)Oncode Institute, Amsterdam UMC, Meibergdreef 9, 1105AZ, Amsterdam, The 
Netherlands. l.vermeulen@amsterdamumc.nl.

BACKGROUND: There are profound individual differences in clinical outcomes 
between colorectal cancers (CRCs) presenting with identical stage of disease. 
Molecular stratification, in conjunction with the traditional TNM staging, is a 
promising way to predict patient outcomes. We investigated the interconnectivity 
between tumor stage and tumor biology reflected by the Consensus Molecular 
Subtypes (CMSs) in CRC, and explored the possible value of these insights in 
patients with stage II colon cancer.
METHODS: We performed a retrospective analysis using clinical records and gene 
expression profiling in a meta-cohort of 1040 CRC patients. The 
interconnectivity of tumor biology and disease stage was assessed by 
investigating the association between CMSs and TNM classification. In order to 
validate the clinical applicability of our findings we employed a meta-cohort of 
197 stage II colon cancers.
RESULTS: CMS4 was significantly more prevalent in advanced stages of disease 
(stage I 9.8% versus stage IV 38.5%, p < 0.001). The observed differential gene 
expression between cancer stages is at least partly explained by the biological 
differences as reflected by CMS subtypes. Gene signatures for stage III-IV and 
CMS4 were highly correlated (r = 0.77, p < 0.001). CMS4 cancers showed an 
increased progression rate to more advanced stages (CMS4 compared to CMS2: 1.25, 
95% CI: 1.08-1.46). Patients with a CMS4 cancer had worse survival in the 
high-risk stage II tumors compared to the total stage II cohort (5-year DFS 
41.7% versus 100.0%, p = 0.008).
CONCLUSIONS: Considerable interconnectivity between tumor biology and tumor 
stage in CRC exists. This implies that the TNM stage, in addition to the stage 
of progression, might also reflect distinct biological disease entities. These 
insights can potentially be utilized to optimize identification of high-risk 
stage II colon cancers.

DOI: 10.1186/s12885-020-07316-z
PMCID: PMC7473811
PMID: 32887573 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that they have no competing 
interests. LV received consultancy fees from Bayer, MSD, Genentech, Servier and 
Pierre Fabre but these had no relation with the content of this publication.


39. Ann Oncol. 2018 Nov 1;29(11):2240-2246. doi: 10.1093/annonc/mdy410.

The prognostic impact of consensus molecular subtypes (CMS) and its predictive 
effects for bevacizumab benefit in metastatic colorectal cancer: molecular 
analysis of the AGITG MAX clinical trial.

Mooi JK(1), Wirapati P(2), Asher R(3), Lee CK(3), Savas P(4), Price TJ(5), 
Townsend A(5), Hardingham J(6), Buchanan D(7), Williams D(8), Tejpar S(9), 
Mariadason JM(10), Tebbutt NC(11).

Author information:
(1)Olivia Newton-John Cancer Research Institute, Heidelberg; Department of 
Medicine, University of Melbourne, Melbourne, Australia.
(2)Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, 
Switzerland.
(3)NHMRC Clinical Trials Centre, University of Sydney, Sydney.
(4)Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, 
Melbourne.
(5)Medical Oncology, The Queen Elizabeth Hospital, Woodville; School of 
Medicine, University of Adelaide, Adelaide.
(6)School of Medicine, University of Adelaide, Adelaide; The Basil Hetzel 
Institute, The Queen Elizabeth Hospital, Woodville.
(7)Colorectal Oncogenomics Group, Department of Clinical Pathology, The 
University of Melbourne, Melbourne; University of Melbourne Centre for Cancer 
Research, Victorian Comprehensive Cancer Centre, Parkville; Genetic Medicine and 
Family Cancer Clinic, Royal Melbourne Hospital, Parkville.
(8)Olivia Newton-John Cancer Research Institute, Heidelberg; Department of 
Pathology, Austin Health, Heidelberg; Department of Pathology, University of 
Melbourne, Melbourne, Australia.
(9)Oncology, University Hospital Leuven, Leuven, Belgium.
(10)Olivia Newton-John Cancer Research Institute, Heidelberg; School of Cancer 
Medicine, La Trobe University, Melbourne.
(11)Medical Oncology, Austin Health, Heidelberg, Australia. Electronic address: 
niall.tebbutt@onjcri.org.au.

BACKGROUND: The consensus molecular subtypes (CMS) is a transcriptome-based 
classification of colorectal cancer (CRC) initially described in early-stage 
cohorts, but the associations of CMS with treatment outcomes in the metastatic 
setting are yet to be established. This study aimed to evaluate the prognostic 
impact of CMS classification and its predictive effects for bevacizumab benefit 
in metastatic CRC by correlative analysis of the AGITG MAX trial.
PATIENTS AND METHODS: The MAX trial previously reported improved 
progression-free survival (PFS) for the addition of bevacizumab (B) to 
chemotherapy [capecitabine (C)±mitomycin (M)]. Archival primary tumours from 237 
patients (50% of trial population) underwent gene expression profiling and 
classification into CMS groups. CMS groups were correlated to PFS and overall 
survival (OS). The interaction of CMS with treatment was assessed by 
proportional hazards model.
RESULTS: The distribution of CMS in MAX were CMS1 18%, CMS2 47%, CMS3 12%, CMS4 
23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 
was the predominant subtype in left-sided. CMS was prognostic of OS (P = 0.008), 
with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an 
independent prognostic factor in a multivariate analysis. There was a 
significant interaction between CMS and treatment (P-interaction = 0.03), for 
PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS1, 2, 3 and 4: 
0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25), 
respectively.
CONCLUSIONS: This exploratory study found that CMS stratified OS outcomes in 
metastatic CRC regardless of first-line treatment, with prognostic effects of 
CMS groups distinct from those previously reported in early-stage cohorts. In 
CMS associations with treatment, CMS2 and possibly CMS3 tumours may 
preferentially benefit from the addition of bevacizumab to first-line 
capecitabine-based chemotherapy, compared with other CMS groups. Validation of 
these findings in additional cohorts is warranted.
CLINICAL TRIAL NUMBER: This is a molecular sub-study of MAX clinical trial 
(NCT00294359).

DOI: 10.1093/annonc/mdy410
PMID: 30247524 [Indexed for MEDLINE]


40. Cell Death Dis. 2021 Oct 21;12(11):978. doi: 10.1038/s41419-021-04270-x.

Everolimus and plicamycin specifically target chemoresistant colorectal cancer 
cells of the CMS4 subtype.

Deng J(#)(1)(2)(3)(4), Tian AL(#)(2)(3)(4), Pan H(2)(3)(4), Sauvat A(3)(4), 
Leduc M(3)(4), Liu P(3)(4), Zhao L(3)(4), Zhang S(3)(4), Chen H(2)(3)(4), Taly 
V(4), Laurent-Puig P(4)(5), Senovilla L(3)(4)(5), Li Y(6), Kroemer 
G(7)(8)(9)(10)(11), Kepp O(12)(13).

Author information:
(1)MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of 
Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
(2)Université Paris Sud, Paris Saclay, Faculty of Medicine, Kremlin Bicêtre, 
France.
(3)Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, 
Université Paris Saclay, Villejuif, France.
(4)Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le 
cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 
5096, Institut Universitaire de France, Paris, France.
(5)Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), 
Universidad de Valladolid - CSIC, Valladolid, Spain.
(6)MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of 
Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. 
lsslyq@mail.sysu.edu.cn.
(7)Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, 
Université Paris Saclay, Villejuif, France. kroemer@orange.fr.
(8)Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le 
cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 
5096, Institut Universitaire de France, Paris, France. kroemer@orange.fr.
(9)Pôle de Biologie, Institut du Cancer Paris Carpem, APHP, Hôpital Européen 
Georges Pompidou, Paris, France. kroemer@orange.fr.
(10)Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, 
Suzhou, Jiangsu, China. kroemer@orange.fr.
(11)Karolinska Institutet, Department of Women's and Children's Health, 
Karolinska University Hospital, Stockholm, Sweden. kroemer@orange.fr.
(12)Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, 
Université Paris Saclay, Villejuif, France. captain.olsen@gmail.com.
(13)Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le 
cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 
5096, Institut Universitaire de France, Paris, France. captain.olsen@gmail.com.
(#)Contributed equally

Colorectal cancers (CRC) can be classified into four consensus molecular 
subtypes (CMS), among which CMS1 has the best prognosis, contrasting with CMS4 
that has the worst outcome. CMS4 CRC is notoriously resistant against 
therapeutic interventions, as demonstrated by preclinical studies and 
retrospective clinical observations. Here, we report the finding that two 
clinically employed agents, everolimus (EVE) and plicamycin (PLI), efficiently 
target the prototypic CMS4 cell line MDST8. As compared to the prototypic CMS1 
cell line LoVo, MDST8 cells treated with EVE or PLI demonstrated stronger 
cytostatic and cytotoxic effects, increased signs of apoptosis and autophagy, as 
well as a more pronounced inhibition of DNA-to-RNA transcription and 
RNA-to-protein translation. Moreover, nontoxic doses of EVE and PLI induced the 
shrinkage of MDST8 tumors in mice, yet had only minor tumor growth-reducing 
effects on LoVo tumors. Altogether, these results suggest that EVE and PLI 
should be evaluated for their clinical activity against CMS4 CRC.

© 2021. The Author(s).

DOI: 10.1038/s41419-021-04270-x
PMCID: PMC8531384
PMID: 34675191 [Indexed for MEDLINE]

Conflict of interest statement: GK and OK are cofounders of Samsara 
Therapeutics. GK is a cofounder of Therafast Bio. The remaining authors declare 
no competing interests.


41. World J Clin Oncol. 2021 Nov 24;12(11):1000-1008. doi: 
10.5306/wjco.v12.i11.1000.

Consensus molecular subtypes of colorectal cancer in clinical practice: A 
translational approach.

Valenzuela G(1), Canepa J(1), Simonetti C(1), Solo de Zaldívar L(1), Marcelain 
K(1), González-Montero J(2).

Author information:
(1)Basic and Clinical Oncology Department, University of Chile, Santiago 
8380453, Chile.
(2)Basic and Clinical Oncology Department, University of Chile, Santiago 
8380453, Chile. jagonzalez@ug.uchile.cl.

The identification of several genetic mutations in colorectal cancer (CRC) has 
allowed a better comprehension of the prognosis and response to different 
antineoplastic treatments. Recently, through a systematic process, consensus 
molecular subtypes (CMS) have been described to characterize genetic and 
molecular mutations in CRC patients. Through CMS, CRC patients can be 
categorized into four molecular subtypes of CRC by wide transcriptional genome 
analysis. CMS1 has microsatellite instability and mutations in CIMP and BRAF 
pathways. CMS2, distinguished by mutations in specific pathways linked to 
cellular metabolism, also has a better prognosis. CMS3 has a KRAS mutation as a 
hallmark. CMS4 presents mutations in fibrogenesis pathways and 
mesenchymal-epithelial transition, associated with a worse prognosis. CMS 
classification can be a meaningful step in providing possible answers to 
important issues in CRC, such as the use of adjuvant chemotherapy in stage II, 
personalized first-line chemotherapy for metastasic CRC, and possible new target 
treatments that address specific pathways in each molecular subtype. 
Understanding CMS is a crucial step in personalized medicine, although 
prospective clinical trials selecting patients by CMS are required to pass 
proof-of-concept before becoming a routine clinical tool in oncology routine 
care.

©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights 
reserved.

DOI: 10.5306/wjco.v12.i11.1000
PMCID: PMC8641009
PMID: 34909395

Conflict of interest statement: Conflict-of-interest statement: The authors have 
no conflicts of interest to declare.


42. Biomedicines. 2021 Dec 2;9(12):1815. doi: 10.3390/biomedicines9121815.

SSCS: A Stage Supervised Subtyping System for Colorectal Cancer.

Zhao L(1), Pan Y(2).

Author information:
(1)Department of Medicine, Stanford University, Palo Alto, CA 94305, USA.
(2)Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 
Shenzhen University Town, Shenzhen 518055, China.

Colorectal cancer (CRC) is heterogeneous and deadly, and the exact cause of the 
disease is unknown. Recent progress indicated that CRC is not a single disease, 
but a group of diseases with significant heterogeneity. Three previous CRC 
subtyping systems: microsatellite instability (MSI), consensus molecular 
subtypes (CMS), and tumor-node-metastases (TNM) stage were evaluated for their 
molecular and clinical implications. Results suggested that the MSI and CMS 
systems are prognostic and predictive mostly in early-stage CRC. As the stage 
remains an influential factor for CRC subtype analysis, we developed a new 
subtyping system named stage supervised CRC subtypes (SSCS), in order to better 
stratify CRC biologically and clinically. Our subtyping system can be used to 
classify CRC patients into five subtypes (SSCS1-5). SSCS1 was found to have the 
highest frequency of MSI-H cases compared to the remaining four subtypes. SSCS2 
had the most favorable prognosis, whereas the worst prognosis was seen in SSCS4. 
SSCS3 had cell cycle and metabolism-related gene sets upregulation, and SSCS5 
subtype was enriched with amplicon-associated gene sets. Moreover, 
tumor-infiltrating fibroblast was found to be predictive for poor disease-free 
survival (DFS) only within the SSCS4 subtype. Conventional dendritic cells 
(cDC), on the contrary, were associated with favorable DFS in the SSCS3 subtype. 
Our study provides a new subtyping system SSCS, which can be used for better 
stratify CRC patients compared to current standards. Further exploration of the 
subtype-specific cell types has the potential to be novel therapies for CRC.

DOI: 10.3390/biomedicines9121815
PMCID: PMC8698601
PMID: 34944631

Conflict of interest statement: The authors declare that they have no competing 
interests.


43. Oncogene. 2020 Jan;39(5):987-1003. doi: 10.1038/s41388-019-1047-4. Epub 2019 Oct 
7.

Targeting chemoresistant colorectal cancer via systemic administration of a BMP7 
variant.

Veschi V(1), Mangiapane LR(1), Nicotra A(1), Di Franco S(1), Scavo E(1), Apuzzo 
T(1), Sardina DS(1), Fiori M(2), Benfante A(1), Colorito ML(1), Cocorullo G(1), 
Giuliante F(3)(4), Cipolla C(1), Pistone G(5), Bongiorno MR(5), Rizzo A(6), Tate 
CM(7), Wu X(7), Rowlinson S(7), Stancato LF(7), Todaro M(5), De Maria 
R(#)(8)(9), Stassi G(#)(10).

Author information:
(1)Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), 
University of Palermo, 90127, Palermo, Italy.
(2)Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 
Rome, Italy.
(3)Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, 00168, 
Rome, Italy.
(4)Fondazione Policlinico Universitario A. Gemelli-I.R.C.C.S., 00168, Rome, 
Italy.
(5)Department of Health Promotion Sciences, Internal Medicine and Medical 
Specialties (PROMISE), University of Palermo, 90127, Palermo, Italy.
(6)Pathology Unit, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
(7)Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, 
USA.
(8)Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, 00168, 
Rome, Italy. ruggero.demaria@unicatt.it.
(9)Fondazione Policlinico Universitario A. Gemelli-I.R.C.C.S., 00168, Rome, 
Italy. ruggero.demaria@unicatt.it.
(10)Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), 
University of Palermo, 90127, Palermo, Italy. giorgio.stassi@unipa.it.
(#)Contributed equally

Despite intense research and clinical efforts, patients affected by advanced 
colorectal cancer (CRC) have still a poor prognosis. The discovery of colorectal 
(CR) cancer stem cell (CSC) as the cell compartment responsible for tumor 
initiation and propagation may provide new opportunities for the development of 
new therapeutic strategies. Given the reduced sensitivity of CR-CSCs to 
chemotherapy and the ability of bone morphogenetic proteins (BMP) to promote 
colonic stem cell differentiation, we aimed to investigate whether an enhanced 
variant of BMP7 (BMP7v) could sensitize to chemotherapy-resistant CRC cells and 
tumors. Thirty-five primary human cultures enriched in CR-CSCs, including four 
from chemoresistant metastatic lesions, were used for in vitro studies and to 
generate CR-CSC-based mouse avatars to evaluate tumor growth and progression 
upon treatment with BMP7v alone or in combination with standard therapy or PI3K 
inhibitors. BMP7v treatment promotes CR-CSC differentiation and recapitulates 
the cell differentiation-related gene expression profile by suppressing Wnt 
pathway activity and reducing mesenchymal traits and survival of CR-CSCs. 
Moreover, in CR-CSC-based mouse avatars, BMP7v exerts an antiangiogenic effect 
and sensitizes tumor cells to standard chemotherapy regardless of the 
mutational, MSI, and CMS profiles. Of note, tumor harboring PIK3CA mutations 
were affected to a lower extent by the combination of BMP7v and chemotherapy. 
However, the addition of a PI3K inhibitor to the BMP7v-based combination 
potentiates PIK3CA-mutant tumor drug response and reduces the metastatic lesion 
size. These data suggest that BMP7v treatment may represent a useful 
antiangiogenic and prodifferentiation agent, which renders CSCs sensitive to 
both standard and targeted therapies.

DOI: 10.1038/s41388-019-1047-4
PMCID: PMC6989400
PMID: 31591478 [Indexed for MEDLINE]

Conflict of interest statement: Authors affiliated with Eli Lilly and Company 
have Eli Lilly and Company shares received via 401 (k) and bonus plans. RDM is 
an Advisory Board member of HiberCell. RDM and GS are recipients of grants from 
HiberCell. All other authors declare that they have no conflict of interest.


44. ESMO Open. 2021 Apr;6(2):100073. doi: 10.1016/j.esmoop.2021.100073. Epub 2021 
Mar 3.

Prognostic and predictive impact of consensus molecular subtypes and CRCAssigner 
classifications in metastatic colorectal cancer: a translational analysis of the 
TRIBE2 study.

Borelli B(1), Fontana E(2), Giordano M(3), Antoniotti C(1), Lonardi S(4), 
Bergamo F(4), Pietrantonio F(5), Morano F(6), Tamburini E(7), Boccaccino A(1), 
Santini D(8), Zucchelli G(1), Pella N(9), Maiello E(10), Passardi A(11), 
Zaniboni A(12), Ugolini C(13), Fontanini G(3), Falcone A(1), Nyamundanda G(14), 
Sadanandam A(15), Cremolini C(16).

Author information:
(1)Department of Translational Research and New Technologies in Medicine and 
Surgery, Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, 
University of Pisa, Pisa, Italy.
(2)Division of Molecular Pathology, The Institute of Cancer Research, London, 
UK; Sarah Cannon Research Institute, London, UK.
(3)Department of Surgical, Medical, Molecular Pathology and Critical Area, 
University of Pisa, Pisa, Italy.
(4)Unit of Medical Oncology 1, Department of Oncology, Istituto Oncologico 
Veneto, IRCCS, Padua, Italy.
(5)Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori 
di Milano, Milan, Italy; Oncology and Hemato-Oncology Department, University of 
Milan, Milan, Italy.
(6)Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori 
di Milano, Milan, Italy.
(7)Oncology Unit, Ospedale degli Infermi, Rimini, Italy.
(8)Department of Medical Oncology, University Campus Biomedico, Rome, Italy.
(9)Department of Oncology, University and General Hospital, Udine, Italy.
(10)Oncology Unit, Foundation IRCCS Casa Sollievo della Sofferenza, San Giovanni 
Rotondo, Italy.
(11)Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio 
e la Cura dei Tumori (IRST) IRCSS, Meldola, Italy.
(12)Medical Oncology Unit, Fondazione Poliambulanza, Brescia, Italy.
(13)Unit of Pathological Anatomy, Azienda Ospedaliero-Universitaria Pisana, 
Pisa, Italy.
(14)Division of Molecular Pathology, The Institute of Cancer Research, London, 
UK.
(15)Division of Molecular Pathology, The Institute of Cancer Research, London, 
UK. Electronic address: anguraj.sadanandam@icr.ac.uk.
(16)Department of Translational Research and New Technologies in Medicine and 
Surgery, Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, 
University of Pisa, Pisa, Italy. Electronic address: chiaracremolini@gmail.com.

INTRODUCTION: The consensus molecular subtypes (CMS) demonstrated prognostic 
value in metastatic colorectal cancer (mCRC). Similarly, a prognostic impact was 
suggested for the pre-consensus CRCAssigner (CRCA) classifier in early stages. 
The potential predictive role of these classifiers with regard to the choice of 
the first-line therapy has not been established. We investigated the prognostic 
and predictive impact of CMS and CRCA subtypes among mCRC patients treated in 
the TRIBE2 study.
METHODS: Among 679 randomized patients, 426 and 428 (63%) samples were profiled 
according to CMS and CRCA classifications, respectively. The prognostic and 
predictive impact of both CMS and CRCA subtypes was investigated with univariate 
and multivariate analyses for progression-free survival (PFS), PFS 2 (PFS2), and 
overall survival (OS).
RESULTS: Significant associations of CMS and CRCA subtypes with PFS, PFS2, and 
OS were demonstrated; the CMS classifier confirmed its independent prognostic 
value in the multivariable model (P value for PFS/PFS2/OS = 0.01/0.07/0.08). The 
effect of treatment intensification was independent of CMS subtypes (P value for 
interaction for PFS/PFS2/OS = 0.88/0.75/0.55). A significant interaction effect 
between CRCA subtypes and treatment arm was demonstrated in PFS (P = 0.02), PFS2 
(P = 0.01), and OS (P = 0.008). The benefit of FOLFOXIRI seemed more relevant in 
the stem-like (PFS, hazard ratio = 0.60; P = 0.03) and mixed subtypes (hazard 
ratio = 0.44; P = 0.002). These findings were confirmed in a subgroup of 
patients of the previous TRIBE study.
CONCLUSIONS: We confirmed the independent prognostic role of CMS classification 
in mCRC independently of RAS/BRAF status. CRCA classification may help 
identifying subgroups of patients who may derive more benefit from 
FOLFOXIRI/bevacizumab.

Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/j.esmoop.2021.100073
PMCID: PMC8103536
PMID: 33676295 [Indexed for MEDLINE]

Conflict of interest statement: Disclosure AS received research funding from 
Bristol-Myers Squibb, Merck KGaA, and Pierre Fabre. Patents: (i) ‘Colorectal 
cancer classification with differential prognosis and personalized therapeutic 
responses’ (patent number PCT/IB2013/060416); (ii) ‘Prognostic and treatment 
response predictive method’ [European (EP) patent application number: 
18792565.6], and (iii) ‘Patient classification and prognostic method’ 
(international patent application number: PCT/EP2019/053845). CC is a 
consultant/advisory board member for Roche, Amgen, Bayer, Merck Serono, Servier. 
AF is a consultant/advisory board member for Bayer, Roche, Amgen, Eli-Lilly, 
Merck Serono, Sanofi, Servier. All remaining authors have declared no conflicts 
of interest.


45. Int Biol Biomed J. 2017 Summer;3(3):105-111. Epub 2017 Jun 13.

Consensus Molecular Subtypes of Colorectal Cancer and their Clinical 
Implications.

Thanki K(1), Nicholls ME(1), Gajjar A(1), Senagore AJ(1), Qiu S(2), Szabo C(3), 
Hellmich MR(1), Chao C(1).

Author information:
(1)Department of Surgery, University of Texas Medical Branch at Galveston, 
Galveston, Texas, USA.
(2)Department of Surgical Pathology, University of Texas Medical Branch at 
Galveston, Galveston, Texas, USA.
(3)Department of Anesthesiology, University of Texas Medical Branch at 
Galveston, Galveston, Texas, USA.

The colorectal cancer (CRC) Subtyping Consortium has unified six independent 
molecular classification systems, based on gene expression data, into a single 
consensus system with four distinct groups, known as the Consensus Molecular 
Subtypes (CMS); clinical implications are discussed in this review. This article 
is based on a literature review relevant to the CMS of CRC indexed in PubMed (US 
National Library of Medicine) as well as the authors' own published data. The 
CMS were determined and correlated with epigenomic, transcriptomic, 
microenvironmental, genetic, prognostic and clinical characteristics. The CMS1 
subtype is immunogenic and hypermutated. CMS2 tumors are activated by the 
WNT-β-catenin pathway and have the highest overall survival. CMS3 feature a 
metabolic cancer phenotype and CMS4 cancers have the worst survival and have a 
strong stromal gene signature. The Consensus Molecular Subtypes of CRC may 
better inform clinicians of prognosis, therapeutic response, and potential novel 
therapeutic strategies.

PMCID: PMC5557054
PMID: 28825047

Conflict of interest statement: CONFLICT OF INTEREST M.R.H., C.S., and C.C. are 
officers and/or shareholders of CBS Therapeutics Inc., an UTMB spin-off company 
involved in research and development of H2S biosynthesis inhibitors for the 
therapy of cancer. The other authors declare no potential conflicts of interest.


46. J Clin Oncol. 2021 Dec 10;39(35):3887-3889. doi: 10.1200/JCO.21.01993. Epub 2021 
Sep 20.

Transarterial Radioembolization in Patients With Unresectable Colorectal Cancer 
Liver Metastases.

Lentz RW(1), Messersmith WA(1).

Author information:
(1)Division of Medical Oncology, Department of Medicine, University of Colorado 
Cancer Center, Aurora, CO.

Comment on
    J Clin Oncol. 2021 Dec 10;39(35):3897-3907.

DOI: 10.1200/JCO.21.01993
PMID: 34541862 [Indexed for MEDLINE]

Conflict of interest statement: Wells A. MessersmithConsulting or Advisory Role: 
Five Prime Therapeutics, QED TherapeuticsResearch Funding: Pfizer, 
Roche/Genentech, OncoMed, Immunomedics, Alexo Therapeutics, Takeda, D3, 
BeigeneOther Relationship: https://openpaymentsdata.cms.gov/physician/868582No 
other potential conflicts of interest were reported.


47. Genes Dis. 2019 Oct 30;8(2):133-145. doi: 10.1016/j.gendis.2019.10.013. 
eCollection 2021 Mar.

Molecular subtypes of colorectal cancer: An emerging therapeutic opportunity for 
personalized medicine.

Singh MP(1), Rai S(1), Pandey A(1), Singh NK(1), Srivastava S(1).

Author information:
(1)Department of Biotechnology, Motilal Nehru National Institute of Technology, 
Allahabad, UP, 211004, India.

Molecular subtypes-based therapies offer new potential framework for desired and 
precise outcome in clinical settings. Current treatment strategies in colorectal 
cancer are largely 'one drug fit all' model for patients that display same 
pathological conditions. However, CRC is a very heterogenous set of malignancy 
that does not support for above criteria. Each subtype displays different 
pathological and genetic signatures. Based on these features, therapeutic 
stratification for individual patients may be designed, which may ultimately 
lead to improved therapeutic outcomes. In this comprehensive review, we have 
attempted to briefly outline major CRC pathways. A detailed overview of 
molecular subtypes and their clinical significance has been discussed. Present 
and future methods, governing CRC subtyping in the era of personalized therapy 
with a special emphasis on CMS subtypes of CRC has been reviewed. Together, 
discovery and validation of new CRC patient stratification methods, screening 
for novel therapeutic targets, and enhanced diagnosis of CRC may improve the 
treatment outcome.

© 2019 Chongqing Medical University. Production and hosting by Elsevier B.V.

DOI: 10.1016/j.gendis.2019.10.013
PMCID: PMC8099693
PMID: 33997160


48. J Exp Clin Cancer Res. 2021 Jan 6;40(1):15. doi: 10.1186/s13046-020-01811-8.

Vulnerability to low-dose combination of irinotecan and niraparib in ATM-mutated 
colorectal cancer.

Vitiello PP(1), Martini G(1), Mele L(2), Giunta EF(1), De Falco V(1), Ciardiello 
D(1), Belli V(1), Cardone C(1), Matrone N(1), Poliero L(1), Tirino V(2), 
Napolitano S(1), Della Corte C(1), Selvaggi F(3), Papaccio G(2), Troiani T(1), 
Morgillo F(1), Desiderio V(2), Ciardiello F(1), Martinelli E(4).

Author information:
(1)Department of Precision Medicine, Medical Oncology, Università degli Studi 
della Campania Luigi Vanvitelli, Naples, Campania, Italy.
(2)Department of Experimental Medicine, Università degli Studi della Campania 
Luigi Vanvitelli, Naples, Campania, Italy.
(3)Department of Medical, Surgical, General and oncology surgery, Neurologic, 
Metabolic and Ageing Sciences, Università degli Studi della Campania Luigi 
Vanvitelli, Naples, Campania, Italy.
(4)Department of Precision Medicine, Medical Oncology, Università degli Studi 
della Campania Luigi Vanvitelli, Naples, Campania, Italy. 
erika.martinelli@unicampania.it.

BACKGROUND: Despite the advancements in new therapies for colorectal cancer 
(CRC), chemotherapy still constitutes the mainstay of the medical treatment. For 
this reason, new strategies to increase the efficacy of chemotherapy are 
desirable. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have shown to increase 
the activity of DNA damaging chemotherapeutics used in the treatment of CRC, 
however previous clinical trials failed to validate these results and pointed 
out dose-limiting toxicities that hamper the use of such combinations in 
unselected CRC patients. Nevertheless, in these studies little attention was 
paid to the mutational status of homologous recombination repair (HRR) genes.
METHODS: We tested the combination of the PARPi niraparib with either 
5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly 
annotated CRC cell lines, encompassing the 4 consensus molecular subtypes 
(CMSs). Synergism was calculated using the Chou-Talalay method for drug 
interaction. A correlation between synergism and genetic alterations in genes 
involved in homologous recombination (HR) repair was performed. We used 
clonogenic assays, mice xenograft models and patient-derived 3D spheroids to 
validate the results. The induction of DNA damage was studied by 
immunofluorescence.
RESULTS: We showed that human CRC cell lines, as well as patient-derived 3D 
spheroids, harboring pathogenic ATM mutations are significantly vulnerable to 
PARPi/chemotherapy combination at low doses, regardless of consensus molecular 
subtypes (CMS) and microsatellite status. The strongest synergism was shown for 
the combination of niraparib with irinotecan, and the presence of ATM mutations 
was associated to a delay in the resolution of double strand breaks (DSBs) 
through HRR and DNA damage persistence.
CONCLUSIONS: This work demonstrates that a numerically relevant subset of CRCs 
carrying heterozygous ATM mutations may benefit from the combination treatment 
with low doses of niraparib and irinotecan, suggesting a new potential approach 
in the treatment of ATM-mutated CRC, that deserves to be prospectively validated 
in clinical trials.

DOI: 10.1186/s13046-020-01811-8
PMCID: PMC7789007
PMID: 33407715 [Indexed for MEDLINE]

Conflict of interest statement: EM: advisory board for Amgen, Bayer, Merck, 
Roche, Sanofi, Servier, Biocartis and expert opinion for ESMO (European Society 
of Medical Oncology). TT: advisory board for Amgen, Bayer, Merck, Novartis, 
Roche, Sanofi. FM: advisory board for Lilly, MSD. FC: advisory board for Merck, 
Roche, Amgen, Bayer, Servier, Symphogen,Pfizer and research funding from Roche, 
Merck, Amgen, Bayer, Ipsen. All other Authors declare no potential conflicts of 
interest regarding the following manuscript.


49. PLoS One. 2021 Dec 31;16(12):e0262198. doi: 10.1371/journal.pone.0262198. 
eCollection 2021.

Transcriptomic profiling of adjuvant colorectal cancer identifies three key 
prognostic biological processes and a disease specific role for granzyme B.

Daemen A(1), Udyavar AR(1), Sandmann T(1), Li C(2), Bosch LJW(2), O'Gorman W(3), 
Li Y(2), Au-Yeung A(2), Takahashi C(3), Kabbarah O(2), Bourgon R(1), Hegde P(2), 
Bais C(2), Das Thakur M(2).

Author information:
(1)Bioinformatics & Computational Biology, Genentech Inc., South San Francisco, 
California, United States of America.
(2)Oncology Biomarker Development, Genentech Inc., South San Francisco, 
California, United States of America.
(3)OMNI Biomarker Development, Genentech Inc., South San Francisco, California, 
United States of America.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, 
with a 5% 5-year survival rate for metastatic disease, yet with limited 
therapeutic advancements due to insufficient understanding of and inability to 
accurately capture high-risk CRC patients who are most likely to recur. We aimed 
to improve high-risk classification by identifying biological pathways 
associated with outcome in adjuvant stage II/III CRC.
METHODS AND FINDINGS: We included 1062 patients with stage III or high-risk 
stage II colon carcinoma from the prospective three-arm randomized phase 3 AVANT 
trial, and performed expression profiling to identify a prognostic signature. 
Data from validation cohort GSE39582, The Cancer Genome Atlas, and cell lines 
were used to further validate the prognostic biology. Our retrospective analysis 
of the adjuvant AVANT trial uncovered a prognostic signature capturing three 
biological functions-stromal, proliferative and immune-that outperformed the 
Consensus Molecular Subtypes (CMS) and recurrence prediction signatures like 
Oncotype Dx in an independent cohort. Importantly, within the immune component, 
high granzyme B (GZMB) expression had a significant prognostic impact while 
other individual T-effector genes were less or not prognostic. In addition, we 
found GZMB to be endogenously expressed in CMS2 tumor cells and to be prognostic 
in a T cell independent fashion. A limitation of our study is that these 
results, although robust and derived from a large dataset, still need to be 
clinically validated in a prospective study.
CONCLUSIONS: This work furthers our understanding of the underlying biology that 
propagates stage II/III CRC disease progression and provides scientific 
rationale for future high-risk stratification and targeted treatment evaluation 
in biomarker defined subpopulations of resectable high-risk CRC. Our results 
also shed light on an alternative GZMB source with context-specific implications 
on the disease's unique biology.

DOI: 10.1371/journal.pone.0262198
PMCID: PMC8719661
PMID: 34972191 [Indexed for MEDLINE]

Conflict of interest statement: All authors were employees of, and may have been 
shareholders of, Genentech/Roche at the time this work was completed. This does 
not alter our adherence to PLOS ONE policies on sharing data and materials.


50. Cancers (Basel). 2021 Feb 14;13(4):801. doi: 10.3390/cancers13040801.

AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is 
Associated with Epithelial-Mesenchymal Transition.

Buikhuisen JY(1)(2), Gomez Barila PM(1)(2), Torang A(1)(2), Dekker D(1)(2), de 
Jong JH(1)(2), Cameron K(1)(2), Vitale S(3)(4), Stassi G(5), van Hooff SR(1)(2), 
Castro MAA(6), Vermeulen L(1)(2), Medema JP(1)(2).

Author information:
(1)Laboratory for Experimental Oncology and Radiobiology, Center for 
Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, 
University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
(2)Oncode Institute, 3521 AL Utrecht, The Netherlands.
(3)Dipartimento di Medicina e Chirurgia Traslazionale, Istituto di Patologia 
Generale, Università Cattolica del Sacro Cuore, 20123 Milano, Italy.
(4)Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 
00161 Rome, Italy.
(5)Cellular and Molecular Oncology Section, Department of Surgical, Oncological 
and Stomatological Sciences, University of Palermo, 90127 Palermo, Italy.
(6)Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, 
81520-260 Curitiba, Brazil.

Colorectal cancer (CRC) is a heterogeneous disease that can currently be 
subdivided into four distinct consensus molecular subtypes (CMS) based on gene 
expression profiling. The CMS4 subtype is marked by high expression of 
mesenchymal genes and is associated with a worse overall prognosis compared to 
other CMSs. Importantly, this subtype responds poorly to the standard therapies 
currently used to treat CRC. We set out to explore what regulatory signalling 
networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing 
which kinases were more highly expressed in this subtype compared to others. We 
found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, 
patient derived xenograft (PDX) models and in (primary) cell cultures 
representing CMS4. Importantly, chemical inhibition or knockout of this gene 
hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle 
regulator p27KIP1. Furthermore, high AKT3 expression was associated with high 
expression of epithelial-mesenchymal transition (EMT) genes, and this 
observation could be expanded to cell lines representing other carcinoma types. 
More importantly, this association allowed for the identification of CRC 
patients with a high propensity to metastasise and an associated poor prognosis. 
High AKT3 expression in the tumour epithelial compartment may thus be used as a 
surrogate marker for EMT and may allow for a selection of CRC patients that 
could benefit from AKT3-targeted therapy.

DOI: 10.3390/cancers13040801
PMCID: PMC7918753
PMID: 33673003

Conflict of interest statement: The authors declare no conflict of interest.


51. Gut. 2021 Sep 8:gutjnl-2021-325193. doi: 10.1136/gutjnl-2021-325193. Online 
ahead of print.

Patients with mesenchymal tumours and high Fusobacteriales prevalence have worse 
prognosis in colorectal cancer (CRC).

Salvucci M(1), Crawford N(2), Stott K(2), Bullman S(3), Longley DB(2), Prehn 
JHM(4).

Author information:
(1)Centre for Systems Medicine, Department of Physiology and Medical Physics, 
Royal College of Surgeons in Ireland, Dublin, Ireland.
(2)Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry 
and Biomedical Science, Queen's University Belfast, Belfast, UK.
(3)Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, 
USA.
(4)Centre for Systems Medicine, Department of Physiology and Medical Physics, 
Royal College of Surgeons in Ireland, Dublin, Ireland jprehn@rcsi.ie.

OBJECTIVES: Transcriptomic-based subtyping, consensus molecular subtyping (CMS) 
and colorectal cancer intrinsic subtyping (CRIS) identify a patient 
subpopulation with mesenchymal traits (CMS4/CRIS-B) and poorer outcome. Here, we 
investigated the relationship between prevalence of Fusobacterium nucleatum (Fn) 
and Fusobacteriales, CMS/CRIS subtyping, cell type composition, immune 
infiltrates and host contexture to refine patient stratification and to identify 
druggable context-specific vulnerabilities.
DESIGN: We coupled cell culture experiments with characterisation of 
Fn/Fusobacteriales prevalence and host biology/microenviroment in tumours from 
two independent colorectal cancer patient cohorts (Taxonomy: n=140, colon and 
rectal cases of The Cancer Genome Atlas (TCGA-COAD-READ) cohort: n=605).
RESULTS: In vitro, Fn infection induced inflammation via nuclear factor 
kappa-light-chain-enhancer of activated B cells/tumour necrosis factor alpha in 
HCT116 and HT29 cancer cell lines. In patients, high Fn/Fusobacteriales were 
found in CMS1, microsatellite unstable () tumours, with infiltration of M1 
macrophages, reduced M2 macrophages, and high interleukin (IL)-6/IL-8/IL-1β 
signalling. Analysis of the Taxonomy cohort suggested that Fn was prognostic for 
CMS4/CRIS-B patients, despite having lower Fn load than CMS1 patients. In the 
TCGA-COAD-READ cohort, we likewise identified a differential association between 
Fusobacteriales relative abundance and outcome when stratifying patients in 
mesenchymal (either CMS4 and/or CRIS-B) versus non-mesenchymal (neither CMS4 nor 
CRIS-B). Patients with mesenchymal tumours and high Fusobacteriales had 
approximately twofold higher risk of worse outcome. These associations were null 
in non-mesenchymal patients. Modelling the three-way association between 
Fusobacteriales prevalence, molecular subtyping and host contexture with 
logistic models with an interaction term disentangled the pathogen-host 
signalling relationship and identified aberrations (including NOTCH, CSF1-3 and 
IL-6/IL-8) as candidate targets.
CONCLUSION: This study identifies CMS4/CRIS-B patients with high 
Fn/Fusobacteriales prevalence as a high-risk subpopulation that may benefit from 
therapeutics targeting mesenchymal biology.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No 
commercial re-use. See rights and permissions. Published by BMJ.

DOI: 10.1136/gutjnl-2021-325193
PMID: 34497144

Conflict of interest statement: Competing interests: None declared.


52. NPJ Genom Med. 2021 Jul 14;6(1):59. doi: 10.1038/s41525-021-00223-7.

Metastatic heterogeneity of the consensus molecular subtypes of colorectal 
cancer.

Eide PW(#)(1)(2), Moosavi SH(#)(1)(2)(3), Eilertsen IA(1)(2)(3), Brunsell 
TH(1)(2)(3)(4), Langerud J(1)(2)(3), Berg KCG(1)(2)(3), Røsok BI(2)(4), 
Bjørnbeth BA(2)(4), Nesbakken A(2)(3)(4), Lothe RA(1)(2)(3), Sveen A(5)(6)(7).

Author information:
(1)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, Oslo, Norway.
(2)K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, 
Oslo University Hospital, Oslo, Norway.
(3)Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
(4)Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, 
Norway.
(5)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, Oslo, Norway. anita.sveen@rr-research.no.
(6)K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, 
Oslo University Hospital, Oslo, Norway. anita.sveen@rr-research.no.
(7)Institute for Clinical Medicine, University of Oslo, Oslo, Norway. 
anita.sveen@rr-research.no.
(#)Contributed equally

Gene expression-based subtypes of colorectal cancer have clinical relevance, but 
the representativeness of primary tumors and the consensus molecular subtypes 
(CMS) for metastatic cancers is not well known. We investigated the metastatic 
heterogeneity of CMS. The best approach to subtype translation was delineated by 
comparisons of transcriptomic profiles from 317 primary tumors and 295 liver 
metastases, including multi-metastatic samples from 45 patients and 14 
primary-metastasis sets. Associations were validated in an external data set 
(n = 618). Projection of metastases onto principal components of primary tumors 
showed that metastases were depleted of CMS1-immune/CMS3-metabolic signals, 
enriched for CMS4-mesenchymal/stromal signals, and heavily influenced by the 
microenvironment. The tailored CMS classifier (available in an updated version 
of the R package CMScaller) therefore implemented an approach to regress out the 
liver tissue background. The majority of classified metastases were either CMS2 
or CMS4. Nonetheless, subtype switching and inter-metastatic CMS heterogeneity 
were frequent and increased with sampling intensity. Poor-prognostic value of 
CMS1/3 metastases was consistent in the context of intra-patient tumor 
heterogeneity.

© 2021. The Author(s).

DOI: 10.1038/s41525-021-00223-7
PMCID: PMC8280229
PMID: 34262039

Conflict of interest statement: P.W.E., A.N., R.A.L., and A.S. are co-inventors 
of a pending patent application (Attorney Docket Number: INVEN-35063/US-1/PRO) 
regarding the use of HSP90 inhibitors in relation to the consensus molecular 
subtypes of colorectal cancer. A disclosure of invention of a de novo liver 
metastasis transcriptomic subtyping framework (S.H.M., R.A.L., and A.S.; not 
referred to in this manuscript) has been reported to Inven2, a technology 
transfer office and limited liability company owned by Oslo University Hospital 
and the University of Oslo. The authors have no other competing interests.


53. Exp Mol Pathol. 2021 Oct;122:104668. doi: 10.1016/j.yexmp.2021.104668. Epub 2021 
Jul 22.

The coding microsatellite mutation profile of PMS2-deficient colorectal cancer.

Bajwa-Ten Broeke SW(1), Ballhausen A(2), Ahadova A(3), Suerink M(4), 
Bohaumilitzky L(3), Seidler F(3), Morreau H(5), van Wezel T(5), Krzykalla J(6), 
Benner A(6), de Miranda NF(5), von Knebel Doeberitz M(3), Nielsen M(4), Kloor 
M(3).

Author information:
(1)Department of Genetics, University Medical Center Groningen, Groningen, the 
Netherlands; Department of Clinical Genetics, Leiden University Medical Center, 
Leiden, the Netherlands. Electronic address: s.w.ten.broeke@umcg.nl.
(2)Department of Applied Tumor Biology, Institute of Pathology, University 
Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer 
Research Center (DKFZ), Heidelberg, Germany; Department of Hematology, Oncology 
and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; 
Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, 
Heidelberg, Germany.
(3)Department of Applied Tumor Biology, Institute of Pathology, University 
Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer 
Research Center (DKFZ), Heidelberg, Germany; Molecular Medicine Partnership Unit 
(MMPU), University Hospital Heidelberg, Heidelberg, Germany.
(4)Department of Clinical Genetics, Leiden University Medical Center, Leiden, 
the Netherlands.
(5)Department of Pathology, Leiden University Medical Center, Leiden, the 
Netherlands.
(6)Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, 
Germany.

Lynch syndrome (LS) is caused by a pathogenic heterozygous germline variant in 
one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. 
LS-associated colorectal carcinomas (CRCs) are characterized by MMR deficiency 
and by accumulation of multiple insertions/deletions at coding microsatellites 
(cMS). MMR deficiency-induced variants at defined cMS loci have a driver 
function and promote tumorigenesis. Notably, PMS2 variant carriers face only a 
slightly increased risk of developing CRC. Here, we investigate whether this 
lower penetrance is also reflected by differences in molecular features and cMS 
variant patterns. Tumor DNA was extracted from formalin-fixed paraffin-embedded 
(FFPE) tissue cores or sections (n = 90). Tumors originated from genetically 
proven germline pathogenic MMR variant carriers (including 14 PMS2-deficient 
tumors). The mutational spectrum was analyzed using fluorescently labeled 
primers specific for 18 cMS previously described as mutational targets in 
MMR-deficient tumors. Immune cell infiltration was analyzed by 
immunohistochemical detection of T-cells on FFPE tissue sections. The cMS 
spectrum of PMS2-deficient CRCs did not show any significant differences from 
MLH1/MSH2-deficient CRCs. PMS2-deficient tumors, however, displayed lower 
CD3-positive T-cell infiltration compared to other MMR-deficient cancers (28.00 
vs. 55.00 per 0.1 mm2, p = 0.0025). Our study demonstrates that the spectrum of 
potentially immunogenic cMS variants in CRCs from PMS2 gene variant carriers is 
similar to that observed in CRCs from other MMR gene variant carriers. Lower 
immune cell infiltration observed in PMS2-deficient CRCs could be the result of 
alternative mechanisms of immune evasion or immune cell exclusion, similar to 
those seen in MMR-proficient tumors.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.yexmp.2021.104668
PMID: 34302852 [Indexed for MEDLINE]


54. Int J Med Sci. 2021 Sep 7;18(16):3631-3643. doi: 10.7150/ijms.63953. eCollection 
2021.

Integrated Analysis of Expression and Prognostic Values of Acyl-CoA 
Dehydrogenase short-chain in Colorectal Cancer.

Wu Q(1), Yan T(2), Chen Y(1), Chang J(1), Jiang Y(1), Zhu D(1), Wei Y(1).

Author information:
(1)Department of General Surgery, Zhongshan Hospital, Fudan University, 
Shanghai, 200032, China.
(2)Department of Cardiovascular Surgery, Zhongshan Hospital, Fudan University, 
Shanghai, 200032, China.

Background: Acyl-CoA dehydrogenase short-chain (ACADS) is a crucial enzyme in 
the fatty acid metabolism pathway located in mitochondria. However, the 
expression level and prognostic value of ACADS in colorectal cancer (CRC) remain 
unclear. Methods: The mRNA and protein expression data of ACADS was obtained 
from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis 
Consortium (CPTAC), and Oncomine. Prognostic values of ACADS were calculated 
using Kaplan-Meier survival analysis. Correlations between ACADS and immune 
infiltration were estimated using TIMER, CIBERSORT, EPIC, quanTIseq, and xCell. 
The UALCAN and MEXPRESS databases were utilized for Methylation analysis. The 
co-expression analysis based on mRNA expression and interaction network of ACADS 
were performed via several online tools. Gene Ontology (GO) and Kyoto 
Encyclopedia of Genes and Genomes (KEGG) analysis on ACADS co-expressed genes 
were performed using the Metascape. Results: The expression analysis 
demonstrated that ACADS was down-regulated in CRC tissues compared with paired 
normal tissue. Expression of ACADS was found to be significantly associated with 
clinical cancer stages and the consensus molecular subgroups (CMS) constituent 
ratio in CRC patients. Besides, lower ACADS expression was found to predict poor 
prognosis and be significantly associated with common immune checkpoint genes 
and MMR genes in CRC. ACADS expression levels were positively related to B 
cells, CD4+ T cells, CD8+ T cells, M1 macrophages, neutrophils, and Tregs, while 
negatively correlated with M0 macrophages, M2 macrophages. The methylation level 
of ACADS in normal tissues was significantly higher than that in tumor tissues, 
and several methylation sites were identified. The enrichment analysis suggested 
the co-expressed genes mainly enriched in cell mitochondrial metabolism. 
Conclusions: The present study provided multilevel evidences for expression of 
ACADS in CRC and the function of ACADS in prognostic prediction, immune 
infiltration, and methylation. ACADS might have the potential as the novel 
biomarker and therapeutic target in CRC patients.

© The author(s).

DOI: 10.7150/ijms.63953
PMCID: PMC8579304
PMID: 34790035 [Indexed for MEDLINE]

Conflict of interest statement: Competing Interests: The authors have declared 
that no competing interest exists.


55. Br J Cancer. 2018 Nov;119(10):1244-1251. doi: 10.1038/s41416-018-0230-7. Epub 
2018 Nov 2.

Tumour budding is associated with the mesenchymal colon cancer subtype and 
RAS/RAF mutations: a study of 1320 colorectal cancers with Consensus Molecular 
Subgroup (CMS) data.

Trinh A(1), Lädrach C(2), Dawson HE(2), Ten Hoorn S(3), Kuppen PJK(4), Reimers 
MS(4), Koopman M(5), Punt CJA(6), Lugli A(2), Vermeulen L(3), Zlobec I(7).

Author information:
(1)Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 
Boston, MA, USA.
(2)Institute of Pathology, University of Bern, Bern, Switzerland.
(3)Laboratory for Experimental Oncology and Radiobiology, Center for 
Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, 
University of Amsterdam, Amsterdam, The Netherlands.
(4)Department of Surgery, Leiden University Medical Center, Leiden, The 
Netherlands.
(5)Medical Oncology, University Medical Center Utrecht, Utrecht, The 
Netherlands.
(6)Medical Oncology, Academic Medical Center, University of Amsterdam, 
Amsterdam, The Netherlands.
(7)Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 
Boston, MA, USA. inti.zlobec@pathology.unibe.ch.

BACKGROUND: Tumour budding is an important prognostic factor in colorectal 
cancer (CRC). Molecular profiling of tumour buds suggests (partial) 
epithelial-mesenchymal transition and cancer stem-cell phenotype, similarly 
described in the "mesenchymal" Consensus Molecular Subtype 4 (CMS4), which 
identifies a particularly poor prognostic subgroup. Here, we determine the 
association of tumour budding with CMS classification, prognosis, and response 
to therapy.
METHODS: AMC-AJCCII-90 cohort (n = 76, stage II) was evaluated for peritumoural 
budding on H&E slides. LUMC (n = 270, stage I-IV), CAIRO (n = 504, metastatic 
CRC) and CAIRO2 (n = 472, metastatic CRC) cohorts were investigated for 
intratumoural budding using pan-cytokeratin-stained tissue microarrays. Budding 
was scored as count/area, then classified as <5 or ≥5 buds. For all cohorts, CMS 
classifications were available (gene-expression/immunohistochemistry-based 
classifiers).
RESULTS: High (≥5) budding predicted a worse outcome in multivariate analysis in 
AMC-AJCCII-90 (p = 0.018), LUMC (p < 0.0001), and CAIRO (p = 0.03), and in 
CAIRO2 (continuous variable, p = 0.02). Tumour budding counts were higher in 
CMS4 compared to epithelial CMS2/3 cancers (p < 0.01, all), and associated with 
KRAS/BRAF mutations (p < 0.01, AMC-AJCCII-90, CAIRO, CAIRO2).
CONCLUSION: Tumour budding is an adverse prognostic factor across all CRC stages 
and is associated with the mesenchymal CMS4 phenotype. KRAS/BRAF mutations are 
strongly correlated with tumour budding suggesting their involvement in the 
regulation of this process.

DOI: 10.1038/s41416-018-0230-7
PMCID: PMC6251036
PMID: 30385823 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


56. Cancers (Basel). 2021 Feb 27;13(5):1000. doi: 10.3390/cancers13051000.

Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and 
Breaks the Intestinal Stem Cell.

Sphyris N(1), Hodder MC(1)(2), Sansom OJ(1)(2).

Author information:
(1)Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, 
Glasgow G61 1BD, UK.
(2)Institute of Cancer Sciences, University of Glasgow, Garscube Estate, 
Switchback Road, Glasgow G61 1QH, UK.

The intestinal epithelium fulfils pleiotropic functions in nutrient uptake, 
waste elimination, and immune surveillance while also forming a barrier against 
luminal toxins and gut-resident microbiota. Incessantly barraged by extraneous 
stresses, the intestine must continuously replenish its epithelial lining and 
regenerate the full gamut of specialized cell types that underpin its functions. 
Homeostatic remodelling is orchestrated by the intestinal stem cell (ISC) niche: 
a convergence of epithelial- and stromal-derived cues, which maintains ISCs in a 
multipotent state. Following demise of homeostatic ISCs post injury, plasticity 
is pervasive among multiple populations of reserve stem-like cells, 
lineage-committed progenitors, and/or fully differentiated cell types, all of 
which can contribute to regeneration and repair. Failure to restore the 
epithelial barrier risks seepage of toxic luminal contents, resulting in 
inflammation and likely predisposing to tumour formation. Here, we explore how 
homeostatic niche-signalling pathways are subverted in tumorigenesis, enabling 
ISCs to gain autonomy from niche restraints ("ISC emancipation") and transform 
into cancer stem cells capable of driving tumour initiation, progression, and 
therapy resistance. We further consider the implications of the pervasive 
plasticity of the intestinal epithelium for the trajectory of colorectal cancer, 
the emergence of distinct molecular subtypes, the propensity to metastasize, and 
the development of effective therapeutic strategies.

DOI: 10.3390/cancers13051000
PMCID: PMC7957493
PMID: 33673710

Conflict of interest statement: The authors declare no competing interests.


57. Bull Cancer. 2016 Jul-Aug;103(7-8):643-50. doi: 10.1016/j.bulcan.2016.05.007. 
Epub 2016 Jun 23.

[New molecular classification of colorectal cancer, pancreatic cancer and 
stomach cancer: Towards "à la carte" treatment?].

[Article in French]

Dreyer C(1), Afchain P(1), Trouilloud I(1), André T(2).

Author information:
(1)Hôpital Saint-Antoine, service d'oncologie médicale, Paris, France.
(2)Hôpital Saint-Antoine, service d'oncologie médicale, Paris, France; 
Université Pierre-et-Marie-Curie (UPMC), 75013 Paris, France. Electronic 
address: thierry.andre@aphp.fr.

This review reports 3 of recently published molecular classifications of the 
3 main gastro-intestinal cancers: gastric, pancreatic and colorectal 
adenocarcinoma. In colorectal adenocarcinoma, 6 independent classifications were 
combined to finally hold 4 molecular sub-groups, Consensus Molecular Subtypes 
(CMS 1-4), linked to various clinical, molecular and survival data. CMS1 (14% 
MSI with immune activation); CMS2 (37%: canonical with epithelial 
differentiation and activation of the WNT/MYC pathway); CMS3 (13% metabolic with 
epithelial differentiation and RAS mutation); CMS4 (23%: mesenchymal with 
activation of TGFβ pathway and angiogenesis with stromal invasion). In gastric 
adenocarcinoma, 4 groups were established: subtype "EBV" (9%, high frequency of 
PIK3CA mutations, hypermetylation and amplification of JAK2, PD-L1 and PD-L2), 
subtype "MSI" (22%, high rate of mutation), subtype "genomically stable tumor" 
(20%, diffuse histology type and mutations of RAS and genes encoding integrins 
and adhesion proteins including CDH1) and subtype "tumors with chromosomal 
instability" (50%, intestinal type, aneuploidy and receptor tyrosine kinase 
amplification). In pancreatic adenocarcinomas, a classification in four 
sub-groups has been proposed, stable subtype (20%, aneuploidy), locally 
rearranged subtype (30%, focal event on one or two chromosoms), scattered 
subtype (36%,<200 structural variation events), and unstable subtype (14%,>200 
structural variation events, defects in DNA maintenance). Although currently 
away from the care of patients, these classifications open the way to "à la 
carte" treatment depending on molecular biology.

Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. 
All rights reserved.

DOI: 10.1016/j.bulcan.2016.05.007
PMID: 27345450 [Indexed for MEDLINE]


58. Pathol Oncol Res. 2021 Mar 10;27:587029. doi: 10.3389/pore.2021.587029. 
eCollection 2021.

Increasing Embryonic Morphogen Nodal Expression Suggests Malignant 
Transformation in Colorectal Lesions and as a Potential Marker for CMS4 Subtype 
of Colorectal Cancer.

Wang X(1)(2), Liu S(3), Cao H(3), Li X(2), Rong Y(3), Liu G(2), Du H(2), Shen 
H(1).

Author information:
(1)Department of Pathology, School of Basic Medical Sciences, Southern Medical 
University, Guangzhou, China.
(2)Department of Pathology, Guangzhou First People's Hospital, School of 
Medicine, South China University of Technology, Guangzhou, China.
(3)Department of General Medicine, State Key Laboratory of Oncology in South 
China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen 
University Cancer Center, Guangzhou, China.

Nodal, an embryonic morphogen in TGF-β family, is related with tumorigenicity 
and progression in various tumors including colorectal cancer (CRC). However, 
the difference of Nodal expression between CRC and colorectal polyps has not yet 
been investigated. Besides, whether Nodal can be used as a marker for consensus 
molecular subtype classification-4 (CMS4) of CRC is also worth studying. We 
analyzed Nodal expression in patients of CRC (161), high-grade intraepithelial 
neoplasia (HGIN, 28) and five types of colorectal polyps (116). The Nodal 
expression difference among groups and the association between Nodal expression 
and clinicopathological features were analyzed. Two categories logistic 
regression model was used to predict the odds ratio (OR) of risk factors for 
high tumor-stroma percentage (TSP), and ROC curve was used to assess the 
diagnostic value of Nodal in predicting high TSP in CRC. We found that Nodal 
expression was significantly elevated in CRC and HGIN (p < 0.0001). The 
increased expression of Nodal was related with high TSP, mismatch 
repair-proficient (pMMR) status, lymph node metastasis and advanced AJCC stage 
(p < 0.05). Besides, Nodal expression was the only risk factor for high TSP (OR 
= 6.94; p < 0.001), and ROC curve demonstrated that Nodal expression was able to 
efficiently distinguish high and low TSP. In conclusion, different expression of 
Nodal between CRC/HGIN and benign lesions is suggestive of a promoting role for 
Nodal in colorectal tumor progression. Besides, Nodal might also be used as a 
potential marker for CMS4 subtype of CRC.

Copyright © 2021 Wang, Liu, Cao, Li, Rong, Liu, Du and Shen.

DOI: 10.3389/pore.2021.587029
PMCID: PMC8262187
PMID: 34257534 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that the research was 
conducted in the absence of any commercial or financial relationships that could 
be construed as a potential conflict of interest.


59. Oncol Lett. 2019 Dec;18(6):6361-6370. doi: 10.3892/ol.2019.11055. Epub 2019 Nov 
5.

Colorectal cancer cells differentially impact migration and microRNA expression 
in endothelial cells.

Kim DY(1)(2), Lee SS(1)(2), Bae YK(1).

Author information:
(1)Center for Bioanalysis, Division of Chemical and Medical Metrology, Korea 
Research Institute of Standards and Science, Daejeon 34113, Republic of Korea.
(2)Department of Biological Sciences, Korea Advanced Institute of Science and 
Technology, Daejeon 34141, Republic of Korea.

Angiogenesis is an essential step in cancer progression and metastasis. Changes 
in the microRNA (miRNA or miR) expression profiles of endothelial cells (ECs) 
elicited by cancer cells promote angiogenesis. Vascular endothelial growth 
factor (VEGF), a key pro-angiogenic factor, influences miRNA expression in ECs; 
however, the exact role that VEGF serves in miRNA regulation during angiogenesis 
is poorly defined. The present study aimed to demonstrate the differential 
angiogenic effects on human umbilical vein endothelial cells (HUVECs) of five 
different colorectal cancer (CRC) cell lines by in vitro HUVEC migration and 
angiogenesis assays in response to CRC-conditioned medium (CM). Among the tested 
CMs, LoVo was the most effective cell line in eliciting HUVEC angiogenic 
phenotypes, at least partially due to its high VEGF level. It was also observed 
that pro-angiogenesis-regulatory miRNAs (angio-miRNA) miR-296, miR-132, miR-105 
and miR-200 were upregulated in the VEGF-rich LoVo CM compared with the 
VEGF-scarce SW620 CM. In addition, treatment with VEGF receptor 2 inhibitor 
downregulated the pro-angio-miRNAs, with the exception of miR-132, suggesting 
that VEGF, as well as additional signaling, is required for angio-miRNA 
expression. Quantitative analyses on pro-angio-miRNA target expression suggested 
that independent pathways may be involved in the regulation of their expression. 
Overall, the data from the present study indicated that multiple paracrine 
factors, including VEGF secreted by CRCs, effectively modulated angio-miRNA 
expression, thus impacting their target expression and the angiogenic phenotypes 
of HUVECs.

Copyright: © Kim et al.

DOI: 10.3892/ol.2019.11055
PMCID: PMC6888185
PMID: 31814846


60. Mol Clin Oncol. 2021 May;14(5):98. doi: 10.3892/mco.2021.2260. Epub 2021 Mar 12.

Investigation of clinicopathological characters and gene expression features in 
colorectal signet-ring cell carcinoma utilizing CMS classification.

Tajiri K(1)(2), Sudo T(1)(2), Ishi K(3), Kawahara A(4), Nagasu S(1)(2), 
Shimomura S(1), Yuge K(1), Katagiri M(1)(2), Yomoda T(1), Fujiyoshi K(1), 
Kenichi K(1), Ohchi T(1), Yoshida T(1), Mizobe T(1), Fujita F(1), Akiba J(4), 
Akagi Y(1)(2).

Author information:
(1)Department of Surgery, Kurume University Hospital, Kurume, Fukuoka 830-0011, 
Japan.
(2)Research Center for Innovative Cancer Therapy, Kurume University Hospital, 
Kurume, Fukuoka 830-0011, Japan.
(3)Biostatistics Center, Kurume University Hospital, Kurume, Fukuoka 830-0011, 
Japan.
(4)Department of Diagnostic Pathology, Kurume University Hospital, Kurume, 
Fukuoka 830-0011, Japan.

Signet ring cell carcinoma (SRCC) is a rare pathological type of colorectal 
cancer, of which the clinicopathological features and genetic background have 
not yet been fully investigated. Previous research has focused on the 
optimization of colorectal cancer treatment utilizing consensus molecular 
subtyping (CMS). However, it is not known what type of CMS would be designated 
to SRCC treatment. In the current study, of 1,350 patients diagnosed with 
colorectal cancer who underwent surgery, 14 were diagnosed with SRCC. The 
case-control cohort that fit the clinical background of the SRCC case was 
constructed. Statistical comparison between the SRCC group and the case-control 
cohort was performed among clinicopathological variables. SRCC and well to 
moderately adenocarcinoma case mRNA were submitted to microarray analysis and 
CMS analysis. Compared with the case-control cohort, the SRCC group was located 
more in the right-sided colon, the lymphatic invasion was more severe and the 
peritoneal dissemination was more frequent. The cancer-specific survival and the 
progression-free survival were significantly worse in the SRCC group compared 
with the case-control cohort. Microarray and CMS analysis identified that one 
SRCC case was significantly well assigned in the CMS 4 group and the other case 
was assigned in the CMS 1 group. Gene set analysis revealed the upregulation of 
EMT related genes and the downregulation of fatty acid, glycolysis, 
differentiation, MYC, HNF4A, DNA repair genes. In conclusion, the clinical 
characteristics of SRCC are severe but there is a possibility of the presence of 
different phenotypes according to CMS analysis.

Copyright: © Tajiri et al.

DOI: 10.3892/mco.2021.2260
PMCID: PMC7976453
PMID: 33767867

Conflict of interest statement: The authors declare that they have no competing 
interests.


61. PLoS One. 2020 Dec 17;15(12):e0241148. doi: 10.1371/journal.pone.0241148. 
eCollection 2020.

Transcriptomic and proteomic intra-tumor heterogeneity of colorectal cancer 
varies depending on tumor location within the colorectum.

Árnadóttir SS(1)(2), Mattesen TB(1)(2), Vang S(1)(2), Madsen MR(3), Madsen 
AH(2)(3), Birkbak NJ(1)(2), Bramsen JB(1)(2), Andersen CL(1)(2).

Author information:
(1)Department of Molecular Medicine, Aarhus University Hospital, Aarhus, 
Denmark.
(2)Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
(3)Surgical Research Unit, Department of Surgery, Herning Regional Hospital, 
Herning, Denmark.

BACKGROUND: Intra-tumor heterogeneity (ITH) of colorectal cancer (CRC) 
complicates molecular tumor classification, such as transcriptional subtyping. 
Differences in cellular states, biopsy cell composition, and tumor 
microenvironment may all lead to ITH. Here we analyze ITH at the transcriptomic 
and proteomic levels to ascertain whether subtype discordance between 
multiregional biopsies reflects relevant biological ITH or lack of classifier 
robustness. Further, we study the impact of tumor location on ITH.
METHODS: Multiregional biopsies from stage II and III CRC tumors were analyzed 
by RNA sequencing (41 biopsies, 14 tumors) and multiplex immune protein analysis 
(89 biopsies, 29 tumors). CRC subtyping was performed using consensus molecular 
subtypes (CMS), CRC intrinsic subtypes (CRIS), and TUMOR types. ITH-scores and 
network maps were defined to determine the origin of heterogeneity. A validation 
cohort was used with one biopsy per tumor (162 tumors).
RESULTS: Overall, inter-tumor transcriptional variation exceeded ITH, and 
subtyping calls were frequently concordant between multiregional biopsies. 
Still, some tumors had high transcriptional ITH and were classified 
discordantly. Subtyping of proximal MSS tumors were discordant for 50% of the 
tumors, this ITH was related to differences in the microenvironment. Subtyping 
of distal MSS tumors were less discordant, here the ITH was more cancer-cell 
related. The subtype discordancy reflected actual molecular ITH within the 
tumors. The relevance of the subtypes was reflected at protein level where 
several inflammation markers were significantly increased in immune related 
transcriptional subtypes, which was verified in an independent cohort (Wilcoxon 
rank sum test; p<0.05). Unsupervised hierarchical clustering of the protein data 
identified large ITH at protein level; as the multiregional biopsies clustered 
together for only 9 out of 29 tumors.
CONCLUSION: Our transcriptomic and proteomic analyses show that the tumor 
location along the colorectum influence the ITH of CRC, which again influence 
the concordance of subtyping.

DOI: 10.1371/journal.pone.0241148
PMCID: PMC7746197
PMID: 33332369 [Indexed for MEDLINE]

Conflict of interest statement: The authors have declared that no competing 
interests exist.


62. J Clin Oncol. 2022 Jan 20;40(3):282-293. doi: 10.1200/JCO.21.02554. Epub 2021 
Dec 7.

Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results 
(ABCSG-42/AFT-05/BIG-14-03).

Gnant M(1)(2), Dueck AC(3), Frantal S(2), Martin M(4)(5), Burstein HJ(6), Greil 
R(7), Fox P(8), Wolff AC(9), Chan A(10), Winer EP(6), Pfeiler G(1)(11), Miller 
KD(12), Colleoni M(13), Suga JM(14), Rubovsky G(15), Bliss JM(16), Mayer IA(17), 
Singer CF(1)(11), Nowecki Z(18), Hahn O(19), Thomson J(20), Wolmark N(21), 
Amillano K(22), Rugo HS(23), Steger GG(1), Hernando Fernández de Aránguiz 
B(5)(24), Haddad TC(25), Perelló A(26), Bellet M(27), Fohler H(2), Metzger Filho 
O(5)(28), Jallitsch-Halper A(2), Solomon K(28), Schurmans C(29), Theall KP(30), 
Lu DR(31), Tenner K(25), Fesl C(2), DeMichele A(32), Mayer EL(5); PALLAS groups 
and investigators.

Author information:
(1)Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria.
(2)ABCSG, Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria.
(3)Alliance Statistics and Data Center and Mayo Clinic, Phoenix, AZ.
(4)Hospital General Universitario Gregorio Marañón, Madrid, Spain.
(5)GEICAM Spanish Breast Cancer Group, Madrid, Spain.
(6)Dana-Farber Cancer Institute, Boston, MA.
(7)Department of Internal Medicine III with Haematology, Medical Oncology, 
Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus 
Medical University Salzburg, Salzburg Cancer Research Institute-Center of 
Clinical Cancer and Immunology Trials; Cancer Cluster Salzburg, Salzburg, 
Austria.
(8)Central West Cancer Care Centre, Orange Health Service, Orange, NSW, 
Australia.
(9)Johns Hopkins University, Baltimore, MD.
(10)Breast Cancer Research Centre-WA & Curtin University, Perth, Australia.
(11)Department of Gynecology and Gynecological Oncology, Medical University of 
Vienna, Vienna, Austria.
(12)Indiana University Melvin and Bren Simon Comprehensive Cancer Center, 
Indianapolis, IN.
(13)IEO, European Institute of Oncology, IRCCS, Milan, Italy.
(14)Kaiser Permanente Vallejo Medical Center, Vallejo, CA.
(15)National Institute of Oncology, Budapest, Hungary.
(16)The Institute of Cancer Research, London, United Kingdom.
(17)Vanderbilt University Medical Center, Nashville, TN.
(18)The Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, 
Warsaw, Poland.
(19)University of Chicago, Chicago, IL.
(20)Peninsula Health, Melbourne, Australia.
(21)NSABP Foundation, Inc, and The UPMC Hillman Cancer Center, University of 
Pittsburgh, Pittsburgh, PA.
(22)Hospital Universitari Sant Joan de Reus, Reus, Spain.
(23)University of California San Francisco Comprehensive Cancer Center, San 
Francisco, CA.
(24)Hospital Universitario de Burgos, Burgos, Spain.
(25)Mayo Clinic, Rochester, MN.
(26)Hospital Universitari Son Espases, Palma de Mallorca, Spain.
(27)Vall d'Hebron Institute of Oncology, Barcelona, Spain.
(28)Alliance Foundation Trials, Boston, MA.
(29)BIG, Brussels, Belgium.
(30)Pfizer, Cambridge, MA.
(31)Pfizer, La Jolla, CA.
(32)University of Pennsylvania, Philadelphia, PA.

PURPOSE: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for 
advanced breast cancer. In the adjuvant setting, the potential value of adding 
palbociclib to endocrine therapy for hormone receptor-positive breast cancer has 
not been confirmed.
PATIENTS AND METHODS: In the prospective, randomized, phase III PALLAS trial, 
patients with hormone receptor-positive, human epidermal growth factor receptor 
2-negative early breast cancer were randomly assigned to receive 2 years of 
palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with 
adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 
years). The primary end point of the study was invasive disease-free survival 
(iDFS); secondary end points were invasive breast cancer-free survival, distant 
recurrence-free survival, locoregional cancer-free survival, and overall 
survival.
RESULTS: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide 
over 3 years, 5,761 were included in the intention-to-treat population. At the 
final protocol-defined analysis, at a median follow-up of 31 months, iDFS events 
occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine 
therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy 
alone, with similar results between the two treatment groups (iDFS at 4 years: 
84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant 
differences were observed for secondary time-to-event end points, and subgroup 
analyses did not show any differences by subgroup. There were no new safety 
signals for palbociclib in this trial.
CONCLUSION: At this final analysis of the PALLAS trial, the addition of adjuvant 
palbociclib to standard endocrine therapy did not improve outcomes over 
endocrine therapy alone in patients with early hormone receptor-positive breast 
cancer.

DOI: 10.1200/JCO.21.02554
PMID: 34874182 [Indexed for MEDLINE]

Conflict of interest statement: Michael GnantEmployment: Sandoz (I)Honoraria: 
Amgen, Novartis, AstraZeneca, LillyConsulting or Advisory Role: Daiichi Sankyo, 
Veracyte, Tolmar¸ LifeBrain, Lilly Amylou C. DueckPatents, Royalties, Other 
Intellectual Property: Royalties from licensing fees for a patient symptom 
questionnaire (MPN-SAF) Miguel MartinHonoraria: Roche/Genentech, Lilly, Pfizer, 
Novartis, Pierre FabreConsulting or Advisory Role: Roche/Genentech, Novartis, 
Pfizer, Lilly, AstraZeneca, Taiho Pharmaceutical, PharmaMarSpeakers' Bureau: 
Lilly/ImClone, Roche/Genentech, Pierre FabreResearch Funding: Novartis (Inst), 
Roche (Inst)¸ Puma Biotechnology (Inst)Other Relationship: Roche, Novartis Hal 
J. BursteinThis author is an Associate Editor for Journal of Clinical Oncology. 
Journal policy recused the author from having any role in the peer review of 
this manuscript. Richard GreilHonoraria: Celgene, Roche, Merck, Takeda, 
AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, MSD¸ Sandoz, AbbVie, Gilead 
Sciences, Daiichi SankyoConsulting or Advisory Role: Celgene, Novartis, Roche, 
Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead 
Sciences, Daiichi SankyoResearch Funding: Celgene (Inst), Merck (Inst), Takeda 
(Inst), AstraZeneca (Inst), Novartis (Inst), Amgen (Inst), Bristol Myers Squibb 
(Inst), MSD (Inst), Sandoz (Inst), Gilead Sciences (Inst), Roche (Inst)Travel, 
Accommodations, Expenses: Roche, Amgen, Janssen-Cilag, AstraZeneca, Novartis, 
MSD, Celgene, Gilead Sciences, Bristol Myers Squibb, AbbVie, Daiichi Sankyo 
Antonio C. WolffThis author is an Associate Editor for Journal of Clinical 
Oncology. Journal policy recused the author from having any role in the peer 
review of this manuscript.Consulting or Advisory Role: Ionis 
PharmaceuticalsPatents, Royalties, Other Intellectual Property: A.C.W. has been 
named as an inventor on one or more issued patents or pending patent 
applications related to methylation in breast cancer, has assigned his rights to 
JHU, and participates in a royalty sharing agreement with JHUOpen Payments Link: 
https://openpaymentsdata.cms.gov/physician/357301/summary Arlene ChanHonoraria: 
Novartis, LillyConsulting or Advisory Role: LillyResearch Funding: Eisai Eric P. 
WinerHonoraria: Genomic Health, Genentech/RocheConsulting or Advisory Role: Leap 
Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick 
Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, 
Gilead Sciences, Zymeworks, AthenexResearch Funding: Genentech (Inst)Other 
Relationship: InfiniteMD Georg PfeilerHonoraria: Amgen, Roche/Genentech, Pfizer¸ 
Lilly, AstraZeneca/Merck, AstraZeneca/Daiichi Sankyo, Novartis, UCB, Accord 
HealthcareConsulting or Advisory Role: Pfizer¸ Amgen¸ Lilly, Novartis, 
AstraZeneca/Merck, AstraZeneca/Daiichi Sankyo, UCB, Roche/GenentechSpeakers' 
Bureau: Roche/Genentech, Pfizer, Lilly, Novartis, UCB, AstraZeneca/Merck, 
AstraZeneca/Daiichi Sankyo, Accord Healthcare, Amgen, Accord HealthcareResearch 
Funding: Pfizer, Roche/GenentechTravel, Accommodations, Expenses: Novartis, 
Lilly, Roche/Genentech, Lilly, AstraZeneca/Daiichi Sankyo Kathy MillerThis 
author is an Associate Editor for Journal of Clinical Oncology. Journal policy 
recused the author from having any role in the peer review of this 
manuscript.Consulting or Advisory Role: Merck, Genentech/Roche, Athenex, 
AstraZeneca, Bristol Myers Squibb/CelgeneResearch Funding: Taiho Pharmaceutical 
(Inst), Novartis (Inst), Seattle Genetics (Inst), Pfizer (Inst), Astex 
Pharmaceuticals (Inst), British Biotech (Inst), CytomX Therapeutics (Inst), 
Alphamab (Inst) Marco ColleoniResearch Funding: Roche (Inst) Gabor 
RubovskyConsulting or Advisory Role: Pfizer, Novartis, Roche, Gilead 
SciencesTravel, Accommodations, Expenses: Amgen Judith M. BlissResearch Funding: 
AstraZeneca (Inst), Merck Sharp & Dohme (Inst), Puma Biotechnology (Inst), 
Pfizer (Inst), Roche (Inst), GlaxoSmithKline/Novartis (Inst), Lilly (Inst), 
Janssen-Cilag (Inst), Clovis Oncology (Inst)Travel, Accommodations, Expenses: 
Pfizer Ingrid A. MayerConsulting or Advisory Role: Novartis, AstraZeneca, Lilly, 
Genentech, GlaxoSmithKline, Immunomedics, MacroGenics, Pfizer, AbbVie, Seattle 
Genetics, Puma Biotechnology, Cyclacel, Blueprint Medicines, SanofiResearch 
Funding: Novartis (Inst), Pfizer (Inst), Genentech (Inst) Christian 
SingerHonoraria: Novartis, AstraZeneca/MedImmune, Daiichi Sankyo Europe 
GmbHConsulting or Advisory Role: AstraZeneca/MedImmune, Daiichi-Sankyo, Gilead 
Sciences, Sanofi/Aventis, NovartisSpeakers' Bureau: Novartis, 
AstraZeneca/MedImmuneResearch Funding: Novartis, Sanofi, Myriad Genetics, Roche, 
AstraZeneca/MedImmuneTravel, Accommodations, Expenses: Roche, Novartis Zbigniew 
NoweckiTravel, Accommodations, Expenses: Roche/Genentech Olwen HahnLeadership: 
Via OncologyStock and Other Ownership Interests: Teleflex MedicalHonoraria: 
Cardinal Health (I)Consulting or Advisory Role: Pfizer, hmpglobal.comTravel, 
Accommodations, Expenses: Cardinal Health (I) Jacqui ThomsonHonoraria: MSD 
Oncology, Roche/Genentech Norman WolmarkOpen Payments Link: 
https://openpaymentsdata.cms.gov/physician/159597 Hope S. RugoHonoraria: Puma 
Biotechnology, MylanConsulting or Advisory Role: SamsungResearch Funding: 
MacroGenics (Inst), OBI Pharma (Inst), Eisai (Inst), Pfizer (Inst), Novartis 
(Inst), Lilly (Inst), Genentech (Inst), Merck (Inst), Immunomedics (Inst), 
Odonate Therapeutics (Inst), Daiichi Sankyo (Inst), Seattle Genetics (Inst), 
Sermonix Pharmaceuticals (Inst), AstraZeneca (Inst)Travel, Accommodations, 
Expenses: Pfizer, Novartis, Mylan, AstraZeneca Spain, MerckOpen Payments Link: 
https://openpaymentsdata.cms.gov/summary Guenther G. StegerHonoraria: Pfizer, 
Lilly, Novartis, Roche, AstraZeneca/Daiichi Sankyo, Teva, Pfizer, Lilly, 
NovartisTravel, Accommodations, Expenses: Roche, Teva Blanca Hernando Fernández 
de AránguizHonoraria: GlaxoSmithKline, PharmaMar, Clovis OncologyTravel, 
Accommodations, Expenses: Pfizer, MSD Oncology, Roche Tufia C. HaddadResearch 
Funding: Takeda (Inst) Meritxell Bellet EzquerraConsulting or Advisory Role: 
Pfizer, Lilly, NovartisSpeakers' Bureau: Lilly, Pfizer, Novartis Hannes 
FohlerEmployment: Takeda (I)Research Funding: Pfizer (Inst) Otto 
MetzgerHonoraria: Grupo Oncoclinicas, RocheResearch Funding: Susan G. Komen for 
the Cure (Inst), Pfizer (Inst), Roche/Genentech (Inst), Eisai (Inst), Cascadian 
Therapeutics (Inst), AbbVie (Inst)Travel, Accommodations, Expenses: Grupo 
Oncoclinicas Anita Jallitsch-HalperResearch Funding: Pfizer (Inst) Kadine 
SolomonEmployment: Alliance Foundation TrialsStock and Other Ownership 
Interests: Pfizer, Merck, Moderna Therapeutics Céline SchurmansResearch Funding: 
Pfizer (Inst), Roche/Genentech (Inst), AstraZeneca (Inst), Novartis (Inst), 
Servier (Inst), Pfizer (Inst), Sanofi (Inst)Patents, Royalties, Other 
Intellectual Property: My organization receives royalties from Agendia Kathy P. 
TheallEmployment: PfizerStock and Other Ownership Interests: PfizerHonoraria: 
PfizerTravel, Accommodations, Expenses: Pfizer Dongrui R. LuEmployment: 
PfizerStock and Other Ownership Interests: Pfizer Kathleen TennerStock and Other 
Ownership Interests: Merck Christian FeslResearch Funding: Pfizer (Inst) Angela 
DeMicheleResearch Funding: Pfizer (Inst), Genentech (Inst), Calithera 
Biosciences (Inst), Novartis (Inst) Erica L. MayerConsulting or Advisory Role: 
Lilly, Novartis, AstraZeneca, Gilead SciencesResearch Funding: Pfizer (Inst)No 
other potential conflicts of interest were reported.


63. Int J Cancer. 2020 Dec 1;147(11):3250-3261. doi: 10.1002/ijc.33129. Epub 2020 
Jul 13.

A novel mesenchymal-associated transcriptomic signature for risk-stratification 
and therapeutic response prediction in colorectal cancer.

Matsuyama T(1)(2), Kandimalla R(1), Ishikawa T(3), Takahashi N(4), Yamada Y(4), 
Yasuno M(2), Kinugasa Y(2), Hansen TF(5), Fakih M(6), Uetake H(3), Győrffy 
B(7)(8), Goel A(1)(9).

Author information:
(1)Center for Gastrointestinal Research, Center for Translational Genomics and 
Oncology, Baylor Scott & White Research Institute, Charles A Sammons Cancer 
Center, Baylor University Medical Center, Dallas, Texas, USA.
(2)Department of Gastrointestinal Surgery, Tokyo Medical and Dental University 
Graduate School of Medicine, Tokyo, Japan.
(3)Department of Specialized Surgery, Tokyo Medical and Dental University 
Graduate School of Medicine, Tokyo, Japan.
(4)Department of Gastroenterology, National Cancer Center Hospital, Tokyo, 
Japan.
(5)Department of Oncology, Vejle University Hospital, Vejle, Denmark.
(6)Department of Medical Oncology and Therapeutics Research, City of Hope 
Comprehensive Cancer Center, Duarte, California, USA.
(7)MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, 
Hungarian Academy of Sciences, Budapest, Hungary.
(8)2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
(9)Department of Molecular Diagnostics and Experimental Therapeutics, Beckman 
Research Institute of City of Hope Comprehensive Cancer Center, Duarte, 
California, USA.

Risk stratification in Stage II and III colorectal cancer (CRC) patients is 
critical, as it allows patient selection for adjuvant chemotherapy. In view of 
the inadequacy of current clinicopathological features for risk-stratification, 
we undertook a systematic and comprehensive biomarker discovery effort to 
develop a risk-assessment signature in CRC patients. The biomarker discovery 
phase examined 853 CRC patients, and identified a gene signature for predicting 
recurrence-free survival (RFS). This signature was validated in a meta-analysis 
of 1212 patients from nine independent datasets, and its performance was 
compared against established prognostic signatures and consensus molecular 
subtypes (CMS). In addition, a risk-prediction model was trained (n = 142), and 
subsequently validated in an independent clinical cohort (n = 286). As a result, 
this mesenchymal-associated transcriptomic signature (MATS) identified high-risk 
CRC patients with poor RFS in the discovery (hazard ratio [HR]: 1.79), and nine 
validation cohorts (HR: 1.86). In multivariate analysis, MATS was the most 
significant predictor of RFS compared to established prognostic signatures and 
CMS subtypes. Intriguingly, MATS robustly identified CMS4-subtype in multiple 
CRC cohorts (AUC = 0.92-0.99). In the two clinical cohorts, MATS stratified low 
and high-risk groups with a 5-year RFS in the training (HR: 4.11) and validation 
cohorts (HR: 2.55), as well as predicted response to adjuvant therapy in Stage 
II and III CRC patients. We report a novel prognostic and predictive biomarker 
signature in CRC, which is superior to currently used approaches and have the 
potential for clinical translation in near future.

© 2020 UICC.

DOI: 10.1002/ijc.33129
PMID: 32657428 [Indexed for MEDLINE]


64. Ann Oncol. 2019 Apr 1;30(4):520-527. doi: 10.1093/annonc/mdz052.

Context matters-consensus molecular subtypes of colorectal cancer as biomarkers 
for clinical trials.

Fontana E(1), Eason K(2), Cervantes A(3), Salazar R(4), Sadanandam A(5).

Author information:
(1)Division of Molecular Pathology, The Institute of Cancer Research, London; 
Centre for Molecular Pathology, The Royal Marsden NHS Foundation Trust, London, 
UK.
(2)Division of Molecular Pathology, The Institute of Cancer Research, London.
(3)CIBERONC, Department of Medical Oncology, Biomedical Research Institute 
INCLIVA, University of Valencia, Valencia.
(4)Institut Catala d'Oncologia, L'Institut d'Investigació Biomèdica de 
Bellvitge, Barcelona, Spain.
(5)Division of Molecular Pathology, The Institute of Cancer Research, London; 
Centre for Molecular Pathology, The Royal Marsden NHS Foundation Trust, London, 
UK. Electronic address: anguraj.sadanandam@icr.ac.uk.

The Colorectal Cancer Subtyping Consortium identified four gene expression 
consensus molecular subtypes, CMS1 (immune), CMS2 (canonical), CMS3 (metabolic), 
and CMS4 (mesenchymal), using multiple microarray or RNA-sequencing datasets of 
primary tumor samples mainly from early stage colon cancer patients. 
Consequently, rectal tumors and stage IV tumors (possibly reflective of more 
aggressive disease) were underrepresented, and no chemo- and/or radiotherapy 
pretreated samples or metastatic lesions were included. In view of their 
possible effect on gene expression and consequently subtype classification, 
sample source and treatments received by the patients before collection must be 
carefully considered when applying the classifier to new datasets. Recently, 
several correlative analyses of clinical trials demonstrated the applicability 
of this classification to the metastatic setting, confirmed the prognostic value 
of CMS subtypes after relapse and hinted at differential sensitivity to 
treatments. Here, we discuss why contexts and equivocal factors need to be taken 
into account when analyzing clinical trial data, including potential selection 
biases, type of platform, and type of algorithm used for subtype prediction. 
This perspective article facilitates both our clinical and research 
understanding of the application of this classifier to expedite subtype-based 
clinical trials.

© The Author(s) 2019. Published by Oxford University Press on behalf of the 
European Society for Medical Oncology.

DOI: 10.1093/annonc/mdz052
PMCID: PMC6503627
PMID: 30796810 [Indexed for MEDLINE]


65. J Clin Oncol. 2021 Dec 10;39(35):3897-3907. doi: 10.1200/JCO.21.01839. Epub 2021 
Sep 20.

Radioembolization With Chemotherapy for Colorectal Liver Metastases: A 
Randomized, Open-Label, International, Multicenter, Phase III Trial.

Mulcahy MF(1), Mahvash A(2), Pracht M(3), Montazeri AH(4), Bandula S(5), Martin 
RCG 2nd(6), Herrmann K(7), Brown E(8), Zuckerman D(9), Wilson G(10), Kim TY(11), 
Weaver A(12), Ross P(13), Harris WP(14), Graham J(15), Mills J(16), Yubero 
Esteban A(17), Johnson MS(18), Sofocleous CT(19), Padia SA(20), Lewandowski 
RJ(21), Garin E(22), Sinclair P(23), Salem R(21); EPOCH Investigators.

Author information:
(1)Department of Medicine, Northwestern Feinberg School of Medicine, Chicago, 
IL.
(2)Department of Interventional Radiology, MD Anderson Cancer Center, Houston, 
TX.
(3)Centre Eugene Marquis, Medical Oncology, Rennes, France.
(4)Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, United Kingdom.
(5)University College London Hospital, London, United Kingdom.
(6)University of Louisville, Louisville, KY.
(7)Universitätsklinikum Essen, Essen, Germany.
(8)Western General Hospital, Edinburgh, Scotland.
(9)Yale School of Medicine, New Haven, CT.
(10)The Christie NHS Foundation Trust, Manchester, United Kingdom.
(11)Seoul National University, Seoul, South Korea.
(12)Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.
(13)Guy's Hospital, London, United Kingdom.
(14)University of Washington, Seattle, WA.
(15)Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
(16)Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
(17)Hospital Clínico Lozano Blesa, Zaragoza, Spain.
(18)Indiana University School of Medicine, Indianapolis, IN.
(19)Memorial Sloan Kettering Cancer Center, New York, NY.
(20)University of California-Los Angeles, Los Angeles, CA.
(21)Department of Radiology, Section of Interventional Radiology, Northwestern 
University, Chicago, IL.
(22)Centre Eugene Marquis, Nuclear Medicine, Rennes, France.
(23)Boston Scientific Corporation, Marlborough, MA.

Comment in
    J Clin Oncol. 2021 Dec 10;39(35):3887-3889.

PURPOSE: To study the impact of transarterial Yttrium-90 radioembolization 
(TARE) in combination with second-line systemic chemotherapy for colorectal 
liver metastases (CLM).
METHODS: In this international, multicenter, open-label phase III trial, 
patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line 
therapy were randomly assigned 1:1 to receive second-line chemotherapy with or 
without TARE. The two primary end points were progression-free survival (PFS) 
and hepatic PFS (hPFS), assessed by blinded independent central review. Random 
assignment was performed using a web- or voice-based system stratified by 
unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line 
chemotherapy, and KRAS mutation status.
RESULTS: Four hundred twenty-eight patients from 95 centers in North America, 
Europe, and Asia were randomly assigned to chemotherapy with or without TARE; 
this represents the intention-to-treat population and included 215 patients in 
the TARE plus chemotherapy group and 213 patients in the chemotherapy alone 
group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided P = 
.0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 
7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 
1-sided P < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% 
CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% 
CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided P = .0019) for the 
TARE and chemotherapy groups, respectively. Median overall survival was 14.0 
(95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided P = .7229) 
with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, 
respectively. Grade 3 adverse events were reported more frequently with TARE 
(68.4% v 49.3%). Both groups received full chemotherapy dose intensity.
CONCLUSION: The addition of TARE to systemic therapy for second-line CLM led to 
longer PFS and hPFS. Further subset analyses are needed to better define the 
ideal patient population that would benefit from TARE.

DOI: 10.1200/JCO.21.01839
PMCID: PMC8660005
PMID: 34541864 [Indexed for MEDLINE]

Conflict of interest statement: Mary F. MulcahyResearch Funding: BTG Armeen 
MahvashHonoraria: Sirtex MedicalConsulting or Advisory Role: Sirtex Medical, 
Boston Scientific, AbbiskoSpeakers' Bureau: SIR-TexResearch Funding: BTG, Sirtex 
MedicalTravel, Accommodations, Expenses: BTG, SIR-TexOpen Payments Link: 
https://openpaymentsdata.cms.gov/physician/1192235 Marc PrachtTravel, 
Accommodations, Expenses: MSD Steve BandulaHonoraria: Varian Medical Systems 
Robert C. G. MartinConsulting or Advisory Role: Angiodynamics Ken 
HerrmannLeadership: Sofibio, Theragnostics, Pharma15Stock and Other Ownership 
Interests: Sofibio, Theragnostics, Pharma15, Aktis OncologyConsulting or 
Advisory Role: Novartis, Bain Capital, Bayer, Advanced Accelerator Applications, 
Amgen, BTG, Ipsen, ITG, ROTOP Pharmaka, Siemens Healthineers, GE Healthcare Ewan 
BrownResearch Funding: MSD Oncology Gregory WilsonStock and Other Ownership 
Interests: Tandem Diabetes Care, Regeneron, Novacyt, Spire Hospital 
GroupConsulting or Advisory Role: Delcath Systems Paul RossStock and Other 
Ownership Interests: Perci Health LtdHonoraria: Sirtex Medical, Eisai, Servier, 
Pierre Fabre, Shire, Roche, AstraZeneca, MerckConsulting or Advisory Role: 
Sirtex Medical, Eisai, Servier, Roche, AstraZeneca, AmgenSpeakers' Bureau: 
Amgen, Merck, Servier, Boston ScientificResearch Funding: Sanofi, BayerTravel, 
Accommodations, Expenses: Roche, Ipsen William P. HarrisConsulting or Advisory 
Role: Neo Therma, Eisai, Exelixis, Bristol Myers Squibb, QED Therapeutics, 
Zymeworks, BD Medical, MerckResearch Funding: ArQule, Exelixis, Halozyme, 
Bristol Myers Squibb, MedImmune, Agios, Bayer, Merck, BTG, Boston Scientific, 
Koo Foundation, ZymeworksTravel, Accommodations, Expenses: Eisai Janet 
GrahamHonoraria: Merck Serono, Bristol Myers Squibb, Nucana, BayerConsulting or 
Advisory Role: Merck KGaATravel, Accommodations, Expenses: Nucana Jamie 
MillsTravel, Accommodations, Expenses: GenesisCare UK Matthew S. JohnsonStock 
and Other Ownership Interests: Endoshape, FluidXConsulting or Advisory Role: 
Argon Medical Devices, Boston Scientific, Cook MedicalResearch Funding: Argon 
Medical Devices, Boston Scientific, Black SwanExpert Testimony: Argon Medical 
Devices Constantinos T. SofocleousHonoraria: Ethicon/Johnson & JohnsonConsulting 
or Advisory Role: Varian Medical Systems, BTG, Sirtex Medical, TerumoSpeakers' 
Bureau: Ethicon/Johnson & JohnsonResearch Funding: BTG, Ethicon, Sirtex 
MedicalTravel, Accommodations, Expenses: Ethicon/Johnson & Johnson, Terumo 
Siddharth A. PadiaConsulting or Advisory Role: Boston Scientific, Bristol Meyer 
Squibb, Johnson & Johnson, Teleflex Medical, Varian Medical SystemsResearch 
Funding: Varian Medical Systems Robert J. LewandowskiConsulting or Advisory 
Role: Boston Scientific, BD Bard, Varian Medical Systems, ABKSpeakers' Bureau: 
Boston Scientific Etienne GarinHonoraria: BTG/Boston ScientificConsulting or 
Advisory Role: BTG/Boston ScientificTravel, Accommodations, Expenses: BTG/Boston 
Scientific Philip SinclairEmployment: Boston ScientificStock and Other Ownership 
Interests: Boston Scientific Riad SalemConsulting or Advisory Role: Eisai, Bard 
Medical, Cook Medical, Boston Scientific, Sirtex Medical, AstraZeneca, QED 
Therapeutics, Genentech/Roche, SiemensResearch Funding: Boston ScientificNo 
other potential conflicts of interest were reported.


66. Clin Colorectal Cancer. 2021 Mar;20(1):84-95.e8. doi: 
10.1016/j.clcc.2020.09.003. Epub 2020 Sep 15.

Association of Consensus Molecular Subtypes and Molecular Markers With Clinical 
Outcomes in Patients With Metastatic Colorectal Cancer: Biomarker Analyses From 
LUME-Colon 1.

Lenz HJ(1), Argiles G(2), Yoshino T(3), Tejpar S(4), Ciardiello F(5), Braunger 
J(6), Salnikov AV(6), Gabrielyan O(6), Schmid R(6), Höfler J(7), Kitzing T(6), 
Van Cutsem E(8).

Author information:
(1)University of Southern California Norris Comprehensive Cancer Center, Los 
Angeles, CA. Electronic address: lenz@med.usc.edu.
(2)Vall d'Hebron University Hospital and Institute of Oncology (VHIO), 
Universitat Autònoma de Barcelona, Barcelona, Spain.
(3)National Cancer Center Hospital East, Chiba, Japan.
(4)Digestive Oncology Unit and Centre for Human Genetics, UZ Leuven, Belgium; 
University Hospitals Leuven and KULeuven, Leuven, Belgium.
(5)Dipartimento di Internistica Clinica e Sperimentale, Università degli Studi 
della Campania Luigi Vanvitelli, Naples, Italy.
(6)Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
(7)Staburo GmbH, Munich, Germany.
(8)University Hospitals Leuven and KULeuven, Leuven, Belgium.

INTRODUCTION: LUME-Colon 1 (NCT02149108) was a global, placebo-controlled phase 
III study of nintedanib in advanced colorectal cancer (CRC). Pre-specified 
biomarker analyses investigated the association of CRC consensus molecular 
subtypes (CMS) and tumor genomic and circulating biomarkers with clinical 
outcomes.
MATERIALS AND METHODS: Archival tumor tissue, cell-free DNA (cfDNA), and plasma 
samples were collected for genomic, transcriptomic, and proteomic analyses to 
investigate potential associations between CRC CMS and other biomarkers with 
nintedanib response and clinical outcomes.
RESULTS: Of the 765 treated patients, 735, 245, and 192 patient samples were 
analyzed in the circulating protein, tumor tissue, and cfDNA datasets, 
respectively. Patients were classified as CMS1 (1.7%), CMS2 (27.7%), CMS3 
(0.9%), CMS4 (51.5%), or unclassified (18.2%). Unclassified/mixed CMS was 
associated with longer overall survival (OS) with nintedanib vs. CMS2 or CMS4 
(interaction P-value = .0086); no association was observed for CMS4. Gene 
expression-based pathway analysis revealed an association between vascular 
endothelial growth factor-related signaling and OS for nintedanib (P = .0498). 
The most frequently detected somatic mutations were APC (72.0% [tumor tissue] 
vs. 56.8% [cfDNA]), TP53 (47.1% vs. 34.9%), KRAS (40.8% vs. 28.6%), and PIK3CA 
(16.6% vs. 11.5%); concordance rates were > 80%. Median OS differences were 
observed for APC and TP53 mutations vs. wild-type in cfDNA, indicating a 
potential prognostic value. Circulating ANG-2, CA-9, CEACAM1, collagen-IV, 
IGFBP-1, ICAM-1, IL-8, and uPAR were potentially prognostic for both OS and 
progression-free survival.
CONCLUSION: We demonstrated the feasibility of large-scale biomarker analyses 
and CMS classification within a global clinical trial, and identified signals 
suggesting a potential for greater nintedanib treatment response in the 
unclassified/mixed CMS subgroup, despite these tumors showing heterogeneous 
patterns of CMS mixtures. Our results revealed a high degree of concordance in 
somatic mutations between tumor tissue and cfDNA. Associations with prognosis 
for cfDNA somatic mutations, as well as several protein-based biomarkers, may 
warrant further investigation in future trials.

Copyright © 2020. Published by Elsevier Inc.

DOI: 10.1016/j.clcc.2020.09.003
PMID: 33041226 [Indexed for MEDLINE]


67. Eur J Cancer. 2021 Nov;157:71-80. doi: 10.1016/j.ejca.2021.08.017. Epub 2021 Sep 
8.

Consensus molecular subtypes in metastatic colorectal cancer treated with 
sequential versus combined fluoropyrimidine, bevacizumab and irinotecan 
(XELAVIRI trial).

Stahler A(1), Heinemann V(2), Schuster V(3), Heinrich K(3), Kurreck A(4), 
Gießen-Jung C(3), Fischer von Weikersthal L(5), Kaiser F(6), Decker T(7), Held 
S(8), Graeven U(9), Schwaner I(10), Denzlinger C(11), Schenk M(12), Neumann 
J(13), Kirchner T(14), Jung A(14), Kumbrink J(14), Stintzing S(15), Modest 
DP(15).

Author information:
(1)Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin and 
Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumour 
Immunology, Charitéplatz 1, 10117, Berlin, Germany. Electronic address: 
arndt.stahler@charite.de.
(2)Department of Medicine III, University Hospital, LMU, Munich, Germany; LMU 
Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer 
Research Center (DKFZ), Heidelberg, Germany.
(3)Department of Medicine III, University Hospital, LMU, Munich, Germany.
(4)Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin and 
Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumour 
Immunology, Charitéplatz 1, 10117, Berlin, Germany.
(5)Klinikum St. Marien, Oncology, Amberg, Germany.
(6)Onkologische Praxis, Landshut, Germany.
(7)Onkologische Praxis, Ravensburg, Germany.
(8)ClinAssess GmbH, Leverkusen, Germany.
(9)Department of Hematology, Oncology and Gastroenterology, Kliniken Maria Hilf 
GmbH, Mönchengladbach, Germany.
(10)Onkologische Schwerpunktpraxis Kurfürstendamm, Berlin, Germany.
(11)Marienhospital, Stuttgart, Germany.
(12)Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany.
(13)Institute of Pathology, University of Munich, Germany.
(14)LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German 
Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, 
University of Munich, Germany.
(15)Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin 
and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and 
Tumour Immunology, Charitéplatz 1, 10117, Berlin, Germany; Charité - 
Universitätsmedizin, German Cancer Consortium (DKTK), Partner Site Berlin, 
German Cancer Research Center (DKFZ), Heidelberg, Germany.

BACKGROUND: The XELAVIRI trial compared sequential (fluoropyrimidine and 
bevacizumab; irinotecan (Iri) at progression) versus initial combination therapy 
(fluoropyrimidine, bevacizumab, Iri) of treatment-naïve metastatic colorectal 
cancer (mCRC). In the confirmatory analysis, the primary end-point 
(non-inferiority of sequential therapy regarding time to failure of strategy, 
TFS) was not met. Nevertheless, significant differences regarding treatment 
efficacy were observed according to RAS status. Here, we evaluate the consensus 
molecular subtypes (CMS) as additional biomarkers for sequential versus 
combination therapy.
MATERIAL AND METHODS: Gene expression was measured using NanoString after mRNA 
extraction from formalin-fixed paraffin-embedded tumour specimens. CMS were 
predicted using multinomial regression and correlated with updated data for TFS, 
overall (OS) and progression-free survival.
RESULTS: CMS were predicted in 337 of 421 (80.0%) patients (CMS1: 18.4%; CMS2: 
51.6%; CMS3: 2.7%; CMS4: 27.3%). CMS2 together with RAS/BRAF wild-type status 
was identified as potential predictive marker of benefit from initial 
combination therapy for OS (HR 0.56, 95% CI 0.33-0.96, p = 0.036) and 
progression-free survival (HR 0.28, 95% CI 0.29-0.79, p = 0.004) and also 
trending in TFS (HR 0.63, 90% CI 0.41-0.95, p = 0.066). In patients with 
RAS-mutated mCRC, CMS1 was associated with longer OS after initial combination 
therapy (HR 0.43, 95% CI 0.20-0.95, p = 0.038). Interaction testing (two-sided) 
of CMS and RAS/BRAF status in favour of the combination treatment strategy was 
significant for OS (p = 0.012) CONCLUSIONS: In patients with RAS/BRAF wild-type 
mCRC, CMS2 may serve as an additional biomarker of benefit from the initial 
combination therapy, including Iri.
TRIAL REGISTRATION: Trial registration ID (clinicaltrials.gov) NCT01249638.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ejca.2021.08.017
PMID: 34507244 [Indexed for MEDLINE]


68. Int J Cancer. 2021 Apr 15;148(8):1948-1963. doi: 10.1002/ijc.33393. Epub 2020 
Dec 4.

Multi-omics integration identifies a selective vulnerability of colorectal 
cancer subtypes to YM155.

Zhan T(1)(2), Faehling V(1), Rauscher B(1), Betge J(1)(2), Ebert MP(2), Boutros 
M(1)(2)(3).

Author information:
(1)Division of Signaling and Functional Genomics, German Cancer Research Center 
(DKFZ), Department of Cell and Molecular Biology, Faculty of Medicine Mannheim, 
Heidelberg University, Heidelberg, Germany.
(2)Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty 
Mannheim, Heidelberg University, Mannheim, Germany.
(3)German Cancer Consortium (DKTK), Heidelberg, Germany.

Tumor heterogeneity is a major challenge to the treatment of colorectal cancer 
(CRC). Recently, a transcriptome-based classification was developed, segregating 
CRC into four consensus molecular subtypes (CMS) with distinct biological and 
clinical characteristics. Here, we applied the CMS classification on CRC cell 
lines to identify novel subtype-specific drug vulnerabilities. We combined 
publicly available transcriptome data from multiple resources to assign 157 CRC 
cell lines to CMS. By integrating results from large-scale drug screens, we 
discovered that the CMS1 subtype is highly vulnerable to the BIRC5 suppressor 
YM155. We confirmed our results using an independent panel of CRC cell lines and 
demonstrated a 100-fold higher sensitivity of CMS1. This vulnerability was 
specific to YM155 and not observed for commonly used chemotherapeutic agents. In 
CMS1 CRC, low concentrations of YM155 induced apoptosis and expression 
signatures associated with ER stress-mediated apoptosis signaling. Using a 
genome-wide CRISPR/Cas9 screen, we further discovered a novel role of genes 
involved in LDL-receptor trafficking as modulators of YM155 sensitivity in the 
CRC cell line HCT116. Our work shows that combining drug response data with CMS 
classification in cell lines can reveal selective vulnerabilities and proposes 
YM155 as a novel subtype-specific drug.

© 2020 The Authors. International Journal of Cancer published by John Wiley & 
Sons Ltd on behalf of UICC.

DOI: 10.1002/ijc.33393
PMID: 33186476 [Indexed for MEDLINE]


69. Bull Cancer. 2015 Jun;102(6 Suppl 1):S72-81. doi: 10.1016/S0007-4551(15)31220-0.

[DNA mismatch repair and BRAF status in colorectal cancer: Interest for the 
therapeutic management?].

[Article in French]

Cohen R(1), Cervera P(2), Svrcek M(3), Dumont C(2), Garcia ML(2), Chibaudel 
B(4), de Gramont A(4), Pocard M(5), Duval A(6), Fléjou JF(7), André T(8).

Author information:
(1)Service d'oncologie médicale, Hôpitaux universitaires de l'Est Parisien 
(AP-HP), Site Saint-Antoine 184, rue du Faubourg Saint-Antoine, 75571 Paris 
cedex 12, France; Groupe coopérateur multidisciplinaire en oncologie (GERCOR), 
Paris, France.
(2)Service d'oncologie médicale, Hôpitaux universitaires de l'Est Parisien 
(AP-HP), Site Saint-Antoine 184, rue du Faubourg Saint-Antoine, 75571 Paris 
cedex 12, France.
(3)Service d'oncologie médicale, Hôpitaux universitaires de l'Est Parisien 
(AP-HP), Site Saint-Antoine 184, rue du Faubourg Saint-Antoine, 75571 Paris 
cedex 12, France; Inserm, Unité mixte de recherche scientifique 938, Centre de 
recherche Saint-Antoine, Équipe Instabilité des microsatellites et cancers, 
Équipe labellisée par la Ligue nationale contre le cancer, Paris, France.
(4)Groupe coopérateur multidisciplinaire en oncologie (GERCOR), Paris, France; 
Institut hospitalier franco-britannique, 4 rue Kléber, 92300 Levallois-Perret, 
France.
(5)Hôpital Lariboisière, Paris, France; Université Paris Diderot, Sorbonne Paris 
Cité, CART, Inserm U965, Paris, France.
(6)Inserm, Unité mixte de recherche scientifique 938, Centre de recherche 
Saint-Antoine, Équipe Instabilité des microsatellites et cancers, Équipe 
labellisée par la Ligue nationale contre le cancer, Paris, France.
(7)Service d'oncologie médicale, Hôpitaux universitaires de l'Est Parisien 
(AP-HP), Site Saint-Antoine 184, rue du Faubourg Saint-Antoine, 75571 Paris 
cedex 12, France; Université Pierre et Marie Curie (UPMC), Paris VI, Paris, 
France.
(8)Service d'oncologie médicale, Hôpitaux universitaires de l'Est Parisien 
(AP-HP), Site Saint-Antoine 184, rue du Faubourg Saint-Antoine, 75571 Paris 
cedex 12, France; Université Pierre et Marie Curie (UPMC), Paris VI, Paris, 
France. Electronic address: thierry.andre@sat.aphp.fr.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality 
in France. Recently, colorectal cancer subtyping consortium (CRCSC) identified 4 
consensus molecular subtypes (CMS). CMS1 is enriched for CRC with deficient DNA 
mismatch repair system (dMMR) and tumors with mutated BRAF. Intriguingly, CMS1 
is characterized by better relapse-free survival but worse survival after 
relapse, compared with the other subtypes. In this review, we provide a 
comprehensive overview of prognostic and predictive impacts of MMR and BRAF 
status. We highlight immune checkpoints inhibitors as potentially future 
therapeutics for CRC with deficient MMR. We also focus on the management of BRAF 
mutant metastatic CRC, with a particular interest on targeted therapies.

Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. 
Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

DOI: 10.1016/S0007-4551(15)31220-0
PMID: 26118880 [Indexed for MEDLINE]


70. Oncoimmunology. 2021 Mar 9;10(1):1862529. doi: 10.1080/2162402X.2020.1862529.

Tumor immune infiltration estimated from gene expression profiles predicts 
colorectal cancer relapse.

Kamal Y(1), Dwan D(1), Hoehn HJ(2), Sanz-Pamplona R(3)(4), Alonso MH(3)(4)(5), 
Moreno V(3)(4)(5), Cheng C(6)(7)(8), Schell MJ(9), Kim Y(9), Felder SI(10), 
Rennert HS(11)(12), Melas M(13)(14), Lazaris C(13)(15)(16), Bonner JD(17), 
Siegel EM(18), Shibata D(19), Rennert G(11)(12), Gruber SB(17), Frost HR(1), 
Amos CI(1)(7)(8), Schmit SL(2)(10).

Author information:
(1)Department of Biomedical Data Sciences, Geisel School of Medicine at 
Dartmouth, Hanover, NH, USA.
(2)Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research 
Institute, Tampa, FL, USA.
(3)Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), 
ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet 
de Llobregat, Barcelona, Spain.
(4)Consortium for Biomedical Research in Epidemiology and Public Health 
(CIBERESP), Madrid, Spain.
(5)Department of Clinical Sciences, Faculty of Medicine, University of 
Barcelona, Barcelona, Spain.
(6)Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, 
Houston, TX, USA.
(7)Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
(8)Institute for Clinical and Translational Research, Baylor College of 
Medicine, Houston, TX, USA.
(9)Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center 
and Research Institute, Columbus, OH, USA.
(10)Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and 
Research Institute.
(11)Department of Community Medicine & Epidemiology, Lady Davis Carmel Medical 
Center, Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of 
Technology.
(12)Steve and Cindy Rasmussen Institute for Genomic Medicine, Lady Davis Carmel 
Medical Center and Technion Faculty of Medicine, Clalit National Cancer Control 
Center, Haifa, Israel.
(13)Department of Medical Oncology and Therapeutics Research, Center for 
Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.
(14)Nationwide Children's Hospital, Columbus, OH, USA.
(15)Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
(16)Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 
USA.
(17)Department of Medical Oncology and Therapeutics Research, City of Hope 
National Medical Center, Duarte, CA, USA.
(18)Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research 
Institute.
(19)Department of Surgery, University of Tennessee Health Science Center, 
Memphis, TN, USA.

A substantial fraction of patients with stage I-III colorectal adenocarcinoma 
(CRC) experience disease relapse after surgery with curative intent. However, 
biomarkers for predicting the likelihood of CRC relapse have not been fully 
explored. Therefore, we assessed the association between tumor infiltration by a 
broad array of innate and adaptive immune cell types and CRC relapse risk. We 
implemented a discovery-validation design including a discovery dataset from 
Moffitt Cancer Center (MCC; Tampa, FL) and three independent validation 
datasets: (1) GSE41258 (2) the Molecular Epidemiology of Colorectal Cancer 
(MECC) study, and (3) GSE39582. Infiltration by 22 immune cell types was 
inferred from tumor gene expression data, and the association between immune 
infiltration by each cell type and relapse-free survival was assessed using Cox 
proportional hazards regression. Within each of the four independent cohorts, 
CD4+ memory activated T cell (HR: 0.93, 95% CI: 0.90-0.96; FDR = 0.0001) 
infiltration was associated with longer time to disease relapse, independent of 
stage, microsatellite instability, and adjuvant therapy. Based on our 
meta-analysis across the four datasets, 10 innate and adaptive immune cell types 
associated with disease relapse of which 2 were internally validated using 
multiplex immunofluorescence. Moreover, immune cell type infiltration was a 
better predictors of disease relapse than Consensus Molecular Subtype (CMS) and 
other expression-based biomarkers (Immune-AICMCC:238.1-238.9; CMS-AICMCC: 
241.0). These data suggest that transcriptome-derived immune profiles are 
prognostic indicators of CRC relapse and quantification of both innate and 
adaptive immune cell types may serve as candidate biomarkers for predicting 
prognosis and guiding frequency and modality of disease surveillance.

© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.

DOI: 10.1080/2162402X.2020.1862529
PMCID: PMC7951964
PMID: 33763292 [Indexed for MEDLINE]


71. Ann Oncol. 2018 Oct 1;29(10):2061-2067. doi: 10.1093/annonc/mdy337.

Colorectal premalignancy is associated with consensus molecular subtypes 1 and 
2.

Chang K(1), Willis JA(2), Reumers J(3), Taggart MW(4), San Lucas FA(5), 
Thirumurthi S(6), Kanth P(7), Delker DA(7), Hagedorn CH(8), Lynch PM(6), Ellis 
LM(9), Hawk ET(10), Scheet PA(11), Kopetz S(12), Arts J(3), Guinney J(13), 
Dienstmann R(14), Vilar E(15).

Author information:
(1)Department of Clinical Cancer Prevention, Division of Cancer Prevention and 
Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, 
USA; Graduate School of Biomedical Sciences, The University of Texas MD Anderson 
Cancer Center, Houston, USA.
(2)Hematology and Oncology Fellowship Program, Division of Cancer Medicine, The 
University of Texas MD Anderson Cancer Center, Houston, USA.
(3)Janssen Oncology Research & Development, Pharmaceutical Companies of Johnson 
& Johnson, Beerse, Belgium.
(4)Department of Pathology, Division of Pathology and Laboratory Medicine, The 
University of Texas MD Anderson Cancer Center, Houston, USA.
(5)Department of Epidemiology, Division of Cancer Prevention and Population 
Sciences, The University of Texas MD Anderson Cancer Center, Houston, USA.
(6)Department of Gastroenterology Hepatology and Nutrition, Division of Internal 
Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA; 
Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer 
Center, Houston, USA.
(7)Division of Gastroenterology, University of Utah Huntsman Cancer Institute, 
Salt Lake City, USA.
(8)Central Arkansas Veterans Healthcare System and University of Arkansas for 
Medical Sciences, Little Rock, USA.
(9)Graduate School of Biomedical Sciences, The University of Texas MD Anderson 
Cancer Center, Houston, USA; Department of Surgical Oncology, Division of 
Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA.
(10)Department of Clinical Cancer Prevention, Division of Cancer Prevention and 
Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, 
USA.
(11)Graduate School of Biomedical Sciences, The University of Texas MD Anderson 
Cancer Center, Houston, USA; Department of Epidemiology, Division of Cancer 
Prevention and Population Sciences, The University of Texas MD Anderson Cancer 
Center, Houston, USA.
(12)Graduate School of Biomedical Sciences, The University of Texas MD Anderson 
Cancer Center, Houston, USA; Department of GI Medical Oncology, Division of 
Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, 
USA.
(13)Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, USA.
(14)Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, USA; 
Oncology Data Science (ODysSey) Group, Vall d'Hebron Institute of Oncology 
(VHIO), Barcelona, Spain. Electronic address: rdienstmann@vhio.net.
(15)Department of Clinical Cancer Prevention, Division of Cancer Prevention and 
Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, 
USA; Graduate School of Biomedical Sciences, The University of Texas MD Anderson 
Cancer Center, Houston, USA; Clinical Cancer Genetics Program, The University of 
Texas MD Anderson Cancer Center, Houston, USA; Department of GI Medical 
Oncology, Division of Cancer Medicine, The University of Texas MD Anderson 
Cancer Center, Houston, USA. Electronic address: evilar@mdanderson.org.

BACKGROUND: Gene expression-based profiling of colorectal cancer (CRC) can be 
used to identify four molecularly homogeneous consensus molecular subtype (CMS) 
groups with unique biologic features. However, its applicability to colorectal 
premalignant lesions remains unknown.
PATIENTS AND METHODS: We assembled the largest transcriptomic premalignancy 
dataset by integrating different public and proprietary cohorts of adenomatous 
and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient 
populations and carried out a comprehensive analysis of carcinogenesis pathways 
using the CMS random forest (RF) classifier.
RESULTS: Overall, transcriptomic subtyping of sporadic and hereditary polyps 
revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in 
premalignancy. Pathway enrichment analysis showed that adenomatous polyps from 
sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like 
phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps 
with CMS1-like phenotype harbored prominent immune activation. Rare adenomas 
with CMS4-like phenotype showed significant enrichment for stromal signatures 
along with transforming growth factor-β activation. There was a strong 
association of CMS1-like polyps with serrated pathology, right-sided anatomic 
location and BRAF mutations.
CONCLUSIONS: Based on our observations made in premalignancy, we propose a model 
of pathway activation associated with CMS classification in colorectal 
carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most 
hyperplastic and serrated polyps are CMS1 and may transition into other CMS 
groups during evolution into carcinomas. Our findings shed light on the 
transcriptional landscape of premalignant colonic polyps and may help guide the 
development of future biomarkers or preventive treatments for CRC.

DOI: 10.1093/annonc/mdy337
PMCID: PMC6225810
PMID: 30412224 [Indexed for MEDLINE]


72. Cell Death Differ. 2018 Mar;25(3):616-633. doi: 10.1038/s41418-017-0011-5. Epub 
2018 Jan 5.

Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro 
and in vivo models.

Linnekamp JF(1)(2), Hooff SRV(1)(2), Prasetyanti PR(1)(2), Kandimalla R(1)(2), 
Buikhuisen JY(1)(2), Fessler E(1)(2)(3), Ramesh P(1)(2), Lee KAST(1)(2), Bochove 
GGW(1)(2), de Jong JH(1)(2), Cameron K(1)(2), Leersum RV(1)(2), Rodermond 
HM(1)(2), Franitza M(4)(5), Nürnberg P(4)(5), Mangiapane LR(6), Wang X(7), 
Clevers H(2)(8)(9), Vermeulen L(1), Stassi G(6), Medema JP(10)(11).

Author information:
(1)Cancer Center Amsterdam, Laboratory of Experimental Oncology and Radiobiology 
(LEXOR), CEMM, Academic Medical Center, Meibergdreef 9, 1105AZ, Amsterdam, The 
Netherlands.
(2)Cancer Genomics Netherlands, Utrecht, The Netherlands.
(3)Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität 
München, Feodor-Lynen-Straße 25, 81377, Munich, Germany.
(4)Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
(5)Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated 
Diseases (CECAD), University of Cologne, Cologne, Germany.
(6)Cellular and Molecular Pathophysiology Laboratory, Department of Surgical and 
Oncological Sciences, University of Palermo, Via del Vespro 131, Palermo, 90134, 
Italy.
(7)Department of Biomedical Sciences, City University of Hong Kong, Kowloon 
Tong, Hong Kong.
(8)Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and 
University Medical Centre (UMC), 3584 CT, Utrecht, The Netherlands.
(9)Princess Máxima Centre for Pediatric Oncology, Utrecht, 3584 CT, The 
Netherlands.
(10)Cancer Center Amsterdam, Laboratory of Experimental Oncology and 
Radiobiology (LEXOR), CEMM, Academic Medical Center, Meibergdreef 9, 1105AZ, 
Amsterdam, The Netherlands. j.p.medema@amc.nl.
(11)Cancer Genomics Netherlands, Utrecht, The Netherlands. j.p.medema@amc.nl.

Colorectal cancer (CRC) is a highly heterogeneous disease both from a molecular 
and clinical perspective. Several distinct molecular entities, such as 
microsatellite instability (MSI), have been defined that make up biologically 
distinct subgroups with their own clinical course. Recent data indicated that 
CRC can be best segregated into four groups called consensus molecular subtypes 
(CMS1-4), each of which has a unique biology and gene expression pattern. In 
order to develop improved, subtype-specific therapies and to gain insight into 
the molecular wiring and origin of these subtypes, reliable models are needed. 
This study was designed to determine the heterogeneity and identify the presence 
of CMSs in a large panel of CRC cell lines, primary cultures and patient-derived 
xenografts (PDX). We provide a repository encompassing this heterogeneity and 
moreover describe that a large part of the models can be robustly assigned to 
one of the four CMSs, independent of the stromal contribution. We subsequently 
validate our CMS stratification by functional analysis which for instance shows 
mesenchymal enrichment in CMS4 and metabolic dysregulation in CMS3. Finally, we 
observe a clear difference in sensitivity to chemotherapy-induced apoptosis, 
specifically between CMS2 and CMS4. This relates to the in vivo efficacy of 
chemotherapy, which delays outgrowth of CMS2, but not CMS4 xenografts. Combined 
our data indicate that molecular subtypes are faithfully modelled in CRC cell 
cultures and PDXs, representing tumour cell intrinsic and stable features. This 
repository provides researchers with a platform to study CRC using the existing 
heterogeneity.

DOI: 10.1038/s41418-017-0011-5
PMCID: PMC5864202
PMID: 29305587 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that they have no competing 
financial interests.


73. Cancer Manag Res. 2020 Oct 1;12:9405-9415. doi: 10.2147/CMAR.S260129. 
eCollection 2020.

Curcumin Modifies Epithelial-Mesenchymal Transition in Colorectal Cancer Through 
Regulation of miR-200c/EPM5.

Wang H(1), Cai X(1), Ma L(1).

Author information:
(1)Department of Emergency Surgery, Shaanxi Provincial People's Hospital, Xi'an, 
Shaanxi Province, People's Republic of China.

BACKGROUND: The serious side effect of current conventional treatments for 
patients with metastatic colorectal cancer (CRC) highlights the requirement of 
an alternative treatment strategy. Natural compounds, such as curcumin, have 
been gained much attention due to its low toxicity and anti-tumor effect.
METHODS: qPCR and Western blot were used to measure the molecular changes 
induced by curcumin. Wound-healing assay and transwell assay were conducted to 
study the effect on cell migration and invasion. RT1 PCR array was performed to 
identify the miRNAs involved in curcumin-repressed EMT. Three algorithms and 
luciferase reporter assay were used to identify EPM5 as a target of miR-200c. 
The bioinformatical analysis of TCGA-COAD and other CRC cohorts were used to 
examine the association of EPM5 with EMT signatures and clinical relevance. The 
ectopic expression or siRNA-mediated knockdown of EPM5 was applied to study the 
role of EPM5 in CRC.
RESULTS: Treatment with curcumin changed the epithelial-mesenchymal transition 
(EMT)-related gene expression, repressed cell migration and invasion in CRC 
cells. Its anti-tumor capability required the upregulation of miR-200c. EPM5 was 
a direct target of miR-200c and enriched in the consensus molecular subtype 
(CMS) 4 of CRC. Ectopic expression of EPM5 alone was sufficient to induce EMT in 
CRC. Downregulation of EPM5 was necessary for curcumin-repressed EMT, migration, 
and invasion. Higher expression of EPM5 was associated with the advanced TNM 
stages and poor survival in CRC.
CONCLUSION: Our data provide the first evidence that the curcumin inhibits EMT 
in CRC by upregulation of miR-200c and downregulation of EPM5, and the use of 
curcumin might be able to prevent or delay CRC progression.

© 2020 Wang et al.

DOI: 10.2147/CMAR.S260129
PMCID: PMC7534868
PMID: 33061628

Conflict of interest statement: None of the authors has any financial or 
non-financial conflict of interest related to this study to disclose.


74. Clin Cancer Res. 2021 Jan 1;27(1):120-130. doi: 10.1158/1078-0432.CCR-20-2403. 
Epub 2020 Oct 27.

Development and Validation of a Gene Signature Classifier for Consensus 
Molecular Subtyping of Colorectal Carcinoma in a CLIA-Certified Setting.

Morris JS(1), Luthra R(2), Liu Y(3), Duose DY(2), Lee W(4), Reddy NG(2), Windham 
J(5), Chen H(4), Tong Z(2), Zhang B(2), Wei W(6), Ganiraju M(7), Broom BM(7), 
Alvarez HA(2), Mejia A(2), Veeranki O(2), Routbort MJ(2), Morris VK(8), Overman 
MJ(8), Menter D(8), Katkhuda R(9), Wistuba II(2), Davis JS(10), Kopetz S(#)(8), 
Maru DM(#)(11).

Author information:
(1)Department of Biostatistics, Epidemiology and Informatics, University of 
Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
(2)Division of Pathology and Laboratory Medicine, The University of Texas MD 
Anderson Cancer Center, Houston, Texas.
(3)Department of Biostatistics, University of Chicago School of Medicine, 
Chicago, Illinois.
(4)Department of Biostatistics, The University of Texas MD Anderson Cancer 
Center, Houston, Texas.
(5)NanoString Technologies Inc., Seattle, Washington.
(6)Cleveland Clinic Foundation, Cleveland, Ohio.
(7)Department of Bioinformatics and Computational Biology, The University of 
Texas MD Anderson Cancer Center, Houston, Texas.
(8)Department of Gastrointestinal Medical Oncology, The University of Texas MD 
Anderson Cancer Center, Houston, Texas.
(9)Department of Pathology, University of Chicago Medical Center, Chicago, 
Illinois.
(10)Department of Epidemiology, The University of Texas MD Anderson Cancer 
Center, Houston, Texas.
(11)Division of Pathology and Laboratory Medicine, The University of Texas MD 
Anderson Cancer Center, Houston, Texas. dmaru@mdanderson.org.
(#)Contributed equally

PURPOSE: Consensus molecular subtyping (CMS) of colorectal cancer has potential 
to reshape the colorectal cancer landscape. We developed and validated an assay 
that is applicable on formalin-fixed, paraffin-embedded (FFPE) samples of 
colorectal cancer and implemented the assay in a Clinical Laboratory Improvement 
Amendments (CLIA)-certified laboratory.
EXPERIMENTAL DESIGN: We performed an in silico experiment to build an optimal 
CMS classifier using a training set of 1,329 samples from 12 studies and 
validation set of 1,329 samples from 14 studies. We constructed an assay on the 
basis of NanoString CodeSets for the top 472 genes, and performed analyses on 
paired flash-frozen (FF)/FFPE samples from 175 colorectal cancers to adapt the 
classifier to FFPE samples using a subset of genes found to be concordant 
between FF and FFPE, tested the classifier's reproducibility and repeatability, 
and validated in a CLIA-certified laboratory. We assessed prognostic 
significance of CMS in 345 patients pooled across three clinical trials.
RESULTS: The best classifier was weighted support vector machine with high 
accuracy across platforms and gene lists (>0.95), and the 472-gene model 
outperforming existing classifiers. We constructed subsets of 99 and 200 genes 
with high FF/FFPE concordance, and adapted FFPE-based classifier that had strong 
classification accuracy (>80%) relative to "gold standard" CMS. The classifier 
was reproducible to sample type and RNA quality, and demonstrated poor prognosis 
for CMS1-3 and good prognosis for CMS2 in metastatic colorectal cancer (P < 
0.001).
CONCLUSIONS: We developed and validated a colorectal cancer CMS assay that is 
ready for use in clinical trials, to assess prognosis in standard-of-care 
settings and explore as predictor of therapy response.

©2020 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-20-2403
PMCID: PMC8713413
PMID: 33109741 [Indexed for MEDLINE]


75. J Natl Cancer Inst. 2018 Dec 1;110(12):1409-1417. doi: 10.1093/jnci/djy067.

Molecular Landscape of ERBB2/ERBB3 Mutated Colorectal Cancer.

Loree JM(1), Bailey AM(2), Johnson AM(2), Yu Y(3), Wu W(3), Bristow CA(4), Davis 
JS(3), Shaw KR(2), Broaddus R(5), Banks KC(6), Lanman RB(6), Meric-Bernstam 
F(4), Overman MJ(1), Kopetz S(1), Raghav K(1).

Author information:
(1)Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer 
Center, Houston, TX.
(2)Sheikh Khalifa Bin Zayed Al Nahyan Institute of Personalized Cancer Therapy, 
The University of Texas MD Anderson Cancer Center, Houston, TX.
(3)Department of Epidemiology, The University of Texas MD Anderson Cancer 
Center, Houston, TX.
(4)Institute for Applied Cancer Science, The University of Texas MD Anderson 
Cancer Center, Houston, TX.
(5)Department of Pathology, The University of Texas MD Anderson Cancer Center, 
Houston, TX.
(6)Guardant Health, Inc., Redwood City, CA.

BACKGROUND: Despite growing therapeutic relevance of ERBB2 amplifications in 
colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed 
to characterize these subsets of CRC.
METHODS: We performed a retrospective analysis of 419 CRC patients from MD 
Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health 
Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, 
mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant 
patients. A third cohort of 1623 CRC patients with ctDNA assays characterized 
the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided.
RESULTS: ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% 
to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of 
MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 
5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue 
cohorts. Age, stage, and tumor location were not associated with either 
mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio 
[OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 
11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = 
.002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. 
Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in 
tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations 
in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% 
CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and 
ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < 
.001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 
subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but 
not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated 
with worse overall survival.
CONCLUSIONS: MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. 
Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling 
that needs consideration when targeting ERBB2/ERBB3.

DOI: 10.1093/jnci/djy067
PMCID: PMC6292791
PMID: 29718453 [Indexed for MEDLINE]


76. Cancer Epidemiol Biomarkers Prev. 2019 Oct;28(10):1720-1724. doi: 
10.1158/1055-9965.EPI-19-0208. Epub 2019 Aug 2.

Association of Epigenetic Clock with Consensus Molecular Subtypes and Overall 
Survival of Colorectal Cancer.

Zheng C(1), Li L(2), Xu R(3).

Author information:
(1)Department of Population and Quantitative Health Sciences, Institute of 
Computational Biology, School of Medicine, Case Western Reserve University, 
Cleveland, Ohio.
(2)Department of Family Medicine, School of Medicine, University of Virginia, 
Charlottesville, Virginia. rxx@case.edu ll8nv@virginia.edu.
(3)Department of Population and Quantitative Health Sciences, Institute of 
Computational Biology, School of Medicine, Case Western Reserve University, 
Cleveland, Ohio. rxx@case.edu ll8nv@virginia.edu.

BACKGROUND: Epigenetic clock, or DNA methylation age, has been shown to highly 
correlate with chronologic age. Epigenetic age acceleration, the difference 
between DNA methylation age and individual's chronologic age, was observed in 
colorectal cancer. However, the association of epigenetic age acceleration with 
colorectal cancer tumor molecular characteristics, clinical characteristics, and 
patient outcomes has not been systematically investigated.
METHODS: DNA methylation ages of 345 patients with colorectal cancer from The 
Cancer Genome Atlas (TCGA) were computed using the Horvath age prediction model. 
Multivariate linear regression was used to assess the association of epigenetic 
age acceleration with molecular and clinical features of colorectal cancer, 
including consensus molecular subtypes (CMS1-CMS4) and tumor stage Cox 
proportional hazards regression was used to assess the association of epigenetic 
age acceleration with survival.
RESULTS: Epigenetic age acceleration is significantly associated with CMS. 
Compared with CMS2, epigenetic age acceleration for CMS1, CMS3, and CMS4 was 
23.90 years [P = 5.55E-11; 95% confidence interval (CI): 17.10-30.69], 9.16 
years (P = 5.84E-03; 95% CI: 2.68-15.65), and 6.05 years (P = 2.69E-02; 95% CI: 
0.70-11.41), respectively. Furthermore, epigenetic age acceleration is 
statistically significantly and positively associated with total mortality (HR = 
1.97; 95% CI: 1.14-3.39; P = 0.014).
CONCLUSIONS: Epigenetic age acceleration is associated with colorectal cancer 
tumor molecular characteristics, and a significant predictor of overall survival 
of colorectal cancer, along with age and tumor stage.
IMPACT: Combining information of colonic tissue epigenetic age acceleration and 
tumor molecular characteristics may improve prognosis prediction in colorectal 
cancer.

©2019 American Association for Cancer Research.

DOI: 10.1158/1055-9965.EPI-19-0208
PMCID: PMC6774810
PMID: 31375479 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of Interest: The authors declare that 
they have no competing interests.


77. Clin Cancer Res. 2020 Nov 15;26(22):5887-5894. doi: 
10.1158/1078-0432.CCR-20-1803. Epub 2020 Jul 21.

Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with 
Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial).

Kawazoe A(1), Kuboki Y(1), Shinozaki E(2), Hara H(3), Nishina T(4), Komatsu 
Y(5), Yuki S(6), Wakabayashi M(7), Nomura S(7), Sato A(7), Kuwata T(8), Kawazu 
M(9), Mano H(9), Togashi Y(10), Nishikawa H(10), Yoshino T(11).

Author information:
(1)Department of Gastroenterology and Gastrointestinal Oncology, National Cancer 
Center Hospital East, Kashiwa, Japan.
(2)Department of Gastroenterology, Cancer Institute Hospital of the Japanese 
Foundation for Cancer Research, Tokyo, Japan.
(3)Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan.
(4)Department of Gastrointestinal Medical Oncology, Shikoku Cancer Center, 
Matsuyama, Japan.
(5)Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer 
Center, Hokkaido, Japan.
(6)Department of Gastroenterology and Hepatology, Hokkaido University Hospital, 
Hokkaido, Japan.
(7)Clinical Research Support Office, National Cancer Center Hospital East, 
Chiba, Japan.
(8)Department of Pathology and Clinical Laboratories, National Cancer Center 
Hospital East, Chiba, Japan.
(9)Division of Cellular Signaling, National Cancer Center, Tokyo, Japan.
(10)Division of Cancer Immunology, Exploratory Oncology Research and Clinical 
Trial Center, National Cancer Center Hospital East, Chiba, Japan.
(11)Department of Gastroenterology and Gastrointestinal Oncology, National 
Cancer Center Hospital East, Kashiwa, Japan. tyoshino@east.ncc.go.jp.

Comment in
    Clin Cancer Res. 2020 Nov 15;26(22):5775-5777.

PURPOSE: This is a phase I/II trial to assess the efficacy and safety of 
napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC).
PATIENTS AND METHODS: Phase I was conducted to determine the recommended phase 2 
dose (RP2D) in a dose escalation design of napabucasin (240 to 480 mg twice 
daily) with 200 mg pembrolizumab every 3 weeks. Phase II included cohort A (n = 
10, microsatellite instability high, MSI-H) and cohort B (n = 40, microsatellite 
stable, MSS). The primary endpoint was immune-related objective response rate 
(irORR). PD-L1 combined positive score (CPS), genomic profiles, and the 
consensus molecular subtypes (CMS) of colorectal cancer were assessed.
RESULTS: A total of 55 patients were enrolled in this study. In phase I, no 
patients experienced dose-limiting toxicities, and napabucasin 480 mg was 
determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In 
cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS < 1, 1≤ CPS <10, and CPS ≥ 
10, respectively. Patients with objective response tended to have higher tumor 
mutation burden than those without. Of evaluable 18 patients for CMS 
classification in cohort B, the irORR was 33.3%, 0%, 33.3%, and 33.3% in CMS1, 
CMS2, CMS3, and CMS4, respectively. The common grade 3 or higher 
treatment-related adverse events included fever (10.0%) in cohort A and 
decreased appetite (7.5%) and diarrhea (5.0%) in cohort B.
CONCLUSIONS: Napabucasin with pembrolizumab showed antitumor activity with 
acceptable toxicities for patients with MSS mCRC as well as MSI-H mCRC, although 
it did not meet the primary end point. The impact of related biomarkers on the 
efficacy warrants further investigations in the additional cohort.See related 
commentary by Nusrat, p. 5775.

©2020 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-20-1803
PMID: 32694160 [Indexed for MEDLINE]


78. PLoS One. 2021 Feb 19;16(2):e0247233. doi: 10.1371/journal.pone.0247233. 
eCollection 2021.

Colony-stimulating factor 3 signaling in colon and rectal cancers: Immune 
response and CMS classification in TCGA data.

Saunders AS(1), Bender DE(1), Ray AL(1), Wu X(2)(3), Morris KT(1).

Author information:
(1)Department of Surgery, The University of Oklahoma Health Sciences Center, 
Oklahoma City, Oklahoma, United States of America.
(2)Academy of Integrative Medicine, Fujian University of Traditional Chinese 
Medicine, Fuzhou, Fujian, China.
(3)Fujian Key Laboratory of Integrative Medicine in Geriatrics, Fujian 
University of Traditional Chinese Medicine, Fuzhou, Fujian, China.

Colorectal cancer is the 2nd leading cause of cancer-related deaths in the 
world. The mechanisms underlying CRC development, progression, and resistance to 
treatment are complex and not fully understood. The immune response in the tumor 
microenvironment has been shown to play a significant role in many cancers, 
including colorectal cancer. Colony-stimulating factor 3 (CSF3) has been 
associated with changes to the immune environment in colorectal cancer animal 
models. We hypothesized that CSF3 signaling would correlate with pro-tumor tumor 
microenvironment changes associated with immune infiltrate and response. We 
utilized publicly available datasets to guide future mechanistic studies of the 
role CSF3 and its receptor (CSF3R) play in colorectal cancer development and 
progression. Here, we use bioinformatics data and mRNA from patients with colon 
(n = 242) or rectal (n = 92) cancers, obtained from The Cancer Genome Atlas 
Firehose Legacy dataset. We examined correlations of CSF3 and CSF3R expression 
with patient demographics, tumor stage and consensus molecular subtype 
classification. Gene expression correlations, cell type enrichment, Estimation 
of STromal and Immune cells in MAlignant Tumor tissues using Expression data 
scores and Gene Ontology were used to analyze expression of receptor and ligand, 
tumor microenvironment infiltration of immune cells, and alterations in 
biological pathways. We found that CSF3 and CSF3R expression is highest in 
consensus molecular subtype 1 and consensus molecular subtype 4. Ligand and 
receptor expression are also correlated with changes in T cell and macrophage 
signatures. CSF3R significantly correlates with a large number of genes that are 
associated with poor colorectal cancer prognosis.

DOI: 10.1371/journal.pone.0247233
PMCID: PMC7895368
PMID: 33606788 [Indexed for MEDLINE]

Conflict of interest statement: The authors have declared that no competing 
interests exist.


79. Expert Rev Mol Diagn. 2015;15(9):1117-24. doi: 10.1586/14737159.2015.1069184. 
Epub 2015 Jul 27.

Exact Sciences' experience with the FDA and CMS parallel review program.

Ridge JR(1), Statz S.

Author information:
(1)a Exact Sciences Corporation, 441 Charmany Drive, Madison, WI 53719, USA.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the 
second leading cause of cancer death among men and women combined in the USA. 
Although the benefits of early CRC detection are widely recognized, screening 
rates are suboptimal. Cologuard is a multitarget stool DNA screening test that 
offers a unique non-invasive option for CRC screening. Cologuard was the first 
product to be reviewed under a pilot parallel review program jointly conducted 
by the US FDA and the Centers for Medicare & Medicaid Services (CMS). This 
parallel review process shortened the overall review for Cologuard and resulted 
in a preliminary National Coverage Determination that coincided with FDA 
approval.

DOI: 10.1586/14737159.2015.1069184
PMID: 26211481 [Indexed for MEDLINE]


80. J Pathol. 2018 May;245(1):19-28. doi: 10.1002/path.5051. Epub 2018 Mar 25.

Prospective patient stratification into robust cancer-cell intrinsic subtypes 
from colorectal cancer biopsies.

Alderdice M(1), Richman SD(2), Gollins S(3), Stewart JP(1), Hurt C(4), Adams 
R(4), McCorry AM(1), Roddy AC(1), Vimalachandran D(5), Isella C(6)(7), Medico 
E(6)(7), Maughan T(8), McArt DG(1), Lawler M(1), Dunne PD(1).

Author information:
(1)Centre for Cancer Research and Cell Biology, Queens's University Belfast, 
Belfast, UK.
(2)Department of Pathology and Tumour Biology, Leeds Institute of Cancer and 
Pathology, St James Hospital, Leeds, UK.
(3)North Wales Cancer Treatment Centre, Rhyl, UK.
(4)Centre for Trials Research, Cardiff University, Cardiff, UK.
(5)Countess of Chester Hospital, Chester, UK.
(6)University of Torino, Department of Oncology, Candiolo, Torino, Italy.
(7)Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
(8)CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, 
Oxford, UK.

Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also 
relevant for patient stratification in molecularly-guided clinical trials. The 
consensus molecular subtypes (CMSs) and colorectal cancer intrinsic subtypes 
(CRISs) transcriptional signatures have potential clinical utility for improving 
prognostic/predictive patient assignment. However, their ability to provide 
robust classification, particularly in pretreatment biopsies from multiple 
regions or at different time points, remains untested. In this study, we 
undertook a comprehensive assessment of the robustness of CRC transcriptional 
signatures, including CRIS and CMS, using a range of tumour sampling 
methodologies currently employed in clinical and translational research. These 
include analyses using (i) laser-capture microdissected CRC tissue, (ii) eight 
publically available rectal cancer biopsy data sets (n = 543), (iii) serial 
biopsies (from AXEBeam trial, NCT00828672; n = 10), (iv) multi-regional biopsies 
from colon tumours (n = 29 biopsies, n = 7 tumours), and (v) pretreatment 
biopsies from the phase II rectal cancer trial COPERNCIUS (NCT01263171; n = 44). 
Compared to previous results obtained using CRC resection material, we 
demonstrate that CMS classification in biopsy tissue is significantly less 
capable of reliably classifying patient subtype (43% unknown in biopsy versus 
13% unknown in resections, p = 0.0001). In contrast, there was no significant 
difference in classification rate between biopsies and resections when using the 
CRIS classifier. Additionally, we demonstrated that CRIS provides significantly 
better spatially- and temporally- robust classification of molecular subtypes in 
CRC primary tumour tissue compared to CMS (p = 0.003 and p = 0.02, 
respectively). These findings have potential to inform ongoing biopsy-based 
patient stratification in CRC, enabling robust and stable assignment of patients 
into clinically-informative arms of prospective multi-arm, multi-stage clinical 
trials. © 2018 The Authors. The Journal of Pathology published by John Wiley & 
Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd 
on behalf of Pathological Society of Great Britain and Ireland.

DOI: 10.1002/path.5051
PMCID: PMC5947827
PMID: 29412457 [Indexed for MEDLINE]


81. Cancer Genet. 2020 Oct;248-249:1-10. doi: 10.1016/j.cancergen.2020.08.006. Epub 
2020 Aug 21.

NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer.

O'Cathail SM(1), Wu CH(2), Lewis A(3), Holmes C(4), Hawkins MA(5), Maughan T(6).

Author information:
(1)Institute of Cancer Sciences, University of Glasgow, United Kingdom. 
Electronic address: Sean.OCathail@glasgow.ac.uk.
(2)Department of Statistics, University of Southampton, United Kingdom.
(3)Department of Life science, CHMLS, Brunel University London, United Kingdom.
(4)Department of Statistics, University of Southampton, United Kingdom; Nuffield 
Department of Medicine, University of Oxford, United Kingdom; Alan Turing 
Institute, London, United Kingdom.
(5)University College London, United Kingdom.
(6)Oxford Institute of Radiation Oncology, University of Oxford, United Kingdom.

We hypothesise that the NRF2 transcription factor would act a biomarker of poor 
prognosis in colorectal cancer. We derived and validated an mRNA based metagene 
signature of NRF2 signalling and validated it in 1360 patients from 4 different 
datasets as an independent biomarker of poor prognosis. This is a novel insight 
into the molecular signalling of colorectal cancer.
BACKGROUND: NRF2 over activity confers poor prognosis in some cancers but its 
prognostic role in colorectal cancer (CRC) is unknown. As a transcription 
factor, we hypothesise a signature of NRF2 regulated genes could act as a 
prognostic biomarker in CRC and reveal novel biological insights.
METHODS: Using known NRF2 regulated genes, differentially expressed in CRC, we 
defined a signature of NRF2 pathway activity using principal component analysis 
and Cox proportional hazard models and tested it in four independent mRNA 
datasets, profiled on three different mRNA platforms.
RESULTS: 36 genes comprised the final NRF2 signature. 1360 patients were 
included in the validation. High NRF2 was associated with worse disease free 
survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR=1.55, 
95% C.I 1.2-2.004, p = 0.0008; GSE39582 HR=1.24, 95% C.I 1.086-1.416, p = 0.001; 
GSE87211 HR=1.431, 95% C.I 1.06-1.93, p = 0.056; MRC FOCUS trial HR=1.14, 95% 
C.I 1.04-1.26, p = 0.008). In multivariate analyses, NRF2 remained significant 
when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and 
BRAF V600E mutation and sidedness in stage IV disease. NRF2 activity was 
particularly enriched in Consensus Molecular Subtype (CMS) 4.
CONCLUSION: For the first time, NRF2 is shown to be a consistent, robust 
prognostic biomarker across all stages of colorectal cancer with additional 
clinical value to current known prognostic biomarkers. High NRF2 signalling in 
CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, 
suggesting avenues of further study.

Copyright © 2020. Published by Elsevier Inc.

DOI: 10.1016/j.cancergen.2020.08.006
PMID: 32871287 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of Competing Interest Dr. Maughan 
reports grants from Medical Research Council, grants from Cancer Research UK, 
during the conduct of the study; non-financial support and other from Astra 
Zeneca, personal fees from Pierre Fabre, outside the submitted work. Dr Holmes 
reports funding from Novartis for research collaboration outside the submitted 
work.


82. Oncologist. 2020 Dec;25(12):e1968-e1979. doi: 10.1002/ONCO.13521. Epub 2020 Sep 
28.

Immunohistochemistry-Based Consensus Molecular Subtypes as a Prognostic and 
Predictive Biomarker for Adjuvant Chemotherapy in Patients with Stage II 
Colorectal Cancer.

Li Y(#)(1)(2), Yao Q(#)(3)(2), Zhang L(1)(4)(2), Mo S(1)(2), Cai S(1)(2), Huang 
D(3)(2), Peng J(1)(2).

Author information:
(1)Department of Colorectal Surgery, Fudan University, Shanghai, People's 
Republic of China.
(2)Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 
People's Republic of China.
(3)Department of Pathology, Fudan University, Shanghai, People's Republic of 
China.
(4)Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, 
Shanghai, People's Republic of China.
(#)Contributed equally

BACKGROUND: For stage II colorectal cancer (CRC), the efficacy of adjuvant 
chemotherapy remains controversial. Consensus molecular subtype (CMS) has been 
validated to be a prognostic tool for CRCs. In this study, CMS status was 
investigated as a prognostic biomarker for the efficacy of adjuvant chemotherapy 
for stage II colorectal cancer.
MATERIALS AND METHODS: The tissue microarray was retrospectively constructed of 
165 nonconsecutive, primary, and sporadic stage II CRCs. CMS status was 
determined by immunohistochemistry staining of CDX2, HTR2B, FRMD6, and ZEB1, 
combining with microsatellite instability testing. The prognostic for adjuvant 
chemotherapy efficacy of CMS status was calculated by Kaplan-Meier curves and 
Cox regression analysis. Subgroup analyses were conducted according to tumor 
location.
RESULTS: Kaplan-Meier curves indicated that CMS was associated with overall 
survival (OS) and disease-free survival for stage II CRCs. Cox regression 
analysis showed that CMS was an independent risk factor for OS. Among high-risk 
clinicopathological factors, patients with CMS2/3 (hazard ratio [HR]: 0.445, 95% 
confidence interval [CI]: 0.227-0.875), left-sided tumors (HR: 0.488, 95% CI: 
0.247-0.968), or fewer than 12 lymph nodes examined (HR: 0.307, 95% CI: 
0.097-0.974) had survival benefit from adjuvant chemotherapy. Subgroup analysis 
showed that adjuvant chemotherapy only improved OS for patients with left-sided 
tumors of CMS2/3 subtype. Regardless of CMS, right-sided tumors had no benefit 
from adjuvant chemotherapy.
CONCLUSION: CMS is a better prognostic factor for adjuvant chemotherapy for 
stage II CRCs. Together with tumor location, CMS classification will aid in 
personalized treatment for stage II CRCs.
IMPLICATIONS FOR PRACTICE: For stage II colorectal cancer (CRC), the efficacy of 
adjuvant chemotherapy remains controversial, in that its minimal benefit (no 
more than 5% on average) is considered not worth the toxic effects of the drugs. 
There are still no effective prognostic and predictive biomarkers. This study 
showed that consensus molecular subtype (CMS) status is a predictive marker for 
adjuvant chemotherapy efficacy. Patients with left-sided tumors of CMS2/3 
subtype have survival benefit by receiving adjuvant chemotherapy, which will aid 
in personalized treatment for stage II CRCs. Moreover, this test of CMS based on 
immunohistochemistry is cheap, not time consuming, and easily conducted in the 
laboratories of most hospitals.

© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf 
of AlphaMed Press.

DOI: 10.1002/ONCO.13521
PMCID: PMC8186407
PMID: 32926498 [Indexed for MEDLINE]

Conflict of interest statement: Disclosures of potential conflicts of interest 
may be found at the end of this article.


83. Future Oncol. 2018 Sep;14(21):2097-2102. doi: 10.2217/fon-2017-0708. Epub 2018 
Aug 13.

Prognostic and predictive biomarkers in nonmetastatic colorectal cancers.

Haddad FG(1), Eid R(1), Kourie HR(1), Barouky E(2), Ghosn M(1).

Author information:
(1)Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University, 
Beirut, Lebanon.
(2)General Surgery Department, Faculty of Medicine, Saint Joseph University, 
Beirut, Lebanon.

DOI: 10.2217/fon-2017-0708
PMID: 30101612 [Indexed for MEDLINE]


84. Mol Oncol. 2021 Dec;15(12):3348-3362. doi: 10.1002/1878-0261.13098. Epub 2021 
Sep 30.

A panel of DNA methylation markers for the classification of consensus molecular 
subtypes 2 and 3 in patients with colorectal cancer.

van den Berg I(1), Smid M(2), Coebergh van den Braak RRJ(1), van de Wiel MA(3), 
van Deurzen CHM(4), de Weerd V(2), Martens JWM(2), IJzermans JNM(1), Wilting 
SM(2).

Author information:
(1)Department of Surgery, Erasmus MC - University Medical Center Rotterdam, The 
Netherlands.
(2)Department of Medical Oncology, Erasmus MC Cancer Institute, University 
Medical Center Rotterdam, The Netherlands.
(3)Department of Epidemiology & Data Science, Amsterdam University Medical 
Center, Amsterdam Public Health research institute, The Netherlands.
(4)Department of Pathology, Erasmus MC - University Medical Center Rotterdam, 
The Netherlands.

Consensus molecular subtypes (CMSs) can guide precision treatment of colorectal 
cancer (CRC). We aim to identify methylation markers to distinguish between CMS2 
and CMS3 in patients with CRC, for which an easy test is currently lacking. To 
this aim, fresh-frozen tumor tissue of 239 patients with stage I-III CRC was 
analyzed. Methylation profiles were obtained using the Infinium 
HumanMethylation450 BeadChip. We performed adaptive group-regularized logistic 
ridge regression with post hoc group-weighted elastic net marker selection to 
build prediction models for classification of CMS2 and CMS3. The Cancer Genome 
Atlas (TCGA) data were used for validation. Group regularization of the probes 
was done based on their location either relative to a CpG island or relative to 
a gene present in the CMS classifier, resulting in two different prediction 
models and subsequently different marker panels. For both panels, even when 
using only five markers, accuracies were > 90% in our cohort and in the TCGA 
validation set. Our methylation marker panel accurately distinguishes between 
CMS2 and CMS3. This enables development of a targeted assay to provide a robust 
and clinically relevant classification tool for CRC patients.

© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on 
behalf of Federation of European Biochemical Societies.

DOI: 10.1002/1878-0261.13098
PMCID: PMC8637568
PMID: 34510716 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflict of interest.


85. JCO Glob Oncol. 2021 Dec;7:1694-1702. doi: 10.1200/GO.21.00273.

Western Honduras Copán Population-Based Cancer Registry: Initial Estimates and a 
Model for Rural Central America.

Norwood DA(1)(2)(3), Montalvan-Sanchez EE(1)(4), Corral JE(5), Estévez-Ordoñez 
D(3), Paredes AA(1)(2), Domínguez LB(1), Rodríguez AA(1)(2), Bravo LE(6)(7), 
Morgan DR(3)(8), Domínguez RL(1).

Author information:
(1)Western Honduras Gastric Cancer Prevention Initiative, Hospital de Occidente, 
Santa Rosa de Copán, Honduras.
(2)Universidad Nacional Autónoma de Honduras, School of Medicine, Honduras.
(3)School of Medicine, The University of Alabama at Birmingham, Birmingham, AL.
(4)Indiana University, Department of Medicine, Indianapolis, IN.
(5)Division of Gatroenterology and Hepatology, Presbyterian Healthcare Services, 
Albuquerque, New Mexico.
(6)IACR Regional Representative for Latin America, International Agency for 
Research on Cancer, Lyon, France.
(7)Departamento de Patología, Universidad del Valle, Cali, Colombia.
(8)Division of Gastroenterology, Hepatology and Nutrition, The University of 
Alabama at Birmingham, Birmingham, AL.

PURPOSE: Population-based cancer registries (PBCRs) are critical for national 
cancer control planning, yet few low- and middle-income countries (LMICs) have 
quality PBCRs. The Central America Four region represents the principal LMIC 
region in the Western hemisphere. We describe the establishment of a PBCR in 
rural Western Honduras with first estimates for the 2013-2017 period.
METHODS: The Western Honduras PBCR was established through a collaboration of 
academic institutions and the Honduras Ministry of Health for collection of 
incident cancer data from public and private health services. Data were recorded 
using the Research Electronic Data Capture (REDCap) web-based platform with data 
monitoring and quality checks. Crude and age-standardized rates (ASRs) were 
calculated at the regional level, following WHO methodology.
RESULTS: The web-based platform for data collection, available ancillary data 
services (eg, endoscopy), and technical support from international centers 
(United States and Colombia) were instrumental for quality control. Crude cancer 
incidence rates were 112.2, 69.8, and 154.6 per 100,000 habitants overall, 
males, and females, respectively (excluding nonmelanoma skin cancer). The 
adjusted ASRs were 84.2, 49.6, and 118.9 per 100,000 overall habitants, males, 
and females, respectively. The most common sites among men were stomach (ASR 
26.0, 52.4%), colorectal (ASR 5.11, 10.15%), and prostate (ASR 2.7, 5.4%). The 
most common sites in women were cervix (ASR 34.2, 36.7%), breast (ASR 11.2, 
12.3%), and stomach (ASR 10.8, 11.7%).
CONCLUSION: The Copán-PBCR represents a successful model to develop cancer 
monitoring in rural LMICs. Innovations included the use of the REDCap platform 
and leverage of Health Ministry resources. This provides the first PBCR data for 
Honduras and the Central America Four and confirms that infection-driven 
cancers, such as gastric and cervical, should be priority targets for cancer 
control initiatives.

DOI: 10.1200/GO.21.00273
PMCID: PMC8691495
PMID: 34914550 [Indexed for MEDLINE]

Conflict of interest statement: Juan E. CorralOpen Payments Link: 
https://openpaymentsdata.cms.gov/physician/1389804 Douglas R. MorganResearch 
Funding: Cancer Prevention Pharmaceuticals (Inst), Thorne Research (Inst), CDx 
Diagnostics (Inst), Freenome (Inst)No other potential conflicts of interest were 
reported.


86. J Geriatr Oncol. 2021 May;12(4):623-631. doi: 10.1016/j.jgo.2020.11.006. Epub 
2020 Dec 2.

The association between patient experience and healthcare outcomes using 
SEER-CAHPS patient experience and outcomes among cancer survivors.

Mohan CS(1), Rotter JS(2), Tan HJ(3), Kent E(2), Bjurlin MA(3), Basch E(4), 
Samuel C(2), Nielsen M(3), Smith AB(5).

Author information:
(1)University of North Carolina, Department of Urology, 2115 Physicians Office 
Building, CB #7235, Chapel Hill, NC 27599-7235, USA.
(2)Department of Health Policy,UNC Gillings School of Global Public Health, 135 
Dauer Drive 1101, McGavran-Greenberg Hall, CB #7411, Chapel Hill, NC 27599-7235, 
USA.
(3)University of North Carolina, Department of Urology, 2115 Physicians Office 
Building, CB #7235, Chapel Hill, NC 27599-7235, USA; Department of Urology, UNC 
School of Medicine; Lineberger Comprehensive Cancer Center, 2115 Physicians 
Office Building, CB #7235, Chapel Hill, NC 27599-7235, USA.
(4)Division of Hematology/Oncology, Department of Medicine, UNC School of 
Medicine, Lineberger Comprehensive Cancer Center, 170 Manning Drive, CB# 7305, 
Chapel Hill, NC 27599, USA.
(5)Division of Hematology/Oncology, Department of Medicine, UNC School of 
Medicine, Lineberger Comprehensive Cancer Center, 170 Manning Drive, CB# 7305, 
Chapel Hill, NC 27599, USA. Electronic address: angela_smith@med.unc.edu.

OBJECTIVE: To understand the relationship between patient experience, as 
measured by scores on the Consumer Assessment of Healthcare Providers and 
Systems (CAHPS®) survey, and clinical and financial outcomes among older cancer 
survivors.
MATERIALS AND METHODS: We analyzed the records of all Fee-for-Service (FFS) 
Medicare beneficiaries 66 years and older who completed one CAHPS survey from 
2001 to 2004 or 2007-2013 with one of the five following cancer types: breast, 
bladder, colorectal, lung, or prostate; and completed a CAHPS survey within 
5 years of cancer diagnosis date. We conducted a multivariate analysis, 
controlling for clinical and demographic variables, to evaluate the association 
between excellent CAHPS scores and the following clinical and financial 
outcomes: mortality, emergency department visits, and total healthcare 
expenditures.
RESULTS: A total of 7395 individuals were present in our cohort, with 57% being 
male and 85.7% non-Hispanic White. Breakdown of the cohort by cancer site is as 
follows: prostate (40.4%), breast (28.6%), colorectal (14.0%), lung (9.4%), and 
bladder (7.6%). When looking at the relationship between CAHPS scores and 
clinical outcomes, there was no significant difference between excellent and 
non-excellent CAHPS score respondents in all three of the clinical outcomes 
studied. Furthermore, there was no association between ED utilization and 
patient experience scores when stratifying by cancer site and race/ethnicity 
among this cohort.
CONCLUSION: In this cohort, a highly rated patient experience, as measured by 
responses on the CAHPS survey, is not associated with improved clinical outcomes 
among older cancer survivors.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.jgo.2020.11.006
PMID: 33277226 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of Competing Interest Charan Mohan 
has nothing to disclose. Jason Rotter has nothing to disclose. Hung-Jui Tan has 
nothing to disclose. Erin Kent has nothing to disclose. Marc Bjurlin has nothing 
to disclose. Ethan Basch reports grants the National Cancer Institute and 
Patient-Centered Outcomes Research Institute, and personal fees from Memorial 
Sloan Kettering Cancer Center, Research Triangle Institute/CMS, CareVive 
Systems, Sivan Healthcare, Navigating Cancer, and Self Care Catalysts all 
outside the submitted work. Cleo Samuel reports grants from National Cancer 
Institute, grants from National Comprehensive Cancer Network and Pfizer, 
personal fees from University of Miami, outside the submitted work. Matthew 
Nielsen reports consultant status from American College of Physicians and 
American Urological Association, and medical advisory board membership on Grand 
Rounds, outside the submitted work. Angela Smith reports consultant status with 
Photocure, consultant status with Merck, grants from PCORI, medical advisory 
board membership with Urogen, outside the submitted work.


87. Brief Bioinform. 2021 Sep 2;22(5):bbab077. doi: 10.1093/bib/bbab077.

Multilevel prioritization of gene regulators associated with consensus molecular 
subtypes of colorectal cancer.

Song K(1), Cai H(2), Zheng H(1), Yang J(1), Jin L(1), Xiao H(1), Zhang J(1), 
Zhao Z(1), Li X, Zhao W, Li X(1).

Author information:
(1)College of Bioinformatics Science and Technology, Harbin Medical University, 
Harbin 150086, China.
(2)Medical Big Data and Bioinformatics Research Center, First Affiliated 
Hospital of Gannan Medical University, Ganzhou, China.

Consensus molecular subtypes (CMSs) are emerging as critical factor for 
prognosis and treatment of colorectal cancer. Gene regulators, including 
chromatin regulator, RNA-binding protein and transcriptional factor, are 
critical modulators of cancer hallmark, yet little is known regarding the 
underlying functional mechanism in CMSs. Herein, we identified a core set of 235 
functional gene regulators (FGRs) by integrating genome, epigenome, 
transcriptome and interactome of CMSs. FGRs exhibited significant multi-omics 
alterations and impacts on cell lines growth, as well as significantly enriched 
cancer driver genes and pathways. Moreover, common FGRs played different roles 
in the context of CMSs. In accordance with the immune characteristics of CMSs, 
we found that the anti-tumor immune pathways were mainly activated by FGRs (e.g. 
STAT1 and CREBBP) in CMS1, while inhibited by FGRs in CMS2-4. FGRs mediated 
aberrant expression of ligands, which bind to receptor on immune cells, and 
modulated tumor immune microenvironment of subtypes. Intriguingly, systematic 
exploration of datasets using genomic and transcriptome co-similarity reveals 
the coordinated manner in FGRs act in CMSs to orchestrate their pathways and 
patients' prognosis. Expression signatures of the FGRs revealed an optimized CMS 
classifier, which demonstrated 88% concordance with the gold-standard 
classifier, but avoiding the influence of sample composition. Overall, our 
integrative analysis identified FGRs to regulate core tumorigenic 
processes/pathways across CMSs.

© The Author(s) 2021. Published by Oxford University Press. All rights reserved. 
For Permissions, please email: journals.permissions@oup.com.

DOI: 10.1093/bib/bbab077
PMID: 33855351 [Indexed for MEDLINE]


88. BMC Cancer. 2019 Nov 27;19(1):1155. doi: 10.1186/s12885-019-6327-4.

Molecular subtyping improves prognostication of Stage 2 colorectal cancer.

Purcell RV(1), Schmeier S(2), Lau YC(3), Pearson JF(4), Frizelle FA(3).

Author information:
(1)Department of Surgery, University of Otago, PO Box 4345, Christchurch, 8140, 
New Zealand. Rachel.purcell@otago.ac.nz.
(2)School of Natural and Computational Sciences, Massey University, Albany, 
0632, New Zealand.
(3)Department of Surgery, University of Otago, PO Box 4345, Christchurch, 8140, 
New Zealand.
(4)Biostatistics and Computational Biology Unit, University of Otago, PO Box 
4345, Christchurch, 8140, New Zealand.

BACKGROUND: Post-surgical staging is the mainstay of prognostic stratification 
for colorectal cancer (CRC). Here, we compare TNM staging to consensus molecular 
subtyping (CMS) and assess the value of subtyping in addition to stratification 
by TNM.
METHODS: Three hundred and eight treatment-naïve colorectal tumours were 
accessed from our institutional tissue bank. CMS typing was carried out using 
tumour gene-expression data. Post-surgical TNM-staging and CMS were analysed 
with respect to clinicopathologic variables and patient outcome.
RESULTS: CMS alone was not associated with survival, while TNM stage 
significantly explained mortality. Addition of CMS to TNM-stratified tumours 
showed a prognostic effect in stage 2 tumours; CMS3 tumours had a significantly 
lower overall survival (P = 0.006). Stage 2 patients with a good prognosis 
showed immune activation and up-regulation of tumour suppressor genes.
CONCLUSIONS: Although stratification using CMS does not outperform TNM staging 
as a prognostic indicator, gene-expression based subtyping shows promise for 
improved prognostication in stage 2 CRC.

DOI: 10.1186/s12885-019-6327-4
PMCID: PMC6882162
PMID: 31775679 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that they have no competing 
interests.


89. Systematic Reviews on Selected Pharmacogenetic Tests for Cancer Treatment: 
CYP2D6 for Tamoxifen in Breast Cancer, KRAS for anti-EGFR antibodies in 
Colorectal Cancer, and BCR-ABL1 for Tyrosine Kinase Inhibitors in Chronic 
Myeloid Leukemia [Internet].

Terasawa T(1), Dahabreh I(1), Castaldi PJ(1), Trikalinos TA(1).

Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Jun 7.
AHRQ Technology Assessments.

Author information:
(1)Tufts EPC

The challenges in the integration of cancer pharmacogenetics and targeted 
therapies in clinical practice should require evidence of benefit to the 
patients (a favorable balance of harms and benefits of testing), 
cost-effectiveness for the healthcare system, incorporating patient preferences, 
improving provider education, and anticipating potential ethical and social 
implications. It is possible that pharmacogenetic testing and the subsequent use 
of targeted therapies will add cost without producing clinically meaningful 
improvements in patient outcomes. In the absence of data that can address its 
clinical utility and value, integration of pharmacogenetic testing in the 
healthcare system is not straightforward. This Technology Assessment assesses 
the evidence on the benefits and harms of three pharmacogenetic tests employed 
for three different diseases pertinent to the Medicare beneficiary population: 
variations in CYP2D6 and response to tamoxifen in breast cancer; variations in 
KRAS and response to cetuximab and panitumumab in colorectal cancer and 
variations in BCR-ABL1 and response to imatinib, dasatinib and nilotinib in 
chronic myeloid leukemia. The Coverage and Analysis Group at the Centers for 
Medicare and Medicaid Services (CMS) requested this report from The Technology 
Assessment Program (TAP) at the Agency for Healthcare Research and Quality 
(AHRQ). AHRQ assigned this report to the following Evidence-based Practice 
Center: Tufts EPC (HHSA 290 2007 100551).

PMID: 26065050


90. J Transl Med. 2021 Oct 26;19(1):446. doi: 10.1186/s12967-021-03088-7.

The role of PDGFRA as a therapeutic target in young colorectal cancer patients.

Kim TW(1), Hong HK(2), Lee C(3), Kim S(3), Lee WY(4), Yun SH(4), Kim HC(4), Huh 
JW(4), Park YA(4), Joung JG(5)(6), Park WY(7)(8)(9), Cho YB(10)(11)(12).

Author information:
(1)Department of Health Sciences and Technology, SAIHST, Sungkyunkwan 
University, Seoul, Republic of Korea.
(2)Samsung Biomedical Research Institute, Seoul, Republic of Korea.
(3)Samsung Genome Institute, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, 
Seoul, 06351, Republic of Korea.
(4)Department of Surgery, Samsung Medical Center, Sungkyunkwan University School 
of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.
(5)Samsung Genome Institute, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, 
Seoul, 06351, Republic of Korea. jegunjoung@gmail.com.
(6)Department of Biomedical Science, CHA University, Pocheon-si, South Korea. 
jegunjoung@gmail.com.
(7)Department of Health Sciences and Technology, SAIHST, Sungkyunkwan 
University, Seoul, Republic of Korea. woongyang@skku.edu.
(8)Samsung Genome Institute, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, 
Seoul, 06351, Republic of Korea. woongyang@skku.edu.
(9)Department of Molecular Cell Biology, Sungkyunkwan University School of 
Medicine, Seoul, Korea. woongyang@skku.edu.
(10)Department of Health Sciences and Technology, SAIHST, Sungkyunkwan 
University, Seoul, Republic of Korea. gscyb@skku.edu.
(11)Department of Surgery, Samsung Medical Center, Sungkyunkwan University 
School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea. 
gscyb@skku.edu.
(12)Department of Biopharmaceutical Convergence, Sunkyunkwan University, Seoul, 
Korea. gscyb@skku.edu.

BACKGROUND: Young patients with colorectal cancer (CRC) exhibit poor prognoses 
compared to older patients due to the difficulty in early diagnosis and 
treatment. However, the underlying molecular characteristics are still unclear.
METHODS: We conducted a comprehensive analysis of 49 CRC patients without 
hereditary CRC using the whole-exome and RNA sequencing with tumor and matched 
normal samples. A total of 594 TCGA samples and 4 patient-derived cells were 
utilized for validation.
RESULTS: Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were 
enriched in the young (≤ 40 years) and old (> 60 years) age groups, 
respectively. A CMS4-associated gene, platelet-derived growth factor receptor α 
(PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, 
p = 0.0001) and was negatively correlated with age (p = 0.0001, R = - 0.526). 
Moreover, PDGFRA showed a positive co-expression with metastasis-related genes 
in young CRC patients. In vitro validation confirmed that young patient-derived 
cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a 
reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC 
patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old 
CRC patients.
CONCLUSIONS: Our study suggests that CRC in young patients is associated with 
CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic 
strategies and represent a predictive biomarker of response to regorafenib for 
young CRC patients.

© 2021. The Author(s).

DOI: 10.1186/s12967-021-03088-7
PMCID: PMC8546951
PMID: 34702313 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no potential conflicts of 
interest.


91. Clin Cancer Res. 2018 Jan 1;24(1):224-233. doi: 10.1158/1078-0432.CCR-17-1090. 
Epub 2017 Oct 23.

KRAS Mutation and Consensus Molecular Subtypes 2 and 3 Are Independently 
Associated with Reduced Immune Infiltration and Reactivity in Colorectal Cancer.

Lal N(#)(1), White BS(#)(2), Goussous G(1), Pickles O(1), Mason MJ(2), Beggs 
AD(3), Taniere P(4), Willcox BE(1), Guinney J(2), Middleton GW(5)(4).

Author information:
(1)Institute of Immunology and Immunotherapy, University of Birmingham, 
Birmingham, United Kingdom.
(2)Computational Oncology, Sage Bionetworks, Seattle, USA.
(3)Institute of Cancer and Genomic Sciences, University of Birmingham, 
Birmingham, United Kingdom.
(4)University Hospitals Birmingham NHS Foundation Trust, Birmingham, United 
Kingdom.
(5)Institute of Immunology and Immunotherapy, University of Birmingham, 
Birmingham, United Kingdom. g.middleton@bham.ac.uk.
(#)Contributed equally

Purpose:KRAS mutation is a common canonical mutation in colorectal cancer, found 
at differing frequencies in all consensus molecular subtypes (CMS). The 
independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, 
we explored the immunobiological effects of KRAS mutation across the CMS 
spectrum.Experimental Design: Expression analysis of immune genes/signatures was 
performed using The Cancer Genome Atlas (TCGA) RNA-seq and the KFSYSCC 
microarray datasets. Multivariate analysis included KRAS status, CMS, tumor 
location, MSI status, and neoantigen load. Protein expression of STAT1, 
HLA-class II, and CXCL10 was analyzed by digital IHC.Results: The Th1-centric 
co-ordinate immune response cluster (CIRC) was significantly, albeit modestly, 
reduced in KRAS-mutant colorectal cancer in both datasets. Cytotoxic T cells, 
neutrophils, and the IFNγ pathway were suppressed in KRAS-mutant samples. The 
expressions of STAT1 and CXCL10 were reduced at the mRNA and protein levels. In 
multivariate analysis, KRAS mutation, CMS2, and CMS3 were independently 
predictive of reduced CIRC expression. Immune response was heterogeneous across 
KRAS-mutant colorectal cancer: KRAS-mutant CMS2 samples have the lowest CIRC 
expression, reduced expression of the IFNγ pathway, STAT1 and CXCL10, and 
reduced infiltration of cytotoxic cells and neutrophils relative to CMS1 and 
CMS4 and to KRAS wild-type CMS2 samples in the TCGA. These trends held in the 
KFSYSCC dataset.Conclusions:KRAS mutation is associated with suppressed 
Th1/cytotoxic immunity in colorectal cancer, the extent of the effect being 
modulated by CMS subtype. These results add a novel immunobiological dimension 
to the biological heterogeneity of colorectal cancer. Clin Cancer Res; 24(1); 
224-33. ©2017 AACR.

©2017 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-17-1090
PMCID: PMC5777581
PMID: 29061646 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of interest statement: The authors 
declare no potential conflicts of interest.


92. Int J Mol Sci. 2021 Apr 7;22(8):3811. doi: 10.3390/ijms22083811.

BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with 
Molecular Features Identifies Predictors of Response.

Zhang L(1)(2), Ramesh P(1)(2), Steinmetz M(1), Medema JP(1)(2).

Author information:
(1)Laboratory for Experimental Oncology and Radiobiology, Center for 
Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, 
University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
(2)Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Colorectal cancer (CRC) is a heterogeneous disease, which in part explains the 
differential response to chemotherapy observed in the clinic. BH3 mimetics, 
which target anti-apoptotic BCL-2 family members, have shown potential in the 
treatment of hematological malignancies and offer promise for the treatment of 
solid tumors as well. To gain a comprehensive understanding of the response to 
BH3 mimetics in CRC and the underlying molecular factors predicting sensitivity, 
we screened a panel of CRC cell lines with four BH3 mimetics targeting distinct 
anti-apoptotic BCL-2 proteins. Treatment with compounds alone and in combination 
revealed potent efficacy of combined MCL-1 and BCL-XL inhibition in inducing CRC 
cell death, irrespective of molecular features. Importantly, expression of the 
anti-apoptotic protein target of BH3 mimetics on its own did not predict 
sensitivity. However, the analysis did identify consensus molecular subtype 
(CMS) specific response patterns, such as higher resistance to single and 
combined BCL-2 and MCL-1 inhibition in CMS2 cell lines. Furthermore, analysis of 
mutation status revealed that KRAS mutant cell lines were more resistant to 
MCL-1 inhibition. Conclusively, we find that CRC cell lines presented with 
distinct responses to BH3 mimetics that can in part be predicted by their CMS 
profile and KRAS/BRAF mutations. Overall, almost all CRC lines share sensitivity 
in the nanomolar range to combined MCL-1 and BCL-XL targeting suggesting that 
this would be the preferred approach to target these cancers.

DOI: 10.3390/ijms22083811
PMCID: PMC8067732
PMID: 33917026 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflict of interest.


93. Int J Cancer. 2019 Jan 15;144(2):366-371. doi: 10.1002/ijc.31767. Epub 2018 Oct 
22.

Capturing colorectal cancer inter-tumor heterogeneity in patient-derived 
xenograft (PDX) models.

Prasetyanti PR(1)(2), van Hooff SR(1)(2), van Herwaarden T(1)(2), de Vries 
N(1)(2), Kalloe K(1)(2), Rodermond H(1)(2), van Leersum R(1)(2), de Jong 
JH(1)(2), Franitza M(3), Nürnberg P(3), Todaro M(4), Stassi G(5), Medema 
JP(1)(2).

Author information:
(1)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic 
Medical Center, Amsterdam, The Netherlands.
(2)Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands.
(3)Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany 
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated 
Diseases (CECAD), Cologne, Germany.
(4)DIBIMIS, University of Palermo, Palermo, Italy.
(5)Cellular and Molecular Pathophysiology Laboratory, Department of Surgical, 
Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.

Patient-derived xenograft (PDX) models have become an important asset in 
translational cancer research. However, to provide a robust preclinical 
platform, PDXs need to accommodate the tumor heterogeneity that is observed in 
patients. Colorectal cancer (CRC) can be stratified into four consensus 
molecular subtypes (CMS) with distinct biological and clinical features. 
Surprisingly, using a set of CRC patients, we revealed the partial 
representation of tumor heterogeneity in PDX models. The epithelial subtypes, 
the largest subgroups of CRC subtype, were very ineffective in establishing 
PDXs, indicating the need for further optimization to develop an effective 
personalized therapeutic approach to CRC. Moreover, we showed that tumor cell 
proliferation was associated with successful PDX establishment and able to 
distinguish patient with poor clinical outcomes within CMS2 group.

© 2018 The Authors. International Journal of Cancer published by John Wiley & 
Sons Ltd on behalf of UICC.

DOI: 10.1002/ijc.31767
PMCID: PMC6587871
PMID: 30151914 [Indexed for MEDLINE]


94. Curr Drug Targets. 2018;19(15):1731-1737. doi: 
10.2174/1389450119666180803122744.

Genetic Molecular Subtypes in Optimizing Personalized Therapy for Metastatic 
Colorectal Cancer.

Włodarczyk M(1)(2), Włodarczyk J(1), Siwiński P(2), Sobolewska-Włodarczyk 
A(1)(3), Fichna J(1).

Author information:
(1)Department of Biochemistry, Medical University of Lodz, Lodz, Poland.
(2)Department of General and Colorectal Surgery, Medical University of Lodz, 
Lodz, Poland.
(3)Department of Gastroenterology, Medical University of Lodz, Lodz, Poland.

Colorectal cancer (CRC) is a heterogeneous disease entity in terms of both 
molecular carcinogenesis and morphologic carcinogenesis multistep pathways. 
Considerable heterogeneity exists within CRC due to the varied genetic and 
epigenetic mechanisms involved in different carcinogenesis pathways. A better 
understanding of pathophysiology of tumors is necessary to develop modern and 
successful means of treatment in metastatic CRC. Over the last 5 years, there 
has been a surge in interest in the molecular classification of colorectal 
cancer, as its clinical importance both for predicting prognosis and in guiding 
personalized treatment had been acknowledged. Recently, the Colorectal Cancer 
Subtyping Consortium identified four consensus molecular subtypes, CMS 1-4 in 
CRC; however, attempts to stratify CRC using molecular features for prognostic 
and predictive purposes in clinical conditions had limited success. In this 
review, we focused on molecularly defined subtypes of CRC including specific 
mutations and discuss implications for current and future patient management in 
metastatic CRC to achieve the maximal therapeutic response for each patient, 
while reducing adverse side effects of therapy.

Copyright© Bentham Science Publishers; For any queries, please email at 
epub@benthamscience.org.

DOI: 10.2174/1389450119666180803122744
PMID: 30073926 [Indexed for MEDLINE]


95. Cancers (Basel). 2021 Nov 20;13(22):5824. doi: 10.3390/cancers13225824.

Identification of Gene Co-Expression Networks Associated with Consensus 
Molecular Subtype-1 of Colorectal Cancer.

Nunez SK(1), Young CD(1), Griffen TL(1), Ohandjo AQ(2), McKinney LP(1), Kopetz 
S(3), Lillard JW Jr(1).

Author information:
(1)Department of Microbiology, Biochemistry & Immunology, Morehouse School of 
Medicine, Atlanta, GA 30310, USA.
(2)East West Collaborative Research, Marietta, GA 30060, USA.
(3)Department of Gastrointestinal Medical Oncology, The University of Texas M.D. 
Anderson Cancer Center, Houston, TX 77030, USA.

Colorectal cancer (CRC) is driven in part by dysregulated Wnt, Ras-Raf-MAPK, 
TGF-β, and PI3K-Akt signaling. The progression of CRC is also promoted by 
molecular alterations and heterogeneous-yet interconnected-gene mutations, 
chromosomal instability, transcriptomic subtypes, and immune signatures. Genomic 
alterations of CRC progression lead to changes in RNA expression, which support 
CRC metastasis. An RNA-based classification system used for CRC, known as 
consensus molecular subtyping (CMS), has four classes. CMS1 has the lowest 
survival after relapse of the four CRC CMS phenotypes. Here, we identify gene 
signatures and associated coding mRNAs that are co-expressed during CMS1 CRC 
progression. Using RNA-seq data from CRC primary tumor samples, acquired from 
The Cancer Genome Atlas (TCGA), we identified co-expression gene networks 
significantly correlated with CMS1 CRC progression. CXCL13, CXCR5, IL10, PIK3R5, 
PIK3AP1, CCL19, and other co-expressed genes were identified to be positively 
correlated with CMS1. The co-expressed eigengene networks for CMS1 were 
significantly and positively correlated with the TNF, WNT, and ERK1 and ERK2 
signaling pathways, which together promote cell proliferation and survival. This 
network was also aligned with biological characteristics of CMS1 CRC, being 
positively correlated to right-sided tumors, microsatellite instability, 
chemokine-mediated signaling pathways, and immune responses. CMS1 also 
differentially expressed genes involved in PI3K-Akt signaling. Our findings 
reveal CRC gene networks related to oncogenic signaling cascades, cell 
activation, and positive regulation of immune responses distinguishing CMS1 from 
other CRC subtypes.

DOI: 10.3390/cancers13225824
PMCID: PMC8616344
PMID: 34830978

Conflict of interest statement: The authors declare no conflict of interest. The 
funders had no role in the design of the study; in the collection, analyses, or 
interpretation of data; in the writing of the manuscript, or in the decision to 
publish the results.


96. Methods Mol Biol. 2018;1765:179-191. doi: 10.1007/978-1-4939-7765-9_11.

Classification of Colorectal Cancer in Molecular Subtypes by 
Immunohistochemistry.

Ten Hoorn S(1), Trinh A(2)(3), de Jong J(1), Koens L(4), Vermeulen L(5).

Author information:
(1)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental and Molecular Medicine (CEMM), Academic Medical Center & Cancer 
Center Amsterdam, Amsterdam, The Netherlands.
(2)Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing 
Centre, Cambridge, UK.
(3)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 
USA.
(4)Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
(5)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental and Molecular Medicine (CEMM), Academic Medical Center & Cancer 
Center Amsterdam, Amsterdam, The Netherlands. l.vermeulen@amc.uva.nl.

Colorectal cancer (CRC) is a heterogeneous disease, which can be categorized 
into distinct consensus molecular subtypes (CMSs). These subtypes differ in both 
clinical as well as biological properties. The gold-standard classification 
strategy relies on genome-wide expression data, which hampers widespread 
implementation. Here we describe an immunohistochemical (IHC) Mini Classifier, a 
practical tool that, in combination with microsatellite instability testing, 
delivers objective and accurate scoring to classify CRC patients into the main 
molecular disease subtypes. It is a robust immunohistochemical-based assay 
containing four specific stainings (FRMD6, ZEB1, HTR2B, and CDX2) in combination 
with cytokeratin. We also describe an online tool for classification of 
individual samples based on scoring parameters of these stainings.

DOI: 10.1007/978-1-4939-7765-9_11
PMID: 29589308 [Indexed for MEDLINE]


97. J Clin Oncol. 2022 Mar 10;40(8):876-883. doi: 10.1200/JCO.21.01460. Epub 2022 
Jan 7.

Blood-Based Biomarker Panel for Personalized Lung Cancer Risk Assessment.

Fahrmann JF(1), Marsh T(2), Irajizad E(1)(3), Patel N(1), Murage E(1), Vykoukal 
J(1), Dennison JB(1), Do KA(3), Ostrin E(4), Spitz MR(5), Lam S(6), Shete S(7), 
Meza R(8), Tammemägi MC(9)(10), Feng Z(2), Hanash SM(1).

Author information:
(1)Department of Clinical Cancer Prevention, The University of Texas MD Anderson 
Cancer Center, Houston, TX.
(2)Biostatistics Program, Fred Hutchinson Cancer Research Center, Seattle, WA.
(3)Department of Biostatistics, The University of Texas MD Anderson Cancer 
Center, Houston, TX.
(4)Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer 
Center, Houston, TX.
(5)Department of Medicine, Baylor College of Medicine, Houston, TX.
(6)Department of Integrative Oncology, British Columbia Cancer Research 
Institute, Vancouver, British Columbia, Canada.
(7)Department of Epidemiology, The University of Texas MD Anderson Cancer 
Center, Houston, TX.
(8)Department of Epidemiology, University of Michigan, School of Public Health, 
Ann Arbor, MI.
(9)Prevention and Cancer Control, Ontario Health (Cancer Care Ontario), Toronto, 
Ontario, Canada.
(10)Department of Health Sciences, Brock University, St Catharines, Ontario, 
Canada.

PURPOSE: To investigate whether a panel of circulating protein biomarkers would 
improve risk assessment for lung cancer screening in combination with a risk 
model on the basis of participant characteristics.
METHODS: A blinded validation study was performed using prostate lung colorectal 
ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the 
performance of a four-marker protein panel (4MP) consisting of the precursor 
form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and 
cytokeratin-19 fragment in combination with a lung cancer risk prediction model 
(PLCOm2012) compared with current US Preventive Services Task Force (USPSTF) 
screening criteria. The 4MP was assayed in 1,299 sera collected preceding lung 
cancer diagnosis and 8,709 noncase sera.
RESULTS: The 4MP alone yielded an area under the receiver operating 
characteristic curve of 0.79 (95% CI, 0.77 to 0.82) for case sera collected 
within 1-year preceding diagnosis and 0.74 (95% CI, 0.72 to 0.76) among the 
entire specimen set. The combined 4MP + PLCOm2012 model yielded an area under 
the receiver operating characteristic curve of 0.85 (95% CI, 0.82 to 0.88) for 
case sera collected within 1 year preceding diagnosis. The benefit of the 4MP in 
the combined model resulted from improvement in sensitivity at high specificity. 
Compared with the USPSTF2021 criteria, the combined 4MP + PLCOm2012 model 
exhibited statistically significant improvements in sensitivity and specificity. 
Among PLCO participants with ≥ 10 smoking pack-years, the 4MP + PLCOm2012 model 
would have identified for annual screening 9.2% more lung cancer cases and would 
have reduced referral by 13.7% among noncases compared with USPSTF2021 criteria.
CONCLUSION: A blood-based biomarker panel in combination with PLCOm2012 
significantly improves lung cancer risk assessment for lung cancer screening.

DOI: 10.1200/JCO.21.01460
PMCID: PMC8906454
PMID: 34995129

Conflict of interest statement: Johannes F. FahrmannPatents, Royalties, Other 
Intellectual Property: There is IP related to biomarkers for early detection of 
pancreas cancer Nikul PatelPatents, Royalties, Other Intellectual Property: The 
Lung IP Panel Jennifer B. DennisonResearch Funding: Cosmos Wisdom (Inst), Dynex 
(Inst)Patents, Royalties, Other Intellectual Property: IP on pancreas cancer 
early detection biomarkers, IP on lung cancer nodules early detection biomarkers 
Edwin OstrinHonoraria: AstraZeneca/MedImmuneOpen Payments Link: 
https://openpaymentsdata.cms.gov/physician/877532 Stephen LamResearch Funding: 
Nucleix Inc (Inst)Patents, Royalties, Other Intellectual Property: Deep learning 
prediction algorithm to estimate the 3-year lung cancer risk and cancer-related 
mortality for individuals who have two or more screening chest CT scans. Joint 
application by Johns Hopkins University and the BC Cancer Agency Patent pending 
(Inst) Sanjay SheteStock and Other Ownership Interests: Vertex Martin C. 
TammemägiConsulting or Advisory Role: AstraZeneca, Nucleix, Medial EarlySign 
Ziding FengResearch Funding: Exact Sciences (Inst)Patents, Royalties, Other 
Intellectual Property: I am one of the coinventors for a biomarker panel for 
pancreatic cancer. The patent was filed by the UT MD Anderson Cancer Center and 
was licensed to a company by the UT MD Anderson Cancer Center; I am a coinventor 
for a biomarker test. UT MDACCs own the IP. I received a license fee in January 
2019. No other payment has been received after that Samir HanashHonoraria: 
Abbott Laboratories, BMSResearch Funding: Cosmos Wisdom, DynexPatents, 
Royalties, Other Intellectual Property: Patents submitted for lung and 
pancreatic cancer diagnostic markers (Inst)No other potential conflicts of 
interest were reported.


98. Front Immunol. 2021 Apr 9;12:647540. doi: 10.3389/fimmu.2021.647540. eCollection 
2021.

TOX Acts as a Tumor Suppressor by Inhibiting mTOR Signaling in Colorectal 
Cancer.

Yang M(1)(2)(3), Huang Q(2)(3), Li C(2)(3), Jiang Z(1)(2)(3), Sun J(1), Wang 
Z(1), Liang R(2)(3), Li D(2)(3), Li B(2)(3)(4)(5), Zhao H(1).

Author information:
(1)Department of Internal Oncology, Shanghai Jiao Tong University Affiliated 
Sixth People's Hospital, Shanghai, China.
(2)Shanghai Institute of Immunology, Shanghai Jiao Tong University School of 
Medicine, Shanghai, China.
(3)Department of Immunology and Microbiology, Shanghai Jiao Tong University 
School of Medicine, Shanghai, China.
(4)Henan Key Laboratory of Digestive Organ Transplantation, Department of 
Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou 
University, Henan, China.
(5)Institute of Arthritis Research, Guanghua Integrative Medicine Hospital, 
Shanghai, China.

The treatment and prognosis of advanced colorectal cancer (CRC) remain a 
challenging clinical research focus. Here, we describe a new CRC tumor 
suppressor and potential therapeutic target: thymocyte selection associated high 
mobility group box (TOX) protein. The expression of TOX was lower in CRC than 
para-CRC. With the increase of tumor stage, TOX expression decreased, indicating 
the presence of TOX relates to better overall survival (OS). TOX suppressed the 
mechanistic target of rapamycin kinase (mTOR) signaling to inhibit cell 
proliferation, migration, invasion, and change the epithelial-mesenchymal 
transition (EMT) process. In addition, TOX promoted apoptosis. As tumor mutation 
burden and tumor microenvironment play vital roles in the occurrence and 
development of tumors, we analyzed the TOX expression in the immune 
microenvironment of CRC. The high TOX expression was negatively correlated with 
TumorPurity. Moreover, it was positively related to ImmuneScore, StromalScore, 
microsatellite instability (MSI) status, and Consensus Molecular Subtypes (CMS) 
3 typing. Based on gene set enrichment analysis (GSEA), the reduced expression 
of TOX activated mTOR. We found rapamycin, a mTOR inhibitor, partly inhibited 
cell proliferation, invasion, and migration in shTOX HCT116 cells. Lastly, TOX 
suppressed tumorigenesis and lung metastasis of CRC in vivo. Rapamycin alone or 
combined with PD1 inhibitor is more effective than PD1 inhibitor alone in a 
tumor model. Taken together, these findings highlight the tumor-suppressive role 
of TOX in CRC, especially in MSI CRC, and provide valuable information that 
rapamycin alone or combined with PD1 inhibitor has therapeutic potential in CRC.

Copyright © 2021 Yang, Huang, Li, Jiang, Sun, Wang, Liang, Li, Li and Zhao.

DOI: 10.3389/fimmu.2021.647540
PMCID: PMC8062716
PMID: 33897695 [Indexed for MEDLINE]

Conflict of interest statement: BL is a co-founder of Biotheus Inc and chairman 
of its scientific advisory board. The remaining authors declare that the 
research was conducted in the absence of any commercial or financial 
relationships that could be construed as a potential conflict of interest.


99. Pathol Res Pract. 2021 Apr;220:153379. doi: 10.1016/j.prp.2021.153379. Epub 2021 
Mar 5.

A modified protein marker panel to identify four consensus molecular subtypes in 
colorectal cancer using immunohistochemistry.

Li X(1), Larsson P(1), Ljuslinder I(2), Ling A(1), Löfgren-Burström A(1), 
Zingmark C(1), Edin S(1), Palmqvist R(3).

Author information:
(1)Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
(2)Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
(3)Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden. 
Electronic address: richard.palmqvist@umu.se.

Colorectal cancer (CRC) is a heterogeneous disease with different genetic and 
molecular backgrounds, leading to a diverse patient prognosis and treatment 
response. Four consensus molecular subtypes (CMS 1-4) have recently been 
proposed based on transcriptome profiling. A clinically practical 
immunohistochemistry (IHC) based CMS classifier consisting of the four markers 
FRMD6, ZEB1, HTR2B, and CDX2 was then demonstrated. However, the IHC-CMS 
classifier did not distinguish between CMS2 and CMS3 tumours. In this study, we 
have applied the proposed transcriptome based and IHC-based CMS classifiers in a 
CRC cohort of 65 patients and found a concordance of 77.5 %. Further, we 
modified the IHC-CMS classifier by analysing the differentially expressed genes 
between CMS2 and CMS3 tumours using RNA-sequencing data from the TCGA dataset. 
The result showed that WNT signalling was among the most upregulated pathways in 
CMS2 tumours, and the expression level of CTNNB1 (encoding β-catenin), a WNT 
pathway hallmark, was significantly upregulated (P = 1.15 × 10-6). We therefore 
introduced nuclear β-catenin staining to the IHC-CMS classifier. Using the 
modified classifier in our cohort, we found a 71.4 % concordance between the IHC 
and RNA-sequencing based CMS classifiers. Moreover, β-catenin staining could 
classify 16 out of the 19 CMS2/3 tumours into CMS2 or CMS3, thereby showing an 
84.2 % concordance with the RNA-sequencing-based classifier. In conclusion, we 
evaluated CMS classifiers based on transcriptome and IHC analysis. We present a 
modified IHC panel that categorizes CRC tumours into the four CMS groups. To our 
knowledge, this is the first study using IHC to identify all four CMS groups.

Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.

DOI: 10.1016/j.prp.2021.153379
PMID: 33721619 [Indexed for MEDLINE]


100. BMC Cancer. 2020 Aug 18;20(1):776. doi: 10.1186/s12885-020-07236-y.

Improving clinical management of colon cancer through CONNECTION, a nation-wide 
colon cancer registry and stratification effort (CONNECTION II trial): rationale 
and protocol of a single arm intervention study.

van den Berg I(1)(2), van de Weerd S(3)(4)(5), Roodhart JML(2), Vink GR(2)(6), 
van den Braak RRJC(1), Jimenez CR(7), Elias SG(8), van Vliet D(1), Koelink M(2), 
Hong E(9), van Grevenstein WMU(10), van Oijen MGH(2), Beets-Tan RGH(9), van 
Krieken JHJM(4), IJzermans JNM(1), Medema JP(11)(12), Koopman M(2); 
CONNECTION-study group.

Author information:
(1)Department of Surgery, Erasmus MC, University Medical Center Rotterdam, 
Rotterdam, the Netherlands.
(2)Department of Medical Oncology, University Medical Center Utrecht, Utrecht 
University, Utrecht, the Netherlands.
(3)Laboratory for Experimental Oncology and Radiobiology, Center for 
Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, 
University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.
(4)Department of Pathology, Radboud University Medical Centre, Nijmegen, the 
Netherlands.
(5)Oncode Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The 
Netherlands.
(6)Netherlands Comprehensive Cancer Organisation, department of research, 
Utrecht, the Netherlands.
(7)Department of Medical Oncology, Amsterdam UMC- location VUmc, Amsterdam, the 
Netherlands.
(8)Julius Center for Health Sciences and Primary Care, University Medical Center 
Utrecht, Utrecht University, Utrecht, The Netherlands.
(9)Department of radiology, The Netherlands Cancer Institute, Amsterdam, The 
Netherlands.
(10)Department of Surgery, University Medical Center Utrecht, Utrecht 
University, Utrecht, the Netherlands.
(11)Laboratory for Experimental Oncology and Radiobiology, Center for 
Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, 
University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands. 
j.p.medema@amsterdamumc.nl.
(12)Oncode Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The 
Netherlands. j.p.medema@amsterdamumc.nl.

BACKGROUND: It is estimated that around 15-30% of patients with early stage 
colon cancer benefit from adjuvant chemotherapy. We are currently not capable of 
upfront selection of patients who benefit from chemotherapy, which indicates the 
need for additional predictive markers for response to chemotherapy. It has been 
shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, 
have prognostic and/or predictive value. Due to postoperative timing of 
chemotherapy in current guidelines, tumor response to chemotherapy per CMS is 
not known, which makes the differentiation between the prognostic and predictive 
value impossible. Therefore, we propose to assess the tumor response per CMS in 
the neoadjuvant chemotherapy setting. This will provide us with clear data on 
the predictive value for chemotherapy response of the CMSs.
METHODS: In this prospective, single arm, multicenter intervention study, 262 
patients with resectable microsatellite stable cT3-4NxM0 colon cancer will be 
treated with two courses of neoadjuvant and two courses of adjuvant capecitabine 
and oxaliplatin. The primary endpoint is the pathological tumor response to 
neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor 
response, the prognostic value of these responses for recurrence free survival 
and overall survival and the differences in CMS classification of the same tumor 
before and after neoadjuvant chemotherapy. The study is scheduled to be 
performed in 8-10 Dutch hospitals. The first patient was included in February 
2020.
DISCUSSION: Patient selection for adjuvant chemotherapy in early stage colon 
cancer is far from optimal. The CMS classification is a promising new biomarker, 
but a solid chemotherapy response assessment per subtype is lacking. In this 
study we will investigate whether CMS classification can be of added value in 
clinical decision making by analyzing the predictive value for chemotherapy 
response. This study can provide the results necessary to proceed to future 
studies in which (neo) adjuvant chemotherapy may be withhold in patients with a 
specific CMS subtype, who show no benefit from chemotherapy and for whom 
possible new treatments can be investigated.
TRIAL REGISTRATION: This study has been registered in the Netherlands Trial 
Register (NL8177) at 11-26-2019, https://www.trialregister.nl/trial/8177 . The 
study has been approved by the medical ethics committee Utrecht (MEC18/712).

DOI: 10.1186/s12885-020-07236-y
PMCID: PMC7433093
PMID: 32811457 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that they have no competing 
interests.


101. Cancers (Basel). 2021 Dec 28;14(1):136. doi: 10.3390/cancers14010136.

A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 
Colorectal Cancer.

Bueno-Fortes S(1), Muenzner JK(2)(3), Berral-Gonzalez A(1), Hampel C(2)(3), 
Lindner P(2)(3), Berninger A(2)(3), Huebner K(2)(3), Kunze P(2)(3), Bäuerle 
T(4), Erlenbach-Wuensch K(3), Sánchez-Santos JM(1)(5), Hartmann A(3), De Las 
Rivas J(1), Schneider-Stock R(2)(3).

Author information:
(1)Bioinformatics and Functional Genomics Group, Cancer Research Center 
(CiC-IMBCC, CSIC/USAL/IBSAL), Consejo Superior de Investigaciones Científicas 
(CSIC) and University of Salamanca (USAL), 37007 Salamanca, Spain.
(2)Experimental Tumor Pathology, University Hospital of the Friedrich-Alexander 
University Erlangen-Nürnberg, 91054 Erlangen, Germany.
(3)Institute of Pathology, University Hospital of the Friedrich-Alexander 
University Erlangen-Nürnberg, 91054 Erlangen, Germany.
(4)Preclinical Imaging Platform Erlangen (PIPE), Institute of Radiology, 
University Hospital Erlangen-Nuremberg, 91054 Erlangen, Germany.
(5)Department of Statistics, University of Salamanca (USAL), 37008 Salamanca, 
Spain.

The epithelial-mesenchymal transition (EMT) is associated with tumor 
aggressiveness and increased invasion, migration, metastasis, angiogenesis, and 
drug resistance. Although the HCT116 p21-/- cell line is well known for its 
EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, 
the gene signature of this rather intermediate EMT-like cell line has not been 
determined so far. In this work, we present a robust molecular and 
bioinformatics analysis, to reveal the associated gene expression profile and 
its correlation with different types of colorectal cancer tumors. We compared 
the quantitative signature obtained with the NanoString platform with the 
expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes 
(CMS) as identified, and validated the results in a large independent cohort of 
human tumor samples. The expression signature derived from the p21-/- cells 
showed consistent and reliable numbers of upregulated and downregulated genes, 
as evaluated with two machine learning methods against the four CRC subtypes 
(i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated 
gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal 
subtype. At the same time, the upregulated gene signature of the native HCT116 
cells was similar to that of CMS1. Using a multivariate Cox regression model to 
analyze the survival data in the CRC tumor cohort, we selected genes that have a 
predictive risk power (with a significant gene risk incidence score). A set of 
genes of the mesenchymal signature was proven to be significantly associated 
with poor survival, specifically in the CMS4 CRC human cohort. We suggest that 
the gene signature of HCT116 p21-/- cells could be a suitable metric for 
mechanistic studies regarding the CMS4 signature and its functional consequences 
in CRC. Moreover, this model could help to discover the molecular mechanisms of 
intermediate EMT, which is known to be associated with extraordinarily high 
stemness and drug resistance.

DOI: 10.3390/cancers14010136
PMCID: PMC8750372
PMID: 35008299

Conflict of interest statement: The authors declare no conflict of interest.


102. Clin Cancer Res. 2019 Jul 1;25(13):3954-3961. doi: 
10.1158/1078-0432.CCR-19-0311. Epub 2019 Apr 9.

Class 1, 2, and 3 BRAF-Mutated Metastatic Colorectal Cancer: A Detailed 
Clinical, Pathologic, and Molecular Characterization.

Schirripa M(#)(1), Biason P(#)(1), Lonardi S(#)(1), Pella N(2), Pino MS(3), 
Urbano F(4), Antoniotti C(5), Cremolini C(5), Corallo S(6), Pietrantonio 
F(6)(7), Gelsomino F(8), Cascinu S(8), Orlandi A(9), Munari G(1)(10), Malapelle 
U(11), Saggio S(6), Fontanini G(12), Rugge M(10), Mescoli C(10), Lazzi S(13), 
Reggiani Bonetti L(14), Lanza G(15), Dei Tos AP(16), De Maglio G(17), Martini 
M(18)(19), Bergamo F(1), Zagonel V(1), Loupakis F(#)(20), Fassan M(#)(10).

Author information:
(1)Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, 
Italy.
(2)Department of Oncology, University and General Hospital, Udine, Italy.
(3)Medical Oncology Unit, Department of Oncology, Azienda USL Toscana Centro, S. 
Maria Annunziata Hospital, Florence, Italy.
(4)Department of Radiological Sciences, Oncology and Pathology, Policlinico 
Umberto I, Sapienza University of Rome, Rome, Italy.
(5)Unit of Medical Oncology, Department of Translational Research and New 
Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
(6)Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei 
Tumori, Milan, Italy.
(7)Department of Oncology and Hemato-oncology, University of Milan, Milan, 
Italy.
(8)Department of Oncology and Haematology, University Hospital of Modena, 
Modena, Italy.
(9)U.O.C Oncologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 
Rome, Italy.
(10)Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), 
University of Padua, Padua, Italy.
(11)Department of Public Health, University Federico II of Naples, Naples, 
Italy.
(12)Department of Surgical, Medical, Molecular Pathology and Critical Area, 
University of Pisa, Pisa, Italy.
(13)Department of Medical Biotechnology, Section of Pathology, University of 
Siena, Siena, Italy.
(14)Department of Diagnostic Medicine and Public Health, Section of Pathology, 
Università di Modena e Reggio Emilia, Policlinico di Modena, Modena, Italy.
(15)Department of Pathology, University of Ferrara, Ferrara, Italy.
(16)Department of Pathology and Molecular Genetics, Treviso General Hospital, 
Treviso, Italy.
(17)Department of Pathology, University Hospital of Udine, Udine, Italy.
(18)Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità 
Pubblica, area di Anatomia Patologica, Fondazione policlinico Universitario A. 
Gemelli IRCCS, Rome, Italy.
(19)Istituto di Anatomia Patologica, Università Cattolica Del Sacro Cuore, Rome, 
Italy.
(20)Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, 
Italy. fotios.loupakis@iov.veneto.it.
(#)Contributed equally

PURPOSE: BRAF mutations are grouped in activating RAS-independent signaling as 
monomers (class 1-V600E) or as dimers (class 2-codons 597/601), and 
RAS-dependent with impaired kinase activity (class 3-codons 594/596). Although 
clinical, pathologic, and molecular features of V600EBRAF-mutated metastatic 
colorectal cancer (mCRC) are well known, limited data are available from the two 
other classes.
EXPERIMENTAL DESIGN: Data from 117 patients with BRAF (92 class 1, 12 class 2, 
and 13 class 3)-mutated mCRC were collected. A total of 540 BRAF wt mCRCs were 
included as control. IHC profiling was performed to determine the consensus 
molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating 
lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and 
progression-free survival were evaluated by Kaplan-Meier and log-rank test.
RESULTS: Class 3 BRAF-mutated mCRC was more frequently left sided (P = 0.0028), 
pN0 (P = 0.0159), and without peritoneal metastases (P = 0.0176) compared with 
class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as 
compared with BRAF wt, was 2.38 [95% confidence interval (CI), 1.61-3.54] for 
class 1, 1.90 (95% CI, 0.85-4.26) for class 2, and 0.93 (95% CI, 0.51-1.69) for 
class 3 (P < 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher 
median CD3/CD8-positive lymphocyte infiltration was observed in BRAF-mutated 
class 2 (P = 0.033) compared with class 3 cases.
CONCLUSIONS: For the first time, different clinical and pathologic features and 
outcome data were reported according to the three BRAF mutation classes in mCRC. 
Specific targeted treatment strategies should be identified in the near future 
for such patients.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-19-0311
PMID: 30967421 [Indexed for MEDLINE]


103. Front Immunol. 2020 Oct 29;11:550250. doi: 10.3389/fimmu.2020.550250. 
eCollection 2020.

Analysis of Spatial Organization of Suppressive Myeloid Cells and Effector T 
Cells in Colorectal Cancer-A Potential Tool for Discovering Prognostic 
Biomarkers in Clinical Research.

Zwing N(1), Failmezger H(2), Ooi CH(3), Hibar DP(4), Cañamero M(1), Gomes B(5), 
Gaire F(1)(6), Korski K(1)(6).

Author information:
(1)Early Biomarker Development Oncology, pharma Research and Early Development 
(pRED), Roche Innovation Center Munich, Penzberg, Germany.
(2)pharma Research and Early Development Informatics (pREDi), Roche Innovation 
Center Munich, Penzberg, Germany.
(3)Pharmaceutical Sciences-Biomarkers, Bioinformatics and Omics (PS-BiOmics), 
pharma Research and Early Development (pRED), Roche Innovation Center Basel, 
Basel, Switzerland.
(4)Product Development, Personalized Healthcare Analytics, Genentech, Inc., 
South San Francisco, CA, United States.
(5)Early Biomarker Development Oncology, pharma Research and Early Development 
(pRED), Roche Innovation Center Basel, Basel, Switzerland.
(6)Product Development, Personalized Healthcare Data Science Imaging, Roche 
Pharma, Basel, Switzerland.

The development and progression of solid tumors such as colorectal cancer (CRC) 
are known to be affected by the immune system and cell types such as T cells, 
natural killer (NK) cells, and natural killer T (NKT) cells are emerging as 
interesting targets for immunotherapy and clinical biomarker research. In 
addition, CD3+ and CD8+ T cell distribution in tumors has shown positive 
prognostic value in stage I-III CRC. Recent developments in digital 
computational pathology support not only classical cell density based tumor 
characterization, but also a more comprehensive analysis of the spatial cell 
organization in the tumor immune microenvironment (TiME). Leveraging that 
methodology in the current study, we tried to address the question of how the 
distribution of myeloid derived suppressor cells in TiME of primary CRC affects 
the function and location of cytotoxic T cells. We applied multicolored 
immunohistochemistry to identify monocytic (CD11b+CD14+) and granulocytic 
(CD11b+CD15+) myeloid cell populations together with proliferating and 
non-proliferating cytotoxic T cells (CD8+Ki67+/-). Through automated object 
detection and image registration using HALO software (IndicaLabs), we applied 
dedicated spatial statistics to measure the extent of overlap between the areas 
occupied by myeloid and T cells. With this approach, we observed distinct 
spatial organizational patterns of immune cells in tumors obtained from 74 
treatment-naive CRC patients. Detailed analysis of inter-cell distances and 
myeloid-T cell spatial overlap combined with integrated gene expression data 
allowed to stratify patients irrespective of their mismatch repair (MMR) status 
or consensus molecular subgroups (CMS) classification. In addition, generation 
of cell distance-derived gene signatures and their mapping to the TCGA data set 
revealed associations between spatial immune cell distribution in TiME and 
certain subsets of CD8+ and CD4+ T cells. The presented study sheds a new light 
on myeloid and T cell interactions in TiME in CRC patients. Our results show 
that CRC tumors present distinct distribution patterns of not only T effector 
cells but also tumor resident myeloid cells, thus stressing the necessity of 
more comprehensive characterization of TiME in order to better predict cancer 
prognosis. This research emphasizes the importance of a multimodal approach by 
combining computational pathology with its detailed spatial statistics and gene 
expression profiling. Finally, our study presents a novel approach to cancer 
patients' characterization that can potentially be used to develop new 
immunotherapy strategies, not based on classical biomarkers related to CRC 
biology.

Copyright © 2020 Zwing, Failmezger, Ooi, Hibar, Cañamero, Gomes, Gaire and 
Korski.

DOI: 10.3389/fimmu.2020.550250
PMCID: PMC7658632
PMID: 33193316 [Indexed for MEDLINE]


104. Sci Rep. 2018 Jul 26;8(1):11285. doi: 10.1038/s41598-018-29703-0.

Annexin A2 overexpression associates with colorectal cancer invasiveness and 
TGF-ß induced epithelial mesenchymal transition via Src/ANXA2/STAT3.

Rocha MR(1), Barcellos-de-Souza P(2), Sousa-Squiavinato ACM(2), Fernandes PV(3), 
de Oliveira IM(3), Boroni M(4), Morgado-Diaz JA(5).

Author information:
(1)Cellular and Molecular Oncobiology Program, Instituto Nacional de Câncer, 
INCA, Rua André Cavalcanti, 37, 20231-050, Rio de Janeiro, Brazil. 
rochamr.2@gmail.com.
(2)Cellular and Molecular Oncobiology Program, Instituto Nacional de Câncer, 
INCA, Rua André Cavalcanti, 37, 20231-050, Rio de Janeiro, Brazil.
(3)Pathology Division - DIPAT, Instituto Nacional de Câncer, INCA, Av Cordeiro 
da Graça, 156, 20220-400, Rio de Janeiro, Brazil.
(4)Bioinformatics Unit, Instituto Nacional de Câncer, INCA, Rua André 
Cavalcanti, 37, 20231-050, Rio de Janeiro, Brazil.
(5)Cellular and Molecular Oncobiology Program, Instituto Nacional de Câncer, 
INCA, Rua André Cavalcanti, 37, 20231-050, Rio de Janeiro, Brazil. 
jmorgado@inca.gov.br.

Annexin A2 (ANXA2) is upregulated in several malignancies, including colorectal 
cancer (CRC). However, there is little knowledge on the molecular mechanisms 
involved to its upregulation. The aim of this study was to identify the 
mechanism through which ANXA2 overexpression leads to CRC progression and 
evaluate its potential prognostic value. We used human CRC samples to analyse 
the correlation between ANXA2 levels and tumour staging. ANXA2 expression was 
increased in CRC tissues compared to normal colon tissues. In addition, we 
observe increased ANXA2 levels in stage IV tumours and metastasis, when compared 
to stage I-III. Whereas E-cadherin, an epithelial marker, decreased in stage 
II-IV and increased in metastasis. We've also shown that TGF-β, a classic EMT 
inductor, caused upregulation of ANXA2, and internalization of both E-cadherin 
and ANXA2 in CRC cells. ANXA2 silencing hindered TGF-β-induced invasiveness, and 
inhibitors of the Src/ANXA2/STAT3 pathway reversed the EMT. In silico analysis 
confirmed overexpression of ANXA2 and association to the consensus moleculars 
subtypes (CMS) with the worst prognosis. Therefore, ANXA2 overexpression play a 
pivotal role in CRC invasiveness through Src/ANXA2/STAT3 pathway activation. The 
association of ANXA2 to distinct CMSs suggests the possible use of ANXA2 as a 
prognostic marker or directed target therapy.

DOI: 10.1038/s41598-018-29703-0
PMCID: PMC6062537
PMID: 30050103 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


105. J Cancer Policy. 2021 Dec;30:100312. doi: 10.1016/j.jcpo.2021.100312. Epub 2021 
Oct 29.

Low-Value Care and Excess Out-Of-Pocket Expenditure Among Older Adults with 
Incident Cancer - A Machine learning approach.

Iloabuchi C(1), Dwibedi N(1), LeMasters T(1), Shen C(2), Ladani A(3), 
Sambamoorthi U(4).

Author information:
(1)Department of Pharmaceutical Systems and Policy, West Virginia University 
School of Pharmacy, Robert C. Byrd Health Sciences Center [North], P.O. Box 9510 
Morgantown, WV 26506-9510.
(2)Division of Outcomes Research and Quality, Department of Surgery, College of 
Medicine, Pennsylvania State University, Hershey, PA, USA.
(3)Department of Medicine, Division of Rheumatology, West Virginia University 
Medicine, Morgantown, WV, USA.
(4)Department of Pharmacotherapy, College of Pharmacy, "Vashisht" Professor of 
Disparities, Health Education, Awareness & Research in Disparities (HEARD) 
Scholar, Texas Center for Health Disparities, University of North Texas Health 
Sciences Center, 3500 Camp Bowie Blvd, Fort Worth, Texas, 76107. Professor 
Emerita, West Virginia University School of Pharmacy, Pharmaceutical Systems and 
Policy, Morgantown, WV, USA, Cell: 732-740-3760.

OBJECTIVE: To evaluate the association of low-value care with excess 
out-of-pocket expenditure among older adults diagnosed with incident breast, 
prostate, colorectal cancers, and Non-Hodgkin's Lymphoma.
METHODS: We used a retrospective cohort study design with 12-month baseline and 
follow-up periods. We identified a cohort of older adults (age ≥ 66 years) 
diagnosed with breast, prostate, colorectal cancers, or Non-Hodgkin's lymphoma 
between January 2014 and December 2014. We assessed low-value care and patient 
out-of-pocket expenditure in the follow-up period. We identified relevant 
low-value services using ICD9/ICD10 and CPT/HCPCS codes from the linked health 
claims and patient out-of-pocket expenditure from Medicare claim files and 
expressed expenditure in 2016 USD.
RESULTS: About 29% of older adults received at least one low-value care 
procedure during the follow-up period. Low-value care differed by gender, and 
rates were higher in women with colorectal cancer (32.7%) vs. (28.8%) and NHL 
(40%) vs. (39%) compared to men. Individuals who received one or more low-value 
care had significantly higher mean out-of-pocket expenditure ($8,726±$7,214) vs. 
($6,802±$6,102). XGBOOST, a machine learning algorithm revealed that low-value 
care was among the five leading predictors of OOP expenditure.
CONCLUSION: One in four older adults with incident cancer received low-value 
care in 12-months after a cancer diagnosis. Across all cancer populations, 
individuals who received low-value care had significantly higher out-of-pocket 
expenditure. Excess out-of-pocket expenditure was driven by low-value care, 
fragmentation of care, and an increasing number of pre-existing chronic 
conditions.
POLICY STATEMENT: This study focuses on health policy issues, specifically 
value-based care and its findings have important clinical and policy 
implications for Centers for Medicare and Medicaid Services (CMS) which has 
issued a roadmap for states to accelerate the adoption of value-based care, with 
the Department of Health and Human Services (HHS) setting a goal of converting 
50% of traditional Medicare payment systems to alternative payment models tied 
to value-based care by 2022.

DOI: 10.1016/j.jcpo.2021.100312
PMCID: PMC8916690
PMID: 35281326 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no potential conflicts of 
interest.


106. Rev Med Chil. 2017 Apr;145(4):419-430. doi: 10.4067/S0034-98872017000400001.

[Characterization of patients with sporadic colorectal cancer following the new 
Consensus Molecular Subtypes (CMS)].

[Article in Spanish]

Wielandt AM(1), Villarroel C(1), Hurtado C(1), Simian D(2), Zamorano D(3), 
Martínez M(4), Castro M(2), Vial MT(4), Kronberg U(3), López-Kostner F(3).

Author information:
(1)Laboratorio de Oncología y Genética Molecular, Clínica Las Condes, Santiago, 
Chile, awielandt@clc.cl.
(2)Dirección Académica, Clínica Las Condes, Santiago, Chile.
(3)Unidad de Coloproctología, Clínica Las Condes, Santiago, Chile.
(4)Unidad de Anatomía Patológica, Clínica Las Condes, Santiago, Chile.

BACKGROUND: Colorectal cancer (CRC) is an heterogeneous disease. Three 
carcinogenic pathways determine its molecular profile: microsatellite 
instability (MSI), chromosomal instability (CIN) and CpG island methylator 
phenotype (CIMP). Based on the new molecular classification, four consensus CRC 
molecular subtypes (CMS) are established, which are related to clinical, 
pathological and biological characteristics of the tumor.
AIM: To classify Chilean patients with sporadic CRC according to the new 
consensus molecular subtypes of carcinogenic pathways.
MATERIAL AND METHODS: Prospective analytical study of 53 patients with a mean 
age of 70 years (55% males) with CRC, operated at a private clinic, without 
neoadjuvant treatment. From normal and tumor tissue DNA of each patient, CIN, 
MSI and CIMP were analyzed. Combining these variables, tumors were classified as 
CMS1/MSI-immune, CMS2/canonical, CMS3/metabolic and CMS4/mesenchymal.
RESULTS: CMS1 tumors (19%) were located in the right colon, were in early 
stages, had MMR complex deficiencies and 67% had an activating mutation of the 
BRAF oncogene. CMS2 tumors (31%) were located in the left colon, had moderate 
differentiation, absence of vascular invasion, lymphatic and mucin. CMS3 tumors 
(29%) were also left-sided, with absence of vascular and lymphatic invasion, and 
29% had an activating mutation of the KRAS oncogene. CMS4 tumors (21%) showed 
advanced stages and presence of metastases.
CONCLUSIONS: This new molecular classification contributes to understanding the 
heterogeneity of tumors. It is possible to differentiate molecular subgroups of 
a single pathological diagnosis of adenocarcinoma, opening the door to 
personalized medicine.

DOI: 10.4067/S0034-98872017000400001
PMID: 28748988 [Indexed for MEDLINE]


107. Oncotarget. 2017 Oct 27;8(62):105299-105311. doi: 10.18632/oncotarget.22169. 
eCollection 2017 Dec 1.

Immunological landscape of consensus clusters in colorectal cancer.

Karpinski P(1), Rossowska J(2), Sasiadek MM(1).

Author information:
(1)Department of Genetics, Wroclaw Medical University, Wroclaw, Poland.
(2)L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy 
of Sciences, Wroclaw, Poland.

Recent, large-scale expression-based subtyping has advanced our understanding of 
the genomic landscape of colorectal cancer (CRC) and resulted in a consensus 
molecular classification that enables the categorization of most CRC tumors into 
one of four consensus molecular subtypes (CMS). Currently, major progress in 
characterization of immune landscape of tumor-associated microenvironment has 
been made especially with respect to microsatellite status of CRCs. While these 
studies profoundly improved the understanding of molecular and immunological 
profile of CRCs heterogeneity less is known about repertoire of the tumor 
infiltrating immune cells of each CMS. In order to comprehensively characterize 
the immune landscape of CRC we re-analyzed a total of 15 CRC genome-wide 
expression data sets encompassing 1597 tumors and 125 normal adjacent colon 
tissues. After quality filtering, CRC clusters were discovered using a 
combination of multiple clustering algorithms and multiple validity metrics. 
CIBERSORT algorithm was used to compute relative proportions of 22 human 
leukocyte subpopulations across CRC clusters and normal colon tissue. 
Subsequently, differential expression specific to tumor epithelial cells was 
calculated to characterize mechanisms of tumor escape from immune surveillance 
occurring in particular CRC clusters. Our results not only characterize the 
common and cluster-specific influx of immune cells into CRCs but also identify 
several deregulated gene targets that may contribute to improvement of 
immunotherapeutic strategies in CRC.

DOI: 10.18632/oncotarget.22169
PMCID: PMC5739639
PMID: 29285252

Conflict of interest statement: CONFLICTS OF INTEREST The authors declare no 
conflicts of interest.


108. J Am Coll Radiol. 2019 Apr;16(4 Pt B):580-585. doi: 10.1016/j.jacr.2018.12.025.

Relationships Between Health Care Disparities and Coverage Policies for Breast, 
Colon, and Lung Cancer Screening.

Berland LL(1), Monticciolo DL(2), Flores EJ(3), Malak SF(4), Yee J(5), Dyer 
DS(6).

Author information:
(1)Department of Radiology, University of Alabama at Birmingham, Birmingham, 
Alabama. Electronic address: Lberland@gmail.com.
(2)Department of Radiology, Baylor Scott & White Health, Central Texas, Texas 
A&M University Health Sciences, Temple, Texas.
(3)Department of Radiology, Massachusetts General Hospital, Harvard Medical 
School, Boston, Massachusetts.
(4)Department of Radiology, University of Arkansas for Medical Sciences, Little 
Rock, Arkansas.
(5)Department of Radiology, Montefiore Medical Center, Albert Einstein College 
of Medicine, New York, New York.
(6)Department of Radiology, National Jewish Health, Denver, Colorado.

Disparities in outcomes exist for breast, colon, and lung cancer among diverse 
populations, particularly racial and ethnic underrepresented minorities (URMs) 
and individuals from lower socioeconomic status. For example, blacks experience 
mortality rates up to about 42% higher than whites for these cancers. 
Furthermore, although overall death rates have been declining, the differential 
access to screening and care has aggravated disparities. Our purpose is to 
assess how the coverage policies of CMS and the United States Preventive 
Services Task Force (USPSTF) influence these disparities. Additionally, barriers 
are often encountered in accessing screening tests and receiving prompt 
treatment. To narrow, and potentially eliminate, outcomes disparities, CMS and 
USPSTF could consider revising their decision-making processes regarding 
coverage. Some options include (1) extending their evidence base to include 
observational studies that involve groups at higher risk; (2) lowering the 
threshold ages for screening to encompass differences in incidence; (3) CMS 
approving screening CT colonography coverage, which can even increase compliance 
with other screening tests; (4) clarifying and streamlining guidelines; (5) 
supporting research on improving access to screening; and (6) encouraging the 
development of more navigation services for URMs.

Copyright © 2019 American College of Radiology. Published by Elsevier Inc. All 
rights reserved.

DOI: 10.1016/j.jacr.2018.12.025
PMID: 30947890 [Indexed for MEDLINE]


109. Curr Treat Options Oncol. 2021 Nov 6;22(12):113. doi: 
10.1007/s11864-021-00913-5.

The Evolving Role of Consensus Molecular Subtypes: a Step Beyond Inpatient 
Selection for Treatment of Colorectal Cancer.

Ros J(1)(2), Baraibar I(3), Martini G(4), Salvà F(3), Saoudi N(3), 
Cuadra-Urteaga JL(5), Dienstmann R(6), Tabernero J(3)(5)(7), Élez E(3).

Author information:
(1)Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron 
Institute of Oncology (VHIO), Barcelona, Spain. fjros@vhio.net.
(2)Department of Precision Medicine, Medical Oncology, Università Degli Studi 
Della Campania Luigi Vanvitelli, Naples, Campania, Italy. fjros@vhio.net.
(3)Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron 
Institute of Oncology (VHIO), Barcelona, Spain.
(4)Department of Precision Medicine, Medical Oncology, Università Degli Studi 
Della Campania Luigi Vanvitelli, Naples, Campania, Italy.
(5)IOB, Barcelona, Spain.
(6)Oncology Data Science (ODysSey) Group, Vall D'Hebron Institute of Oncology 
(VHIO), Hospital Universitari Vall D'Hebron, Vall D'Hebron Barcelona Hospital 
Campus (Spain), Barcelona, Spain.
(7)UVic-UCC, Vic, Spain.

The heterogenous nature of colorectal cancer (CRC) renders it a major clinical 
challenge. Increasing genomic understanding of CRC has improved our knowledge of 
this heterogeneity and the main cancer drivers, with significant improvements in 
clinical outcomes. Comprehensive molecular characterization has allowed 
clinicians a more precise range of treatment options based on biomarker 
selection. Furthermore, this deep molecular understanding likely extends 
therapeutic options to a larger number of patients. The biological associations 
of consensus molecular subtypes (CMS) with clinical outcomes in localized CRC 
have been validated in retrospective clinical trials. The prognostic role of CMS 
has also been confirmed in the metastatic setting, with CMS2 having the best 
prognosis, whereas CMS1 tumors are associated with a higher risk of progression 
and death after chemotherapy. Similarly, according to mesenchymal features and 
immunosuppressive molecules, CMS1 responds to immunotherapy, whereas CMS4 has a 
poorer prognosis, suggesting that a CMS1 signature could identify patients who 
may benefit from immune checkpoint inhibitors regardless of microsatellite 
instability (MSI) status. The main goal of these comprehensive analyses is to 
switch from "one marker-one drug" to "multi-marker drug combinations" allowing 
oncologists to give "the right drug to the right patient." Despite the revealing 
data from transcriptomic analyses, the high rate of intra-tumoral heterogeneity 
across the different CMS subgroups limits its incorporation as a predictive 
biomarker. In clinical practice, when feasible, comprehensive genomic tests 
should be performed to identify potentially targetable alterations, particularly 
in RAS/BRAF wild-type, MSI, and right-sided tumors. Furthermore, CMS has not 
only been associated with clinical outcomes and specific tumor and patient 
phenotypes but also with specific microbiome patterns. Future steps will include 
the integration of clinical features, genomics, transcriptomics, and microbiota 
to select the most accurate biomarkers to identify optimal treatments, improving 
individual clinical outcomes. In summary, CMS is context specific, identifies a 
level of heterogeneity beyond standard genomic biomarkers, and offers a means of 
maximizing personalized therapy.

© 2021. The Author(s), under exclusive licence to Springer Science+Business 
Media, LLC, part of Springer Nature.

DOI: 10.1007/s11864-021-00913-5
PMID: 34741675 [Indexed for MEDLINE]


110. Ann Surg Oncol. 2020 Sep;27(9):3138-3146. doi: 10.1245/s10434-019-08088-y. Epub 
2019 Dec 2.

CMS Hospital Compare System of Star Ratings and Surgical Outcomes Among Patients 
Undergoing Surgery for Cancer: Do the Ratings Matter?

Mehta R(1), Paredes AZ(1), Tsilimigras DI(1), Farooq A(1), Sahara K(1), Merath 
K(1), Hyer JM(1), White S(1), Ejaz A(1), Tsung A(1), Dillhoff M(1), Cloyd JM(1), 
Pawlik TM(2).

Author information:
(1)Department of Surgery, Division of Surgical Oncology, The Ohio State 
University Wexner Medical Center, 395 West 12th Avenue, Suite 670, Columbus, OH, 
USA.
(2)Department of Surgery, Division of Surgical Oncology, The Ohio State 
University Wexner Medical Center, 395 West 12th Avenue, Suite 670, Columbus, OH, 
USA. tim.pawlik@osumc.edu.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) Hospital 
Compare star rating system has been proposed as a means to assess hospital 
quality performance. The current study aimed to investigate outcomes and 
payments among patients undergoing surgery for colorectal, lung, esophageal, 
pancreatic, and liver cancer across hospital star rating groups.
METHODS: The Medicare Standard Analytic Files (SAF) from 2013 to 2015 were used 
to derive the analytic cohort. The association of star ratings to perioperative 
outcomes and expenditures was examined.
RESULTS: Among 119,854 patients, the majority underwent surgery at a 3-star 
(n = 34,901, 29.1%) or 4-star (n = 30,492, 25.4%) hospital. Only 12.2% 
(n = 14,732) were treated at a 5-star hospital. Across all procedures examined, 
patients who underwent surgery at a 1-star hospital had greater odds of death 
within 90 days than patients who had surgery at a 5-star hospital (colorectal, 
1.41 [95% confidence interval {CI}, 1.25-1.60]; lung, 1.97 [95% CI 1.56-2.48]; 
esophagectomy, 1.83 [95% CI 0.81-4.16]; pancreatectomy, 1.70 [95% CI 1.20-2.41]; 
hepatectomy, 1.63 [95% CI 0.96-2.77]). A similar trend was noted for failure to 
rescue (FTR), with the greatest odds of FTR associated with 1-star hospitals. 
The median expenditure associated with an abdominal operation was $1661 more at 
a 1-star hospital than at a 5-star hospital (1-star: $17,399 vs 5-star: 
$15,738). A similar trend was noted for thoracic operations.
CONCLUSION: The risk of FTR, 90-day mortality, and increased hospital 
expenditure were all higher at a 1-star hospital. Further research is needed to 
investigate barriers to care at 5-star-rated hospitals and to target specific 
interventions to improve outcomes at 1-star hospitals.

DOI: 10.1245/s10434-019-08088-y
PMID: 31792714 [Indexed for MEDLINE]


111. Front Cell Dev Biol. 2021 Nov 30;9:765578. doi: 10.3389/fcell.2021.765578. 
eCollection 2021.

Single-Cell RNA Sequencing Analysis of the Heterogeneity in Gene Regulatory 
Networks in Colorectal Cancer.

Wang RQ(1), Zhao W(1), Yang HK(1), Dong JM(1), Lin WJ(1), He FZ(1), Cui M(1), 
Zhou ZL(1).

Author information:
(1)Department of Pharmacy, Zhuhai People's Hospital, Zhuhai Hospital Affiliated 
with Jinan University, Zhuhai, China.

Colorectal cancer (CRC) manifests as gastrointestinal tumors with high 
intratumoral heterogeneity. Recent studies have demonstrated that CRC may 
consist of tumor cells with different consensus molecular subtypes (CMS). The 
advancements in single-cell RNA sequencing have facilitated the development of 
gene regulatory networks to decode key regulators for specific cell types. 
Herein, we comprehensively analyzed the CMS of CRC patients by using single-cell 
RNA-sequencing data. CMS for all malignant cells were assigned using CMScaller. 
Gene set variation analysis showed pathway activity differences consistent with 
those reported in previous studies. Cell-cell communication analysis confirmed 
that CMS1 was more closely related to immune cells, and that monocytes and 
macrophages play dominant roles in the CRC tumor microenvironment. On the basis 
of the constructed gene regulation networks (GRNs) for each subtype, we 
identified that the critical transcription factor ERG is universally activated 
and upregulated in all CMS in comparison with normal cells, and that it 
performed diverse roles by regulating the expression of different downstream 
genes. In summary, molecular subtyping of single-cell RNA-sequencing data for 
colorectal cancer could elucidate the heterogeneity in gene regulatory networks 
and identify critical regulators of CRC.

Copyright © 2021 Wang, Zhao, Yang, Dong, Lin, He, Cui and Zhou.

DOI: 10.3389/fcell.2021.765578
PMCID: PMC8669944
PMID: 34917613

Conflict of interest statement: The authors declare that the research was 
conducted in the absence of any commercial or financial relationships that could 
be construed as a potential conflict of interest.


112. Cancer Metastasis Rev. 2017 Jun;36(2):273-288. doi: 10.1007/s10555-017-9678-9.

The potential role of platelets in the consensus molecular subtypes of 
colorectal cancer.

Lam M(1), Roszik J(2), Kanikarla-Marie P(1), Davis JS(3), Morris J(4), Kopetz 
S(1), Menter DG(5).

Author information:
(1)Department of Gastrointestinal Medical Oncology, M. D. Anderson Cancer, Unit 
0426, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
(2)Department of Melanoma Medical Oncology, M. D. Anderson Cancer Center, Unit 
430, 1515 Holcombe Blvd, Houston, 77030, TX, USA.
(3)Department of Epidemiology, M. D. Anderson Cancer Center, Unit 1340, 1515 
Holcombe Blvd, Houston, 77030, TX, USA.
(4)Department of Biostatistics, M. D. Anderson Cancer Center, Unit 1411, 1515 
Holcombe Blvd, Houston, 77030, TX, USA.
(5)Department of Gastrointestinal Medical Oncology, M. D. Anderson Cancer, Unit 
0426, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. dmenter@mdanderson.org.

The consensus molecular subtypes (CMS) in colorectal cancer (CRC) represent 
distinct molecular subcategories of disease as reflected by comprehensive 
molecular profiling. The four CMS subtypes represent unique biology. CMS1 
represents high immune infiltration. CMS2 demonstrates upregulation of canonical 
pathways such as WNT signaling. Widespread metabolic changes are seen in CMS3. 
CMS4 represents a mesenchymal phenotype with hallmark features including 
complement activation, matrix remodeling, angiogenesis, epithelial-mesechymal 
transition (EMT), integrin upregulation and stromal infiltration. In contrast to 
this new paradigm, a number of observations regarding CRC remain disconnected. 
Cancers are associated with thrombocytosis. Venous thromboembolic events are 
more likely in malignancy and may signify worse prognosis. Aspirin, an 
anti-platelet agent, has been linked in large observational studies to decrease 
incidence of adenocarcinoma and less advanced presentations of cancer, in 
particular CRC. Inflammatory bowel disease is a risk factor for CRC. Gross 
markers to recognize the immunothrombotic link such as the platelet to 
lymphocyte ratio are associated with poorer outcomes in many cancers. Platelets 
are increasingly recognized for their dual roles in coordinating the immune 
response in addition to hemostasis. Here, we explore how these different but 
related observations coalesce. Platelets, as first responders to pathogens and 
injury, form the link between hemostasis and immunity. We outline how platelets 
contribute to tumorigenesis and how some disconnected ideas may be linked 
through inflammation. CMS4 through its shared mechanisms has predicted platelet 
activation as a hallmark feature. We demonstrate a platelet gene expression 
signature that predicts platelet presence within CMS4 tumors.

DOI: 10.1007/s10555-017-9678-9
PMID: 28681242 [Indexed for MEDLINE]


113. Ann Oncol. 2019 Oct 1;30(10):1622-1629. doi: 10.1093/annonc/mdz287.

Relative contribution of clinicopathological variables, genomic markers, 
transcriptomic subtyping and microenvironment features for outcome prediction in 
stage II/III colorectal cancer.

Dienstmann R(1), Villacampa G(2), Sveen A(3), Mason MJ(4), Niedzwiecki D(5), 
Nesbakken A(6), Moreno V(7), Warren RS(8), Lothe RA(3), Guinney J(4).

Author information:
(1)Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona, 
Spain; Computational Oncology Group, Sage Bionetworks, Seattle, USA. Electronic 
address: rdienstmann@vhio.net.
(2)Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona, 
Spain.
(3)Department of Molecular Oncology, Institute for Cancer Research and K.G. 
Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, 
Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, 
Oslo, Norway.
(4)Computational Oncology Group, Sage Bionetworks, Seattle, USA.
(5)Department of Bioinformatics and Biostatistics, Duke University, Durham, USA.
(6)Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, 
Oslo, Norway; Department of Gastrointestinal Surgery, K.G. Jebsen Colorectal 
Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
(7)Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, 
Catalan Institute of Oncology, Oncobell Program of IDIBELL, CIBERESP, University 
of Barcelona, Barcelona, Spain.
(8)Department of Surgery, The Helen Diller Family Comprehensive Cancer Center, 
University of California San Francisco, San Francisco, USA.

BACKGROUND: It remains unknown to what extent consensus molecular subtype (CMS) 
groups and immune-stromal infiltration patterns improve our ability to predict 
outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability 
(MSI) status in early-stage colorectal cancer (CRC).
PATIENTS AND METHODS: We carried out a comprehensive retrospective biomarker 
analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and 
treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS 
scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated 
fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes 
(CMSclassifier and MCPcounter R packages); constructed a stratified 
multivariable Cox model for disease-free survival (DFS); and calculated the 
relative proportion of explained variation by each marker (clinicopathological 
[ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and 
microenvironment cells [MicroCells: CytoLym+CAF]).
RESULTS: In multivariable models, only ClinPath and MicroCells remained 
significant prognostic factors, with both CytoLym and CAF infiltration scores 
improving survival prediction beyond other markers. The explained variation for 
DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 
5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, 
respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had 
better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite 
stable tumors had the strongest signal for improved outcomes with CytoLym high 
scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores 
was limited to stage III disease (interaction P = 0.04).
CONCLUSIONS: Our results confirm that tumor microenvironment infiltration 
patterns represent potent determinants of the risk for distant dissemination in 
early-stage CRC. Multivariable models suggest that the prognostic value of MSI 
and CMS groups is largely explained by CytoLym and CAF infiltration patterns.

© The Author(s) 2019. Published by Oxford University Press on behalf of the 
European Society for Medical Oncology.

DOI: 10.1093/annonc/mdz287
PMCID: PMC6857614
PMID: 31504112 [Indexed for MEDLINE]


114. Gut. 2019 Mar;68(3):465-474. doi: 10.1136/gutjnl-2017-315664. Epub 2018 Jan 30.

Lymphocytic response to tumour and deficient DNA mismatch repair identify 
subtypes of stage II/III colorectal cancer associated with patient outcomes.

Williams DS(1)(2), Mouradov D(3)(4), Jorissen RN(3)(4), Newman MR(1), Amini 
E(5), Nickless DK(6), Teague JA(6), Fang CG(2), Palmieri M(3)(4), Parsons MJ(4), 
Sakthianandeswaren A(3)(4), Li S(4), Ward RL(7), Hawkins NJ(8), Faragher I(9), 
Jones IT(10), Gibbs P(3)(4)(11)(12), Sieber OM(3)(4)(13)(14).

Author information:
(1)Department of Pathology, Austin Health, Heidelberg, Victoria, Australia.
(2)Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, 
Australia.
(3)Department of Medical Biology, The University of Melbourne, Parkville, 
Victoria, Australia.
(4)Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall 
Institute of Medical Research, Parkville, Victoria, Australia.
(5)Clinipath Pathology, Sonic Healthcare, Perth, Western Australia, Australia.
(6)Australian Clinical Labs, The Northern Hospital, Epping, Victoria, Australia.
(7)Office of the Deputy Vice-Chancellor (Research), The University of 
Queensland, Brisbane, Queensland, Australia.
(8)Faculty of Medicine, The University of Queensland, Brisbane, Queensland, 
Australia.
(9)Department of Surgery, Western Health, Footscray, Australia.
(10)Department of Surgery, Royal Melbourne Hospital, Parkville, Victoria, 
Australia.
(11)Department of Medical Oncology, Walter and Eliza Hall Institute of Medical 
Research, Parkville, Victoria, Australia.
(12)Department of Medical Oncology, Western Health, Footscray, Victoria, 
Australia.
(13)Department of Surgery, The University of Melbourne, Parkville, Victoria, 
Australia.
(14)School of Biomedical Sciences, Monash University, Clayton, Victoria, 
Australia.

OBJECTIVE: Tumour-infiltrating lymphocyte (TIL) response and deficient DNA 
mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. 
Although highly correlated, evidence suggests that these are independent 
predictors of outcome. However, the prognostic significance of combined TIL/MMR 
classification and how this compares to the major genomic and transcriptomic 
subtypes remain unclear.
DESIGN: A prospective cohort of 1265 patients with stage II/III cancer was 
examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype 
(CMS) status was determined for 142 cases. Associations with 5-year disease-free 
survival (DFS) were evaluated and validated in an independent cohort of 602 
patients.
RESULTS: Tumours were categorised into four subtypes based on TIL and MMR 
status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), 
TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR 
tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% 
CI=1.88 to 6.64; Pmultivariate<0.001) and TIL-low/pMMR tumours (HR=2.67; 95% 
CI=1.47 to 4.84; Pmultivariate=0.001) showed poor DFS. Outcomes of patients with 
TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed 
intermediate survival rates. These findings were validated in an independent 
cohort. TIL/MMR status was a more significant predictor of prognosis than 
National Comprehensive Cancer Network high-risk features and was a superior 
predictor of prognosis compared with genomic (dMMR, pMMR/BRAFwt /KRASwt , 
pMMR/BRAFmut /KRASwt , pMMR/BRAFwt /KRASmut ) and transcriptomic (CMS 1-4) 
subtypes.
CONCLUSION: TIL/MMR classification identified subtypes of stage II/III 
colorectal cancer associated with different outcomes. Although dMMR status is 
generally considered a marker of good prognosis, we found this to be dependent 
on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior 
compared with histopathological, genomic and transcriptomic subtypes.

© Article author(s) (or their employer(s) unless otherwise stated in the text of 
the article) 2019. All rights reserved. No commercial use is permitted unless 
otherwise expressly granted.

DOI: 10.1136/gutjnl-2017-315664
PMID: 29382774 [Indexed for MEDLINE]

Conflict of interest statement: Competing interests: None declared.


115. ESMO Open. 2019 Jun 24;4(3):e000523. doi: 10.1136/esmoopen-2019-000523. 
eCollection 2019.

Exploratory analyses of consensus molecular subtype-dependent associations of 
TP53 mutations with immunomodulation and prognosis in colorectal cancer.

Smeby J(1)(2)(3)(4), Sveen A(1)(2)(4), Bergsland CH(1)(2)(4), Eilertsen 
IA(1)(2)(4), Danielsen SA(1)(2), Eide PW(1)(2), Hektoen M(1)(2), Guren MG(2)(3), 
Nesbakken A(2)(4)(5), Bruun J(1)(2), Lothe RA(1)(2)(4).

Author information:
(1)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, Oslo, Norway.
(2)K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, 
Oslo University Hospital, Oslo, Norway.
(3)Department of Oncology, Oslo University Hospital, Oslo, Norway.
(4)Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 
Oslo, Norway.
(5)Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, 
Norway.

BACKGROUND: Accumulating evidence suggests immunomodulatory and 
context-dependent effects of TP53 mutations in cancer. We performed an 
exploratory analysis of the transcriptional, immunobiological and prognostic 
associations of TP53 mutations within the gene expression-based consensus 
molecular subtypes (CMSs) of colorectal cancer (CRC).
MATERIALS AND METHODS: In a single-hospital series of 401 stage I-IV primary 
CRCs, we sequenced the whole coding region of TP53 and analysed CMS-dependent 
transcriptional consequences of the mutations by gene expression profiling. 
Immunomodulatory associations were validated by multiplex, fluorescence-based 
immunohistochemistry of immune cell markers. Prognostic associations of TP53 
mutations were analysed in an aggregated series of 635 patients classified 
according to CMS, including publicly available data from a French multicentre 
cohort (GSE39582).
RESULTS: TP53 mutations were found in 60% of the CRCs. However, gene set 
enrichment analyses indicated that their transcriptional consequences varied 
among the CMSs and were most pronounced in CMS1-immune and CMS4-mesenchymal. 
Subtype specificity was primarily seen as an upregulation of gene sets 
reflecting cell cycle progression in CMS4 and a downregulation of T cell 
activity in CMS1. The subtype-dependent immunomodulatory associations were 
reinforced by significant depletion of several immune cell populations in 
mutated tumours compared with wild-type (wt) tumours exclusively in CMS1, 
including cytotoxic lymphocytes (adjusted p value in CMS1=0.002 and CMS2-4>0.9, 
Microenvironment Cell Populations (MCP)-counter algorithm). This was validated 
by immunohistochemistry-based quantification of tumour infiltrating CD8+ cells. 
Within CMS1, the immunomodulatory association of TP53 mutations was strongest 
among microsatellite stable (MSS) tumours, and this translated into a propensity 
for metastatic disease and poor prognostic value of the mutations specifically 
in the CMS1/MSS subtype (both series overall survival: TP53 mutation vs wt: HR 
5.52, p=0.028).
CONCLUSIONS: Integration of TP53 mutation status with the CMS framework in 
primary CRC suggested subtype-dependent immunobiological associations with 
prognostic and potentially immunotherapeutic implications, warranting 
independent validation.

DOI: 10.1136/esmoopen-2019-000523
PMCID: PMC6598553
PMID: 31321083

Conflict of interest statement: Competing interests: None declared.


116. Bull Cancer. 2019 Feb;106(2):151-161. doi: 10.1016/j.bulcan.2018.09.008. Epub 
2019 Jan 11.

[Going beyond microsatellite instability for immunotherapy in metastatic 
colorectal cancer: Consensus molecular subtypes and tumor mutational burden].

[Article in French]

Cohen R(1), Heran M(1), Pudlarz T(1), Hilmi M(2), Tournigand C(3), André T(1), 
Rousseau B(4).

Author information:
(1)Assistance publique-Hôpitaux de Paris, hôpital Saint-Antoine, Sorbonne 
université, département d'oncologie médicale, 75012 Paris, France.
(2)Assistance publique-Hôpitaux de Paris, hôpital Henri-Mondor, département 
d'oncologie médicale, 94000 Créteil, France.
(3)Assistance publique-Hôpitaux de Paris, hôpital Henri-Mondor, département 
d'oncologie médicale, 94000 Créteil, France; Université Paris Est Créteil, 
faculté de médecine, 94000 Créteil, France.
(4)Assistance publique-Hôpitaux de Paris, hôpital Henri-Mondor, département 
d'oncologie médicale, 94000 Créteil, France; Institut Mondor de recherche 
biomédicale, INSERM U955 Équipe 18, 94000 Créteil, France. Electronic address: 
benoit.rousseau@inserm.fr.

Next generation immunotherapies have limited efficacy in colorectal cancer. 
Immune checkpoints inhibitors demonstrated their benefit in mismatch 
repair-deficient tumors, which also exhibit microsatellite instability (MSI). 
The Consensual Molecular Subtype (CMS) classification has been recently proposed 
and highlights specific immune escape mechanisms for each subtype. CMS1 "immune" 
subtype is hypermutated with a favorable immune microenvironment for immune 
checkpoints inhibitors activity. Importantly, CMS1 is not restricted to MSI 
tumors and includes also exonucleasic domain POLE mutated tumors which are good 
candidates for immunotherapy. The scope of this comprehensive review is to 
described immune anomalies and propose immunomodulating strategies for each CMS 
subtype in colorectal cancer. Finally, the potential interest of tumor mutation 
burden and the Immunoscore® in colorectal cancer is discussed taking into 
account the molecular classification and obstacles to antitumoral immune 
activity.

Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. 
All rights reserved.

DOI: 10.1016/j.bulcan.2018.09.008
PMID: 30638897 [Indexed for MEDLINE]


117. J Gen Intern Med. 2016 Apr;31(4):372-9. doi: 10.1007/s11606-015-3552-7.

Variation in Screening Abnormality Rates and Follow-Up of Breast, Cervical and 
Colorectal Cancer Screening within the PROSPR Consortium.

Tosteson AN(1)(2), Beaber EF(3), Tiro J(4), Kim J(5), McCarthy AM(6), Quinn 
VP(7), Doria-Rose VP(8), Wheeler CM(9), Barlow WE(10), Bronson M(11), Garcia 
M(3), Corley DA(12), Haas JS(13), Halm EA(14), Kamineni A(15), Rutter CM(16), 
Tosteson TD(11)(17), Trentham-Dietz A(18), Weaver DL(19); PROSPR consortium.

Author information:
(1)Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. 
Anna.Tosteson@Dartmouth.edu.
(2)Norris Cotton Cancer Center, Lebanon, NH, USA. Anna.Tosteson@Dartmouth.edu.
(3)Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
(4)University of Texas Southwestern, Dallas, TX, USA.
(5)Harvard T.H. Chan School of Public Health, Boston, MA, USA.
(6)Massachusetts General Hospital, Boston, MA, USA.
(7)Kaiser Permanente Southern California, Pasadena, CA, USA.
(8)National Cancer Institute, Bethesda, MD, USA.
(9)University of New Mexico, Albuquerque, NM, USA.
(10)Cancer Research and Biostatistics, Seattle, WA, USA.
(11)Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
(12)Kaiser Permanente Northern California, Oakland, CA, USA.
(13)Brigham and Women's Hospital, Boston, MA, USA.
(14)University of Texas Southwestern Medical Center, Dallas, TX, USA.
(15)Group Health, Seattle, WA, USA.
(16)RAND Corporation, Santa Monica, CA, USA.
(17)Norris Cotton Cancer Center, Lebanon, NH, USA.
(18)University of Wisconsin, Madison, WI, USA.
(19)University of Vermont, Burlington, VT, USA.

Comment in
    J Gen Intern Med. 2016 Apr;31(4):411.

BACKGROUND: Primary care providers and health systems have prominent roles in 
guiding effective cancer screening.
OBJECTIVE: To characterize variation in screening abnormality rates and timely 
initial follow-up for common cancer screening tests.
DESIGN: Population-based cohort undergoing screening in 2011, 2012, or 2013 at 
seven research centers comprising the National Cancer Institute-sponsored 
Population-based Research Optimizing Screening through Personalized Regimens 
(PROSPR) consortium.
PARTICIPANTS: Adults undergoing mammography with or without digital breast 
tomosynthesis (n = 97,683 ages 40-75 years), fecal occult blood or fecal 
immunochemical tests (n = 759,553 ages 50-75 years), or Papanicolaou with or 
without human papillomavirus tests (n = 167,330 ages 21-65 years).
INTERVENTION: Breast, colorectal, or cervical cancer screening.
MAIN MEASURES: Abnormality rates per 1000 screens; percentage with timely 
initial follow-up (within 90 days, except 9-month window for BI-RADS 3). Primary 
care clinic-level variation in percentage with screening abnormality and 
percentage with timely initial follow-up.
KEY RESULTS: There were 10,248/97,683 (104.9 per 1000) abnormal breast cancer 
screens, 35,847/759,553 (47.2 per 1000) FOBT/FIT-positive colorectal cancer 
screens, and 13,266/167,330 (79.3 per 1000) abnormal cervical cancer screens. 
The percentage with timely follow-up was 93.2 to 96.7 % for breast centers, 46.8 
to 68.7  % for colorectal centers, and 46.6 % for the cervical cancer screening 
center (low-grade squamous intraepithelial lesions or higher). The primary care 
clinic variation (25th to 75th percentile) was smaller for the percentage with 
an abnormal screen (breast, 8.5-10.3 %; colorectal, 3.0-4.8 %; cervical, 6.3-9.9 
%) than for the percentage with follow-up within 90 days (breast, 90.2-95.8 %; 
colorectal, 43.4-52.0 %; cervical, 29.6-61.4 %).
CONCLUSIONS: Variation in both the rate of screening abnormalities and their 
initial follow-up was evident across organ sites and primary care clinics. This 
highlights an opportunity for improving the delivery of cancer screening through 
focused study of patient, provider, clinic, and health system characteristics 
associated with timely follow-up of screening abnormalities.

DOI: 10.1007/s11606-015-3552-7
PMCID: PMC4803707
PMID: 26658934 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflicts of interest. 
Funders This work was supported by the National Cancer Institute (NCI)-funded 
Population-based Research Optimizing Screening through Personalized Regimens 
(PROSPR) consortium (grant numbers U01CA163304 to M.T., W.B.; U54CA163303 to 
D.L.W., B.S.; U54CA163307 to A.N.A.T., T.O., J.H.; U54CA163313 to K.A., M.S.; 
U54CA163308 to C.S.S., E.H.; U54CA163308-04S1 to C.S.S., J.A.T.; U54CA163261 to 
C.R.; U54CA163261-04S1 to J.C., A.K.; U54CA163262 to A.G.Z., D.C., C.D., T.L.; 
U54CA163262-04S1 to D.C., M.S.; and U54CA164336 to C.W.). The content of this 
manuscript is solely the responsibility of the authors and does not necessarily 
represent the official views of the Department of Veterans Affairs or the United 
States government.


118. Br J Cancer. 2021 Oct;125(8):1080-1088. doi: 10.1038/s41416-021-01477-9. Epub 
2021 Jul 12.

Molecular subtype-specific efficacy of anti-EGFR therapy in colorectal cancer is 
dependent on the chemotherapy backbone.

Ten Hoorn S(1)(2), Sommeijer DW(1)(3)(4), Elliott F(5), Fisher D(6), de Back 
TR(1)(2), Trinh A(7)(8), Koens L(9), Maughan T(10), Seligmann J(5), Seymour 
MT(5), Quirke P(5), Adams R(11), Richman SD(5), Punt CJA(3)(12), Vermeulen 
L(13)(14)(15).

Author information:
(1)Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and 
Molecular Medicine, Cancer Center Amsterdam, Amsterdam, The Netherlands.
(2)Oncode Institute, Amsterdam UMC, Amsterdam, The Netherlands.
(3)Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, 
Amsterdam, The Netherlands.
(4)Flevohospital, Department of Internal Medicine, Almere, The Netherlands.
(5)Leeds Institute of Medical Research at St James's, University of Leeds, St 
James's University Hospital, Leeds, UK.
(6)MRC Clinical Trials Unit, University College London, London, UK.
(7)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 
USA.
(8)Department of Medicine, Harvard Medical School, Boston, MA, USA.
(9)Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, 
The Netherlands.
(10)Department of Oncology, University of Oxford, Oxford, UK.
(11)Centre for Trials Research Cardiff University and Velindre Hospital, 
Cardiff, Wales, UK.
(12)Department of Epidemiology, Julius Center for Health Sciences and Primary 
Care, University Medical Center, Utrecht University, Utrecht, The Netherlands.
(13)Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and 
Molecular Medicine, Cancer Center Amsterdam, Amsterdam, The Netherlands. 
l.vermeulen@amsterdamumc.nl.
(14)Oncode Institute, Amsterdam UMC, Amsterdam, The Netherlands. 
l.vermeulen@amsterdamumc.nl.
(15)Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, 
Amsterdam, The Netherlands. l.vermeulen@amsterdamumc.nl.

BACKGROUND: Patient selection for addition of anti-EGFR therapy to chemotherapy 
for patients with RAS and BRAF wildtype metastatic colorectal cancer can still 
be optimised. Here we investigate the effect of anti-EGFR therapy on survival in 
different consensus molecular subtypes (CMSs) and stratified by primary tumour 
location.
METHODS: Retrospective analyses, using the immunohistochemistry-based CMS 
classifier, were performed in the COIN (first-line oxaliplatin backbone with or 
without cetuximab) and PICCOLO trial (second-line irinotecan with or without 
panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), 
respectively.
RESULTS: When using an irinotecan backbone, anti-EGFR therapy is effective in 
both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival 
(PFS): HR 0.44, 95% CI 0.26-0.75, P = 0.003 and HR 0.12, 95% CI 0.04-0.36, 
P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 
0.04-0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to 
left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36-0.96, P = 0.034).
CONCLUSIONS: The subtype-specific efficacy of anti-EGFR therapy is dependent on 
the chemotherapy backbone. This may provide the possibility of subtype-specific 
treatment strategies for a more optimal use of anti-EGFR therapy.

© 2021. The Author(s).

DOI: 10.1038/s41416-021-01477-9
PMCID: PMC8505637
PMID: 34253874 [Indexed for MEDLINE]

Conflict of interest statement: LV received speaker and consultancy fees from 
Genentech, Bayer, Servier, Boehringer-Ingelheim, MSD and Pierre Fabre. LV 
received unrestricted grants from Novartis, Servier, Roche and Roche 
Diagnostics. LV declares ongoing collaborations with Firalis, LeadPharma and 
Genentech. RA received speaker and consultancy fees form Amgen, Bayer, Astra 
Zeneca, Merck. TM received unrestricted grants and speaker fees from Merck KGaA, 
and unrestricted grants and consultancy fees from AstraZeneca. CP reports an 
advisory role for Nordic Pharma. PQ has research funding with Roche, GeneFirst 
and Amgen, previous research funding from Halio, consultancy with Nordlai‐Adlyte 
and advisory boards with Merck, Amgen and Roche. JS received speaker fees from 
Merck Serono; advisory board—Pierre Fabre, Roche; CME—GI Connect. No disclosures 
were reported by the other authors. None of the funders had any role in study 
design, data collection and analysis, decision to publish, or preparation of the 
manuscript.


119. Br J Cancer. 2019 Oct;121(7):593-599. doi: 10.1038/s41416-019-0560-0. Epub 2019 
Sep 2.

CK7 and consensus molecular subtypes as major prognosticators in (V600E)BRAF 
mutated metastatic colorectal cancer.

Loupakis F(1), Biason P(2), Prete AA(2), Cremolini C(3), Pietrantonio F(4)(5), 
Pella N(6), Dell'Aquila E(7), Sperti E(8), Zichi C(8), Intini R(2), Dadduzio 
V(2), Schirripa M(2), Bergamo F(2), Antoniotti C(3), Morano F(4), Cortiula 
F(6)(9), De Maglio G(10), Rimassa L(11), Smiroldo V(11), Calvetti L(12), Aprile 
G(12), Salvatore L(13)(14), Santini D(7), Munari G(2)(15), Salmaso R(15), 
Guzzardo V(15), Mescoli C(15), Lonardi S(2), Rugge M(15), Zagonel V(2), Di Maio 
M(8), Fassan M(16).

Author information:
(1)Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. 
fotios.loupakis@iov.veneto.it.
(2)Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
(3)Department of Translational Research and New Technologies in Medicine and 
Surgery, University of Pisa, Pisa, Italy.
(4)Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei 
Tumori, Milan, Italy.
(5)Department of Oncology and Hemato-oncology, University of Milan, Milan, 
Italy.
(6)Department of Oncology, University and General Hospital, Udine, Italy.
(7)Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, 
Italy.
(8)Department of Oncology, University of Turin at Umberto I "Ordine Mauriziano" 
Hospital, Turin, Italy.
(9)Department of Medicine (DAME), University of Udine, Udine, Italy.
(10)Department of Pathology, University Hospital of Udine, Udine, Italy.
(11)Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas 
Clinical and Research Center-IRCCS Rozzano, Milan, Italy.
(12)Department of Oncology, General Hospital San Bortolo, Unità Locale 
Socio-Sanitaria 8 Berica, Vicenza, Italy.
(13)Unit of Oncology, Polyclinic GB Rossi, AOUI, Verona, Italy.
(14)U.O.C Oncologia, Fondazione Policlinico Universitario Agostino Gemelli 
IRCCS, Roma, Italy.
(15)Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), 
University of Padua, Padua, Italy.
(16)Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), 
University of Padua, Padua, Italy. matteo.fassan@unipd.it.

BACKGROUND: V600EBRAF mutated metastatic colorectal cancer (mCRC) is a subtype 
(10%) with overall poor prognosis, but the clinical experience suggests a great 
heterogeneity in survival. It is still unexplored the real distribution of 
traditional and innovative biomarkers among V600EBRAF mutated mCRC and which is 
their role in the improvement of clinical prediction of survival outcomes.
METHODS: Data and tissue specimens from 155 V600EBRAF mutated mCRC patients 
treated at eight Italian Units of Oncology were collected. Specimens were 
analysed by means of immunohistochemistry profiling performed on tissue 
microarrays. Primary endpoint was overall survival (OS).
RESULTS: CDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03-2.86, p = 0.036), 
as well as high CK7 expression (HR = 2.17, 95%CI 1.10-4.29, p = 0.026). 
According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS 
compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19-0.71, p = 0.003). Samples showing 
less TILs had worse OS (HR = 1.72, 95%CI 1.16-2.56, p = 0.007). Progression-free 
survival analyses led to similar results. At multivariate analysis, CK7 and CMS 
subgrouping retained their significant correlation with OS.
CONCLUSION: The present study provides new evidence on how several 
well-established biomarkers perform in a homogenousV600EBRAF mutated mCRC 
population, with important and independent information added to standard 
clinical prognosticators. These data could be useful to inform further 
translational research, for patients' stratification in clinical trials and in 
routine clinical practice to better estimate patients' prognosis.

DOI: 10.1038/s41416-019-0560-0
PMCID: PMC6889398
PMID: 31474758 [Indexed for MEDLINE]

Conflict of interest statement: F.L. had roles as consultant or advisor for 
Roche, Bayer, Amgen, Genentech. F.P. received honoraria and had roles as 
consultant or advisor for Amgen, Merck, Roche, Sanofi, Bayer, Servier, Lilly. 
S.L. had roles as consultant or advisor for Amgen, Bayer, Merck Serono, Lilly. 
She received research funding from Amgen, Merck Serono and she is part of 
speakers’ bureau of Lilly, BMS. Vittorina Zagonel received honoraria and had 
roles as consultant or advisor for Bristol-Mayers Squibb, Bayer, Roche, Pfizer, 
Janssen, Novartis, Astellas, Servier. She had roles as consultant or advisor for 
Celgene, Merck. M.D.M. received honoraria and had roles as consultant or advisor 
for AstraZeneca, Bristol Myers Squibb, MSD, Takeda and Janssen; received a 
research grant from Tesaro. M.F. received a research grant from Astellas Pharma. 
The remaining authors declare no competing interest.


120. Int J Cancer. 2020 Oct 15;147(8):2303-2315. doi: 10.1002/ijc.33003. Epub 2020 
Apr 24.

Investigating the concordance in molecular subtypes of primary colorectal tumors 
and their matched synchronous liver metastasis.

Schlicker A(1), Ellappalayam A(2), Beumer IJ(2), Snel MHJ(2), Mittempergher 
L(2), Diosdado B(3), Dreezen C(2), Tian S(2), Salazar R(4), Loupakis F(5), 
Pietrantonio F(6)(7), Santos Vivas C(4), Martinez-Villacampa MM(4), Villanueva 
A(8), Sanjuán X(9), Schirripa M(5), Fassan M(10), Martinetti A(6), Fucà G(6), 
Lonardi S(5), Keilholz U(11), Glas AM(2), Bernards R(2)(3), Vecchione L(11)(12).

Author information:
(1)Bayer AG, Berlin, Germany.
(2)Agendia, Amsterdam, The Netherlands.
(3)Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands 
Cancer Institute, Amsterdam, The Netherlands.
(4)Medical Oncology Department, Catalan Institute of Oncology, ONCOBELL - 
lDIBELL, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 
Catalonia, Spain.
(5)Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padova, 
Italy.
(6)Medical Oncology Department, Fondazione IRCCS, Istituto Nazionale dei Tumori, 
Milan, Italy.
(7)Department of Oncology and Hemato-oncology, University of Milan, Milan, 
Italy.
(8)Translational Research Laboratory, Institut d'Investigació Biomèdica de 
Bellvitge (IDIBELL), Institut Català d'Oncologia, Hospitalet, Barcelona, Spain.
(9)Department of Pathology, Bellvitge Hospital, L'Hospitalet de Llobregat, 
Catalonia, Spain.
(10)Department of Medicine, Surgical Pathology Unit, University of Padua, Padua, 
Italy.
(11)Charité Comprehensive Cancer Center, Berlin, Germany.
(12)Department of Hematology, Oncology and Tumor Immunology (CCM) Charité - 
Universitaetsmedizin Berlin, Berlin, Germany.

To date, no systematic analyses are available assessing concordance of molecular 
classifications between primary tumors (PT) and matched liver metastases (LM) of 
metastatic colorectal cancer (mCRC). We investigated concordance between PT and 
LM for four clinically relevant CRC gene signatures. Twenty-seven fresh and 55 
formalin-fixed paraffin-embedded pairs of PT and synchronous LM of untreated 
mCRC patients were retrospectively collected and classified according to the 
MSI-like, BRAF-like, TGFB activated-like and the Consensus Molecular Subtypes 
(CMS) classification. We investigated classification concordance between PT and 
LM and association of TGFBa-like and CMS classification with overall survival. 
Fifty-one successfully profiled matched pairs were used for analyses. PT and 
matched LM were highly concordant in terms of BRAF-like and MSI-like signatures, 
(90.2% and 98% concordance, respectively). In contrast, 40% to 70% of PT that 
were classified as mesenchymal-like, based on the CMS and the TGFBa-like 
signature, respectively, lost this phenotype in their matched LM (60.8% and 
76.5% concordance, respectively). This molecular switch was independent of the 
microenvironment composition. In addition, the significant change in subtypes 
was observed also by using methods developed to detect cancer cell-intrinsic 
subtypes. More importantly, the molecular switch did not influence the survival. 
PT classified as mesenchymal had worse survival as compared to nonmesenchymal PT 
(CMS4 vs CMS2, hazard ratio [HR] = 5.2, 95% CI = 1.5-18.5, P = .0048; TGFBa-like 
vs TGFBi-like, HR = 2.5, 95% CI = 1.1-5.6, P = .028). The same was not true for 
LM. Our study highlights that the origin of the tissue may have major 
consequences for precision medicine in mCRC.

© 2020 The Authors. International Journal of Cancer published by John Wiley & 
Sons Ltd on behalf of UICC.

DOI: 10.1002/ijc.33003
PMID: 32270478 [Indexed for MEDLINE]


121. Front Cell Dev Biol. 2021 Nov 29;9:758776. doi: 10.3389/fcell.2021.758776. 
eCollection 2021.

Comprehensive Analysis of Subtype-Specific Molecular Characteristics of Colon 
Cancer: Specific Genes, Driver Genes, Signaling Pathways, and Immunotherapy 
Responses.

Hu F(1), Wang J(2), Zhang M(3), Wang S(2), Zhao L(2), Yang H(4), Wu J(5), Cui 
B(1).

Author information:
(1)Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, 
Harbin Medical University, Harbin, China.
(2)Department of Pathology, Harbin Medical University, Harbin, China.
(3)Department of Oncology, Chifeng City Hospital, Chifeng, China.
(4)Department of Radiation Oncology, Inner Mongolia Cancer Hospital & Affiliated 
People's Hospital of Inner Mongolia Medical University, Hohhot, China.
(5)Department of Anaesthesiology, The First Affiliated Hospital of Harbin 
Medical University, Harbin, China.

Colon cancer is a complex, heterogeneous disease. The Colorectal Cancer 
Subtyping Consortium reported a novel classification system for colon cancer in 
2015 to better understand its heterogeneity. This molecular classification 
system divided colon cancer into four distinct consensus molecular subtypes (CMS 
1, 2, 3, and 4). However, the characteristics of different colon cancer 
molecular subtypes have not been fully elucidated. This study comprehensively 
analyzed the molecular characteristics of varying colon cancer subtypes using 
multiple databases and algorithms, including The Cancer Genome Atlas (TCGA) 
database, DriverDBv3 database, CIBERSORT, and MCP-counter algorithms. We 
analyzed the alterations in the subtype-specific genes of different colon cancer 
subtypes, such as the RNA levels and DNA alterations, and showed that specific 
subtype-specific genes significantly affected prognosis. We also explored the 
changes in colon cancer driver genes and representative genes of 10 signaling 
pathways in different subtypes. We identified genes that were altered in 
specific subtypes. We further detected the infiltration of 22 immune cell types 
in four colon cancer subtypes and the infiltration level of primary immune cells 
among these subtypes. Additionally, we explored changes in immune checkpoint 
genes (ICGs) and immunotherapy responses among different colon cancer subtypes. 
This study may provide clues for the molecular mechanism of tumorigenesis and 
progression in colon cancer. It also offers potential biomarkers and targets for 
the clinical diagnosis and treatment of different colon cancer subtypes.

Copyright © 2021 Hu, Wang, Zhang, Wang, Zhao, Yang, Wu and Cui.

DOI: 10.3389/fcell.2021.758776
PMCID: PMC8667669
PMID: 34912802

Conflict of interest statement: The authors declare that the research was 
conducted in the absence of any commercial or financial relationships that could 
be construed as a potential conflict of interest.


122. J Gastrointest Surg. 2021 Jun;25(6):1370-1379. doi: 10.1007/s11605-021-05011-3. 
Epub 2021 Apr 21.

Complications After Complex Gastrointestinal Cancer Surgery: Benefits and Costs 
Associated with Inter-hospital Transfer Among Medicare Beneficiaries.

Pathak P(1), Dalmacy D(1), Tsilimigras DI(1), Hyer JM(1), Diaz A(1), Pawlik 
TM(2).

Author information:
(1)Department of Surgery, The Ohio State University Wexner Medical Center and 
James Cancer Hospital and Solove Research Institute, 395 W. 12th Ave., Suite 
670, Columbus, OH, USA.
(2)Department of Surgery, The Ohio State University Wexner Medical Center and 
James Cancer Hospital and Solove Research Institute, 395 W. 12th Ave., Suite 
670, Columbus, OH, USA. tim.pawlik@osumc.edu.

BACKGROUND: Inter-hospital transfer (IHT) may help reduce failure-to-rescue 
(FTR) by transferring patients to centers with a higher level of expertise than 
the index hospital. We sought to identify factors associated with an IHT and 
examine if IHT was associated with improved outcomes after complex 
gastrointestinal cancer surgery.
METHODS: Medicare Inpatient Standard Analytic Files were utilized to identify 
patients with >1 postoperative complication following resection for esophageal, 
pancreatic, liver, or colorectal cancer between 2013 and 2017. Multivariable 
logistic regression was used to examine the association of different factors 
with the chance of IHT, as well as the impact of IHT on failure-to-rescue (FTR) 
and expenditures.
RESULTS: Among 39,973 patients with >1 postoperative complications, 3090 (7.7%) 
patients were transferred to a secondary hospital. The median LOS at the index 
hospital prior to IHT was 10 days (IQR, 6-17 days). Patients who underwent IHT 
more often had experienced multiple complications at the index hospital compared 
with non-IHT patients (57.7% vs. 38.9%) (p<0.001). Transferred patients more 
commonly had undergone surgery at a low-volume index hospital (n=218, 60.2%) 
compared with non-IHT (n=10,351, 25.9%) patients (p<0.001). On multivariate 
analysis, hospital volume remained strongly associated with transfer to an acute 
care hospital (ACH) (OR 5.53; 95% CI 3.91-7.84; p<0.001), as did multiple 
complications (OR 2.01, 95% CI 1.56-2.57). The incidence of FTR was much higher 
among IHT-ACH patients (20.2%) versus non-IHT patients (11.5%) (OR 1.51, 95% CI 
1.11-2.05) (p<0.001). Medicare expenditures were higher among patients who had 
IHT-ACH ($72.1k USD; IQR, $48.1k-$116.7k) versus non-IHT ($38.5k USD; IQR, 
$28.1k-$59.2k USD) (p<0.001).
CONCLUSION: Approximately 1 in 13 patients had an IHT after complex 
gastrointestinal cancer surgery. IHT was associated with high rates of FTR, 
which was more pronounced among patients who underwent surgery at an index 
low-volume hospital. IHT was associated with higher overall CMS expenditures.

DOI: 10.1007/s11605-021-05011-3
PMID: 33914214 [Indexed for MEDLINE]


123. Oncoimmunology. 2018 Mar 26;7(7):e1445453. doi: 10.1080/2162402X.2018.1445453. 
eCollection 2018.

Complex pattern of immune evasion in MSI colorectal cancer.

Ozcan M(1)(2)(3), Janikovits J(1)(2)(3), von Knebel Doeberitz M(1)(2)(3), Kloor 
M(1)(2)(3).

Author information:
(1)Department of Applied Tumour Biology, Institute of Pathology, University of 
Heidelberg, Heidelberg, Germany.
(2)Collaboration Unit Applied Tumor Biology, German Cancer Research Center 
(DKFZ), Heidelberg, Germany.
(3)Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, 
Germany.

Mismatch repair (MMR)-deficient cancers accumulate multiple insertion/deletion 
mutations at coding microsatellites (cMS), which give rise to frameshift peptide 
neoantigens. The high mutational neoantigen load of MMR-deficient cancers is 
reflected by pronounced anti-tumoral immune responses of the host and high 
responsiveness towards immune checkpoint blockade. However, immune evasion 
mechanisms can interfere with the immune response against MMR-deficient tumors. 
We here performed a comprehensive analysis of immune evasion in MMR-deficient 
colorectal cancers, focusing on HLA class I-mediated antigen presentation. 72% 
of MMR-deficient colorectal cancers of the DFCI database harbored alterations 
affecting genes involved in HLA class I-mediated antigen presentation, and 54% 
of these mutations were predicted to abrogate function. Mutations affecting the 
HLA class I transactivator NLRC5 were observed as a potential new immune evasion 
mechanism in 26% (6% abrogating) of the analyzed tumors. NLRC5 mutations in 
MMR-deficient cancers were associated with decreased levels of HLA class I 
antigen expression. In summary, the majority of MMR-deficient cancers display 
mutations interfering with HLA class I antigen presentation that reflect active 
immune surveillance and immunoselection during tumor development. Clinical 
studies focusing on immune checkpoint blockade in MSI cancer should account for 
the broad variety of immune evasion mechanisms as potential biomarkers of 
therapy success.

DOI: 10.1080/2162402X.2018.1445453
PMCID: PMC5993484
PMID: 29900056


124. J Manag Care Pharm. 2007 Aug;13(6 Suppl C):S19-26. doi: 
10.18553/jmcp.2007.13.s6-c.19.

Medicare challenges and solutions--reimbursement issues in treating the patient 
with colorectal cancer.

Kaa K(1).

Author information:
(1)Lash Group, San Bruno, California 94066, USA. Kathleen.Kaa@ashgroup.com

BACKGROUND: Medicare covers costs far more than 50% of all cancer patients, and 
most private payers follow Medicare's lead on coverage and benefits for cancer 
care. Medicare and private payers are legally required by federal statute to 
cover anticancer chemotherapeutic products based on U.S. Food and drug 
administration-approved labeling and indicate how off-label uses are covered.
OBJECTIVE: To review reimbursement issues unique to Medicare with regard to 
oncology drugs.
SUMMARY: Currently, the Centers for Medicare & Medicaid Services (CMS) 
recognizes 2 compendia for purposes of evaluating off-label uses of drugs. 
Coverage determinations can be pursued nationally, locally, and case by case. 
Because of the impact and scope of colorectal cancer on the national budget, CMS 
initiated a process to establish national coverage determinations. This and 
other such Medicare reforms will have significant repercussions for clinicians 
who work with oncology patients. Major administrative and access challenges for 
both health care providers and beneficiaries include a diverse array of plan 
choices. In terms of Medicare Part d, the 25% of patients who are chronically 
ill and prescribed expensive therapies (including antineoplastics and supportive 
care agents) may find the coverage gap ("donut hole") challenging and even 
prohibitive in their access to appropriate care. Lack of coverage could 
potentially affect therapy compliance, and managed care must pursue additional 
payment or coverage support mechanisms. Evaluating formularies will be critical 
for cancer patients and those who use specialty drugs as they select their Part 
d plans in the future.
CONCLUSION: Oncologists and their patients are left with difficult choices 
regarding not only the clinical efficacy of a treatment but also the financial 
considerations of the treatment.

DOI: 10.18553/jmcp.2007.13.s6-c.19
PMID: 17713991 [Indexed for MEDLINE]


125. J Exp Med. 2020 Oct 5;217(10):e20191515. doi: 10.1084/jem.20191515.

AKT-dependent NOTCH3 activation drives tumor progression in a model of 
mesenchymal colorectal cancer.

Varga J(1)(2), Nicolas A(1)(2), Petrocelli V(1)(2), Pesic M(1)(2), Mahmoud 
A(3)(4), Michels BE(1)(5), Etlioglu E(6), Yepes D(5)(7), Häupl B(2)(5)(7), 
Ziegler PK(8), Bankov K(8), Wild PJ(8), Wanninger S(9), Medyouf H(1)(2), Farin 
HF(1)(2)(5), Tejpar S(6), Oellerich T(2)(5)(7), Ruland J(5)(9), Siebel CW(10), 
Greten FR(1)(2)(5).

Author information:
(1)Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 
Frankfurt/Main, Germany.
(2)Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, 
Germany.
(3)German Cancer Research Center, Division of Applied Bioinformatics, 
Heidelberg, Germany.
(4)Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
(5)German Cancer Consortium and German Cancer Research Center, Heidelberg, 
Germany.
(6)Digestive Oncology Unit, Department of Oncology, University Hospital Leuven, 
Leuven, Belgium.
(7)Department of Medicine II, Hematology/Oncology, University Hospital 
Frankfurt, Frankfurt/Main, Germany.
(8)Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, 
Frankfurt/Main, Germany.
(9)Institute of Clinical Chemistry and Pathobiochemistry, Technical University 
of Munich School of Medicine, Technical University of Munich, Munich, Germany.
(10)Department of Discovery Oncology, Genentech, South San Francisco, CA.

Comment in
    J Exp Med. 2020 Oct 5;217(10):

Recently, a transcriptome-based consensus molecular subtype (CMS) classification 
of colorectal cancer (CRC) has been established, which may ultimately help to 
individualize CRC therapy. However, the lack of animal models that faithfully 
recapitulate the different molecular subtypes impedes adequate preclinical 
testing of stratified therapeutic concepts. Here, we demonstrate that 
constitutive AKT activation in intestinal epithelial cells markedly enhances 
tumor invasion and metastasis in Trp53ΔIEC mice (Trp53ΔIECAktE17K) upon 
challenge with the carcinogen azoxymethane. Gene-expression profiling indicates 
that Trp53ΔIECAktE17K tumors resemble the human mesenchymal colorectal cancer 
subtype (CMS4), which is characterized by the poorest survival rate among the 
four CMSs. Trp53ΔIECAktE17K tumor cells are characterized by Notch3 
up-regulation, and treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting 
antibody reduces invasion and metastasis. In CRC patients, NOTCH3 expression 
correlates positively with tumor grading and the presence of lymph node as well 
as distant metastases and is specifically up-regulated in CMS4 tumors. 
Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC 
patients.

© 2020 Varga et al.

DOI: 10.1084/jem.20191515
PMCID: PMC7537393
PMID: 32749453 [Indexed for MEDLINE]

Conflict of interest statement: Disclosures: T. Oellerich reported grants from 
Merck KGaA, grants from Gilead, personal fees from Merck KGaA, and personal fees 
from Gilead outside the submitted work. C. Siebel reported personal fees from 
Genentech during the conduct of the study, and personal fees from Genentech 
outside the submitted work. In addition, C. Siebel had a patent to Methods of 
treating cancer using Notch1 and Notch3 antagonists issued. No other disclosures 
were reported.


126. BMC Cancer. 2018 Dec 18;18(1):1265. doi: 10.1186/s12885-018-5174-z.

Gene expression profiles in genome instability-based classes of colorectal 
cancer.

Barresi V(1)(2), Cinnirella G(3), Valenti G(3), Spampinato G(3), Musso N(3), 
Castorina S(4)(5), Condorelli DF(6)(7).

Author information:
(1)Department of Biomedical and Biotechnological Sciences, Section of Medical 
Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123, Catania, 
Italy. barregi@unict.it.
(2)Laboratory of Complex Systems, Scuola Superiore di Catania, University of 
Catania, Catania, Italy. barregi@unict.it.
(3)Department of Biomedical and Biotechnological Sciences, Section of Medical 
Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123, Catania, 
Italy.
(4)Department of Surgical Medical Sciences and Advanced Technologies "G. F. 
Ingrassia", University of Catania, Catania, Italy.
(5)Fondazione Mediterranea G.B. Morgagni, Catania, Italy.
(6)Department of Biomedical and Biotechnological Sciences, Section of Medical 
Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123, Catania, 
Italy. daniele.condorelli@unict.it.
(7)Laboratory of Complex Systems, Scuola Superiore di Catania, University of 
Catania, Catania, Italy. daniele.condorelli@unict.it.

BACKGROUND: Broad copy number aberrations (BCNAs) represent a common form of 
genome instability in colorectal cancer (CRC). CRCs show large variations in 
their level of aneuploidy: microsatellite-instable (MSI) tumors are known to 
have a near-diploid karyotype while microsatellite-stable (MSS) tumors show high 
level of chromosomal instability. However, MSS tumors have great heterogeneity 
in the number of BCNAs, with a minor percentage of samples showing an almost 
normal karyotype. In the present work we subdivided MSS CRCs according to a 
"BCNA score" and characterized their transcriptome profiles, considered as a 
proxy to their phenotypic features.
METHODS: Microsatellite testing, genome-wide DNA copy number and 
whole-transcript expression analysis (HTA) were performed on 33 tumor samples 
and 25 normal colonic tissue samples from 32 CRC patients. 15.1% of the samples 
were MSI tumors (n = 5), whereas 84.9% were MSS tumors (n = 28). Gene expression 
data of 34 additional MSI tumors was retrieved from a public functional genomics 
data repository.
RESULTS: Using as a threshold the first quartile of the BCNA score distribution, 
MSS samples were classified as low-BCNA (LB, n = 7) or high-BCNA (HB, n = 21). 
LB tumors were enriched for mucinous CRCs and their gene-expression profile 
resembled that of MSI samples for what concerns a subset of genes involved in 
secretory processes, mucosal protection, and extracellular matrix remodeling. HB 
tumors were predominantly non-mucinous adenocarcinomas and showed overexpression 
of a subset of genes typical of surface colonocytes and EGF signaling. A large 
percentage of unclassified samples according to the consensus molecular subtypes 
(CMS) classifier was found in the LB group (43%), whereas 76% HB tumors belonged 
to CMS2.
CONCLUSIONS: A classification of colorectal tumors based on the number of BCNAs 
identifies two groups of MSS tumors which differ for histopathology and gene 
expression profile. Such information can be exploited for its translational 
relevance in different aspects of CRC clinical management.

DOI: 10.1186/s12885-018-5174-z
PMCID: PMC6299572
PMID: 30563495 [Indexed for MEDLINE]

Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: 
Tumor samples were collected from patients who underwent surgical resection at 
“Centro Clinico Diagnostico S.r.l. G.B. Morgagni” in Catania (Italy). All 
patients gave written informed consent for this study, which was approved by the 
Ethics Committee of ASL3 of Catania (Italy). CONSENT FOR PUBLICATION: Not 
applicable. COMPETING INTERESTS: The authors declare that they have no competing 
interests. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to 
jurisdictional claims in published maps and institutional affiliations.


127. Br J Cancer. 2018 Oct;119(7):855-863. doi: 10.1038/s41416-018-0253-0. Epub 2018 
Oct 5.

Analysis of cell proliferation and tissue remodelling uncovers a KLF4 activity 
score associated with poor prognosis in colorectal cancer.

Halim S(1), Markert EK(2), Vazquez A(3)(4).

Author information:
(1)Cancer Research UK Beatson Institute, Glasgow, UK.
(2)Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. 
Elke.Markert@glasgow.ac.uk.
(3)Cancer Research UK Beatson Institute, Glasgow, UK. 
Alexei.VazquezVazquez@glasgow.ac.uk.
(4)Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. 
Alexei.VazquezVazquez@glasgow.ac.uk.

BACKGROUND: Human cancers can be classified based on gene signatures quantifying 
the degree of cell proliferation and tissue remodelling (PR). However, the 
specific factors that drive the increased tissue remodelling in tumours are not 
fully understood. Here we address this question using colorectal cancer as a 
case study.
METHODS: We reanalysed a reported cohort of colorectal cancer patients. The 
patients were stratified based on gene signatures of cell proliferation and 
tissue remodelling. Putative transcription factors activity was inferred using 
gene expression profiles and annotations of transcription factor targets as 
input.
RESULTS: We demonstrate that the PR classification performs better than the 
currently adopted consensus molecular subtyping (CMS). Although CMS 
classification differentiates patients with a mesenchymal signature, it cannot 
distinguish the remaining patients based on survival. We demonstrate that the 
missing factor is cell proliferation, which is indicative of good prognosis. We 
also uncover a KLF4 transcription factor activity score associated with the 
tissue remodelling gene signature. We further show that the KLF4 activity score 
is significantly higher in colorectal tumours with predicted infiltration of 
cells from the myeloid lineage.
CONCLUSION: The KLF4 activity score is associated with tissue remodelling, 
myeloid cell infiltration and poor prognosis in colorectal cancer.

DOI: 10.1038/s41416-018-0253-0
PMCID: PMC6189192
PMID: 30287917 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


128. Clin Cancer Res. 2019 Jul 15;25(14):4431-4442. doi: 
10.1158/1078-0432.CCR-18-3032. Epub 2019 Apr 19.

A Clinically Applicable Gene-Expression Classifier Reveals Intrinsic and 
Extrinsic Contributions to Consensus Molecular Subtypes in Primary and 
Metastatic Colon Cancer.

Piskol R(1), Huw L(2), Sergin I(3), Kljin C(4), Modrusan Z(5), Kim D(6), Kljavin 
N(3), Tam R(6), Patel R(6), Burton J(3), Penuel E(6), Qu X(6), Koeppen H(7), 
Sumiyoshi T(6), de Sauvage F(5), Lackner MR(6), de Sousa E Melo F(#)(8), 
Kabbarah O(#)(6).

Author information:
(1)Bioinformatics and Computational Biology, Genentech, Inc., South San 
Francisco, California. desousaf@gene.com omarkabbarah@gmail.com.
(2)Oncology Biomarker Development, Genentech, Inc., South San Francisco, 
California. desousaf@gene.com omarkabbarah@gmail.com.
(3)Molecular Oncology, Genentech, Inc., South San Francisco, California.
(4)Bioinformatics and Computational Biology, Genentech, Inc., South San 
Francisco, California.
(5)Molecular Biology, Genentech, Inc., South San Francisco, California.
(6)Oncology Biomarker Development, Genentech, Inc., South San Francisco, 
California.
(7)Pathology, Genentech, Inc., South San Francisco, California.
(8)Discovery Oncology, Genentech, Inc., South San Francisco, California. 
desousaf@gene.com omarkabbarah@gmail.com.
(#)Contributed equally

PURPOSE: Four consensus molecular subtypes (CMS1-4) of colorectal cancer were 
identified in primary tumors and found to be associated with distinctive 
biological features and clinical outcomes. Given that distant metastasis largely 
accounts for colorectal cancer-related mortality, we examined the molecular and 
clinical attributes of CMS in metastatic colorectal cancer (mCRC).
EXPERIMENTAL DESIGN: We developed a colorectal cancer-focused NanoString-based 
CMS classifier that is ideally suited to interrogate archival tissues. We 
successfully used this panel in the CMS classification of formalin-fixed 
paraffin-embedded (FFPE) tissues from mCRC cohorts, one of which is composed of 
paired primary tumors and metastases. Finally, we developed novel mouse 
implantation models to enable modeling of colorectal cancer in vivo at relevant 
sites.
RESULTS: Using our classifier, we find that the biological hallmarks of mCRC, 
including CMS, are in general highly similar to those observed in nonmetastatic 
early-stage disease. Importantly, our data demonstrate that CMS1 has the worst 
outcome in relapsed disease, compared with other CMS. Assigning CMS to primary 
tumors and their matched metastases reveals mostly concordant subtypes between 
primary and metastasis. Molecular analysis of matched discordant pairs reveals 
differences in stromal composition at each site. The development of two novel in 
vivo orthotopic implantation models further reinforces the notion that extrinsic 
factors may impact on CMS identification in matched primary and metastatic 
colorectal cancer.
CONCLUSIONS: We describe the utility of a NanoString panel for CMS 
classification of FFPE clinical samples. Our work reveals the impact of 
intrinsic and extrinsic factors on colorectal cancer heterogeneity during 
disease progression.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-18-3032
PMID: 31004000 [Indexed for MEDLINE]


129. Cell Rep. 2017 May 9;19(6):1268-1280. doi: 10.1016/j.celrep.2017.04.045.

Molecular-Subtype-Specific Biomarkers Improve Prediction of Prognosis in 
Colorectal Cancer.

Bramsen JB(1), Rasmussen MH(2), Ongen H(3), Mattesen TB(2), Ørntoft MW(2), 
Árnadóttir SS(2), Sandoval J(4), Laguna T(4), Vang S(2), Øster B(2), Lamy P(2), 
Madsen MR(5), Laurberg S(6), Esteller M(7), Dermitzakis ET(3), Ørntoft TF(2), 
Andersen CL(8).

Author information:
(1)Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, 
Denmark. Electronic address: bramsen@clin.au.dk.
(2)Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, 
Denmark.
(3)Department of Genetic Medicine and Development, University of Geneva Medical 
School, Geneva 1211, Switzerland; Institute for Genetics and Genomics in Geneva 
(iGE3), University of Geneva, Geneva 1211, Switzerland; Swiss Institute of 
Bioinformatics, Geneva 1211, Switzerland.
(4)Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research 
Institute (IDIBELL), L'Hospitalet, Barcelona 08908, Catalonia, Spain.
(5)Department of Surgery, Hospitalsenheden Vest, Herning 7400, Denmark.
(6)Section of Coloproctology, Aarhus University Hospital, Aarhus 8000, Denmark.
(7)Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research 
Institute (IDIBELL), L'Hospitalet, Barcelona 08908, Catalonia, Spain; 
Physiological Sciences Department, School of Medicine and Health Sciences, 
University of Barcelona, Barcelona 08907, Catalonia, Spain; Institucio Catalana 
de Recerca i Estudis Avancats (ICREA), Barcelona 08010, Catalonia, Spain.
(8)Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, 
Denmark. Electronic address: cla@clin.au.dk.

Colorectal cancer (CRC) is characterized by major inter-tumor diversity that 
complicates the prediction of disease and treatment outcomes. Recent efforts 
help resolve this by sub-classification of CRC into natural molecular subtypes; 
however, this strategy is not yet able to provide clinicians with improved tools 
for decision making. We here present an extended framework for CRC 
stratification that specifically aims to improve patient prognostication. Using 
transcriptional profiles from 1,100 CRCs, including >300 previously unpublished 
samples, we identify cancer cell and tumor archetypes and suggest the tumor 
microenvironment as a major prognostic determinant that can be influenced by the 
microbiome. Notably, our subtyping strategy allowed identification of 
archetype-specific prognostic biomarkers that provided information beyond and 
independent of UICC-TNM staging, MSI status, and consensus molecular subtyping. 
The results illustrate that our extended subtyping framework, combining 
subtyping and subtype-specific biomarkers, could contribute to improved patient 
prognostication and may form a strong basis for future studies.

Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.celrep.2017.04.045
PMID: 28494874 [Indexed for MEDLINE]


130. Clin Cancer Res. 2021 Nov 1;27(21):5979-5992. doi: 
10.1158/1078-0432.CCR-21-0818. Epub 2021 Aug 23.

Molecular Subtyping Combined with Biological Pathway Analyses to Study 
Regorafenib Response in Clinically Relevant Mouse Models of Colorectal Cancer.

Lafferty A(1), O'Farrell AC(1), Migliardi G(2)(3), Khemka N(4)(5), Lindner 
AU(4)(5), Sassi F(3), Zanella ER(3), Salvucci M(4)(5), Vanderheyden E(6), Modave 
E(6), Boeckx B(6), Halang L(4)(5), Betge J(7)(8), Ebert MPA(7), Dicker P(9), 
Argilés G(10), Tabernero J(10), Dienstmann R(10), Medico E(2)(3), Lambrechts 
D(6), Bertotti A(2)(3), Isella C(2)(3), Trusolino L(2)(3), Prehn JHM(4)(5), 
Byrne AT(11)(4)(12).

Author information:
(1)Department of Physiology and Medical Physics, Precision Cancer Medicine 
Group, Royal College of Surgeons in Ireland, Dublin, Ireland.
(2)Department of Oncology, University of Torino, Candiolo, Italy.
(3)Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
(4)Department of Physiology and Medical Physics, Royal College of Surgeons in 
Ireland, Dublin, Ireland.
(5)Center for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, 
Ireland.
(6)Department of Human Genetics, VIB Center for Cancer Biology, Leuven, Belgium, 
Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium.
(7)Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 
Mannheim, Germany.
(8)Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and 
Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany.
(9)Department of Epidemiology and Public Health Medicine, Royal College of 
Surgeons in Ireland, Dublin, Ireland.
(10)Vall d'Hebron University Hospital and Institute of Oncology (VHIO), 
Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain.
(11)Department of Physiology and Medical Physics, Precision Cancer Medicine 
Group, Royal College of Surgeons in Ireland, Dublin, Ireland. 
annettebyrne@rcsi.ie.
(12)UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, 
University College Dublin, Belfield, Dublin, Ireland.

PURPOSE: Regorafenib (REG) is approved for the treatment of metastatic 
colorectal cancer, but has modest survival benefit and associated toxicities. 
Robust predictive/early response biomarkers to aid patient stratification are 
outstanding. We have exploited biological pathway analyses in a patient-derived 
xenograft (PDX) trial to study REG response mechanisms and elucidate putative 
biomarkers.
EXPERIMENTAL DESIGN: Molecularly subtyped PDXs were annotated for REG response. 
Subtyping was based on gene expression (CMS, consensus molecular subtype) and 
copy-number alteration (CNA). Baseline tumor vascularization, apoptosis, and 
proliferation signatures were studied to identify predictive biomarkers within 
subtypes. Phospho-proteomic analysis was used to identify novel classifiers. 
Supervised RNA sequencing analysis was performed on PDXs that progressed, or did 
not progress, following REG treatment.
RESULTS: Improved REG response was observed in CMS4, although intra-subtype 
response was variable. Tumor vascularity did not correlate with outcome. In CMS4 
tumors, reduced proliferation and higher sensitivity to apoptosis at baseline 
correlated with response. Reverse phase protein array (RPPA) analysis revealed 4 
phospho-proteomic clusters, one of which was enriched with non-progressor 
models. A classification decision tree trained on RPPA- and CMS-based 
assignments discriminated non-progressors from progressors with 92% overall 
accuracy (97% sensitivity, 67% specificity). Supervised RNA sequencing revealed 
that higher basal EPHA2 expression is associated with REG resistance.
CONCLUSIONS: Subtype classification systems represent canonical "termini a quo" 
(starting points) to support REG biomarker identification, and provide a 
platform to identify resistance mechanisms and novel contexts of vulnerability. 
Incorporating functional characterization of biological systems may optimize the 
biomarker identification process for multitargeted kinase inhibitors.

©2021 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-21-0818
PMID: 34426441 [Indexed for MEDLINE]


131. Radiology. 2010 Feb;254(2):501-8. doi: 10.1148/radiol.2541090484.

Resected colorectal cancer among Medicare beneficiaries:adoption of FDG PET.

Zafar HM(1), Mahmoud NN, Mitra N, Wirtalla C, Armstrong K, Groeneveld PW.

Author information:
(1)Department of Radiology, Hospital of the University of Pennsylvania, 3400 
Spruce St, Philadelphia, PA 19104, USA. hanna.zafar@uphs.upenn.edu

PURPOSE: To investigate early adoption and potential predictors of postoperative 
utilization of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography 
(PET) in patients who underwent colorectal cancer resection between July 2001 
and December 2002 (the first 18 months of Centers for Medicare and Medicaid 
Services [CMS] coverage for FDG PET) and who were observed for 2 years from the 
date of surgery.
MATERIALS AND METHODS: This HIPAA-compliant study was exempt from institutional 
review board approval. Informed consent was waived. This was a retrospective 
cohort study of FDG PET utilization in patients with colorectal cancer following 
resection between July 1, 2001 and December 31, 2002. Utilization data were 
drawn from the Surveillance, Epidemiology and End Results-Medicare files during 
the first 2 years following colorectal surgery. The primary outcome measure was 
FDG PET utilization. Covariates included disease-, patient-, and hospital-level 
characteristics, as well as computed tomography (CT) utilization. Univariate and 
multiple regression analysis were performed.
RESULTS: Of 10630 patients (mean age, 77.5 years) who underwent resection for 
colorectal cancer during the study period, 1056 (10%) patients underwent at 
least one FDG PET examination in the 2-year period following surgery. A 41% 
relative increase in utilization of FDG PET was found among patients who 
underwent resection early in the study period compared with those who underwent 
resection late in the study period; this was a significant difference (P < 
.001). There was no change in CT utilization between these two groups (P = 
.302). The highest utilization of FDG PET was during the first 6 months 
following surgery. Significant predictors of higher FDG PET utilization included 
rectal cancer, later date of initial surgery, higher disease stage, older age, 
marital status, and lower comorbidity.
CONCLUSION: Substantial growth in utilization of FDG PET within 2 years of 
surgery was found among patients who underwent surgery during the first 18 
months of approved CMS coverage, with the highest rates of utilization occurring 
within 6 months of surgery and lower rates occurring subsequently over the 
2-year period following resection.

DOI: 10.1148/radiol.2541090484
PMID: 20093522 [Indexed for MEDLINE]


132. Oncologist. 2015 Jan;20(1):14-8. doi: 10.1634/theoncologist.2014-0252. Epub 2014 
Nov 19.

Cost estimates and economic implications of expanded RAS testing in metastatic 
colorectal cancer.

Kircher SM(1), Mohindra N(2), Nimeiri H(2).

Author information:
(1)Department of Medicine, Division of Hematology-Oncology, Northwestern 
University Feinberg School of Medicine, Chicago, Illinois, USA 
skircher@nmff.org.
(2)Department of Medicine, Division of Hematology-Oncology, Northwestern 
University Feinberg School of Medicine, Chicago, Illinois, USA.

BACKGROUND: In colorectal cancer (CRC), evidence shows that expanding RAS 
testing to analyze more mutations may better predict benefit from anti-EGFR 
therapy. The economic implications of expanding RAS testing for metastatic CRC 
were analyzed.
MATERIALS AND METHODS: Estimates of standard KRAS exon 2 testing were based on 
the Centers for Medicare and Medicaid Services (CMS) 2014 Diagnostic Laboratory 
Fee Schedule, and expanded RAS testing was estimated using a sensitivity 
analysis done with various potential cost scenarios (1, 2, 10, and 30 times the 
cost of the standard KRAS test). The cost estimates for cetuximab and 
panitumumab were based on the CMS payment allowance limits for Medicare Part B.
RESULTS: A total of 28,692 patients with metastatic CRC were estimated to be 
eligible annually for RAS testing. For cetuximab, the societal cost of standard 
KRAS testing plus the drug versus expanded testing plus the drug would be $1.16 
billion versus $816 million if the cost of the tests were the same. If the cost 
of the expanded RAS test were 30 times the cost of the standard test, then the 
societal cost of standard KRAS testing plus the drug versus expanded testing 
plus the drug would be $1.16 billion versus $980 million, a continued savings of 
more than $184 million annually. Similar savings were seen with panitumumab.
CONCLUSION: The increased societal cost of expanded RAS testing versus standard 
approved KRAS exon 2 testing was inconsequential when compared with the amount 
of money saved by not treating the additional 18% of patients who harbor 
additional RAS mutations (beyond exon 2) with anti-EGFR therapy.

©AlphaMed Press.

DOI: 10.1634/theoncologist.2014-0252
PMCID: PMC4294607
PMID: 25410095 [Indexed for MEDLINE]

Conflict of interest statement: Disclosures of potential conflicts of interest 
may be found at the end of this article.


133. J Cell Commun Signal. 2016 Sep;10(3):223-227. doi: 10.1007/s12079-016-0347-5. 
Epub 2016 Sep 10.

A potential role for CCN2/CTGF in aggressive colorectal cancer.

Ubink I(1), Verhaar ER(2), Kranenburg O(1), Goldschmeding R(3)(4).

Author information:
(1)Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, 
Utrecht, The Netherlands.
(2)Department of Pathology, University Medical Center Utrecht, Heidelberglaan 
100, 3584CX, Utrecht, The Netherlands.
(3)Department of Pathology, University Medical Center Utrecht, Heidelberglaan 
100, 3584CX, Utrecht, The Netherlands. r.goldschmeding@umcutrecht.nl.
(4)University Medical Center Utrecht, PO Box 85500, 3508GA, Utrecht, The 
Netherlands. r.goldschmeding@umcutrecht.nl.

CCN2, also known as connective tissue growth factor (CTGF) is a transcriptional 
target of TGF-β signaling. Unlike its original name ("CTGF") suggested, CCN2 is 
not an actual growth factor but a matricellular protein that plays an important 
role in fibrosis, inflammation and connective tissue remodeling in a variety of 
diseases, including cancer. In pancreatic ductal adenocarcinoma, CCN2 signaling 
induces stromal infiltration and facilitates a strong tumor-stromal interaction. 
In many types of cancer, CCN2 overexpression has been associated with poor 
outcome. CMS4 (Consensus Molecular Subtype 4) is a recently identified 
aggressive colorectal cancer subtype, that is characterized by up-regulation of 
genes involved in epithelial-to-mesenchymal transition, TGF-β signaling, 
angiogenesis, complement activation, and extracellular matrix remodeling. In 
addition, a high influx of stromal fibroblasts contributes to the 
mesenchymal-like gene expression profile of this subtype. Furthermore, compared 
with the other three CMS groups, CMS4 tumors have the worst prognosis. Based on 
these observations, we postulated that CCN2 might contribute to colorectal 
cancer progression, especially in the CMS4 subtype. This review discusses the 
available literature on the role of CCN2 in colorectal cancer, with a focus on 
the 'fibrotic subtype' CMS4.

DOI: 10.1007/s12079-016-0347-5
PMCID: PMC5055504
PMID: 27613407


134. PLoS One. 2019 Sep 4;14(9):e0220234. doi: 10.1371/journal.pone.0220234. 
eCollection 2019.

Cost-effectiveness of a multitarget stool DNA test for colorectal cancer 
screening of Medicare beneficiaries.

Naber SK(1), Knudsen AB(2), Zauber AG(3), Rutter CM(4), Fischer SE(3), Pabiniak 
CJ(5), Soto B(3), Kuntz KM(6), Lansdorp-Vogelaar I(1).

Author information:
(1)Erasmus MC, University Medical Center Rotterdam, Department of Public Health, 
Rotterdam, The Netherlands.
(2)Institute for Technology Assessment, Massachusetts General Hospital, Boston, 
Massachusetts, United States of America.
(3)Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer 
Center, New York, New York, United States of America.
(4)RAND Corporation, Santa Monica, California, United States of America.
(5)Kaiser Permanente Washington Health Research Institute, Seattle, Washington, 
United States of America.
(6)Division of Health Policy and Management, School of Public Health, University 
of Minnesota, Minneapolis, Minnesota, United States of America.

BACKGROUND: In 2014, the Centers for Medicare and Medicaid Services (CMS) began 
covering a multitarget stool DNA (mtSDNA) test for colorectal cancer (CRC) 
screening of Medicare beneficiaries. In this study, we evaluated whether mtSDNA 
testing is a cost-effective alternative to other CRC screening strategies 
reimbursed by CMS, and if not, under what conditions it could be.
METHODS: We use three independently-developed microsimulation models to simulate 
a cohort of previously unscreened US 65-year-olds who are screened with 
triennial mtSDNA testing, or one of six other reimbursed screening strategies. 
Main outcome measures are discounted life-years gained (LYG) and lifetime costs 
(CMS perspective), threshold reimbursement rates, and threshold adherence rates. 
Outcomes are expressed as the median and range across models.
RESULTS: Compared to no screening, triennial mtSDNA screening resulted in 82 
(range: 79-88) LYG per 1,000 simulated individuals. This was more than for 
five-yearly sigmoidoscopy (80 (range: 71-89) LYG), but fewer than for every 
other simulated strategy. At its 2017 reimbursement rate of $512, mtSDNA was the 
most costly strategy, and even if adherence were 30% higher than with other 
strategies, it would not be a cost-effective alternative. At a substantially 
reduced reimbursement rate ($6-18), two models found that triennial mtSDNA 
testing was an efficient and potentially cost-effective screening option.
CONCLUSIONS: Compared to no screening, triennial mtSDNA screening reduces CRC 
incidence and mortality at acceptable costs. However, compared to nearly all 
other CRC screening strategies reimbursed by CMS it is less effective and 
considerably more costly, making it an inefficient screening option.

DOI: 10.1371/journal.pone.0220234
PMCID: PMC6726189
PMID: 31483796 [Indexed for MEDLINE]

Conflict of interest statement: This work was supported by contract 
HHSM-500-2012-00008I with The MITRE Corporation. CMR was affiliated with RAND 
Corporation, but did not receive any financial support for this work. BS is 
currently affiliated with CVS Health but was not affiliated at the time of the 
study. There are no patents, products in development or marketed products 
associated with this research to declare. This does not alter our adherence to 
PLOS ONE policies on sharing data and materials.


135. Oncotarget. 2018 Apr 10;9(27):18698-18711. doi: 10.18632/oncotarget.24617. 
eCollection 2018 Apr 10.

Consensus molecular subtypes classification of colorectal cancer as a predictive 
factor for chemotherapeutic efficacy against metastatic colorectal cancer.

Okita A(1)(2), Takahashi S(1)(2), Ouchi K(1)(2), Inoue M(3), Watanabe M(4), Endo 
M(5), Honda H(6), Yamada Y(7)(8), Ishioka C(1)(2).

Author information:
(1)Department of Clinical Oncology, Institute of Development, Aging and Cancer, 
Tohoku University, Aoba-ku, Sendai, Japan.
(2)Department of Medical Oncology, Tohoku University Hospital, Aoba-ku, Sendai, 
Japan.
(3)Department of Clinical Oncology, Akita University Graduate School of 
Medicine, Akita, Japan.
(4)Department of Pathology, Tohoku University Graduate School of Medicine, 
Aobaku, Sendai, Japan.
(5)Department of Pathology, Sendai Kousei Hospital, Aobaku, Sendai, Japan.
(6)Department of Surgery, Tohoku Rosai Hospital, Aobaku, Sendai, Japan.
(7)Department of Clinical Oncology, Hamamatsu University School of Medicine, 
Higashiku, Hamamatsu, Japan.
(8)Department of Oncology, National Center for Global Health and Medicine, 
Tokyo, Japan.

The consensus molecular subtypes (CMS) classification is one of the most robust 
colorectal cancer (CRC) classifications based on comprehensive gene expression 
profiles. This study aimed to clarify whether the CMS is a predictive factor for 
therapeutic effects of standard chemotherapies for metastatic CRC (mCRC). We 
retrospectively enrolled 193 patients with mCRCs, and using comprehensive gene 
expression data, classified them into 4 subtypes: CMS1-CMS4. The associations 
between the subtypes and treatment outcomes were analyzed. Regarding first-line 
chemotherapy, irinotecan (IRI)-based chemotherapy was significantly superior to 
oxaliplatin (OX)-based chemotherapy for progression-free survival (PFS; hazard 
ratio [HR] = 0.31, 95% confidence interval [CI] 0.13-0.64) and overall survival 
(OS; HR = 0.45, 95% CI 0.19-0.99) in CMS4. Regarding the anti-epidermal growth 
factor receptor (anti-EGFR) therapy, CMS1 showed particularly worse PFS (HR = 
2.50, 95% CI 1.31-4.39) and OS (HR = 4.23, 95% CI 1.83-9.04), and CMS2 showed 
particularly good PFS (HR = 0.67, 95% CI 0.44-1.01) and OS (HR = 0.49, 95% CI 
0.27-0.87) compared with the other subtypes. The biological characteristics of 
CMS may influence the efficacy of chemotherapy. CMS might be a new predictive 
factor for the efficacy of chemotherapy against mCRCs.

DOI: 10.18632/oncotarget.24617
PMCID: PMC5922348
PMID: 29721154

Conflict of interest statement: CONFLICTS OF INTEREST Prof. Ishioka reported 
grants from the Japan Agency for Medical Research and Development; the Ministry 
of Education, Culture Sports, Science, and Technology of Japan, during the 
conduct of the study; grants and personal fees from Mochida, Chugai, Novartis, 
Merck-Serono, Daiichi-Sankyo, Takeda, Nihon-Kayaku, Yakult, Taiho, Ono and 
Asahikasei-Pharma; personal fees from Eli Lilly and Bayer; and grants from 
Kyowa-Kirin, Eizai, Tsumura, Astellas, Kissei and Bristol, outside the submitted 
work. Dr. Takahashi reported grants from The Ministry of Education, Culture 
Sports, Science, and Technology of Jaman during the conduct of the study; grants 
and personal fees from Merck-Serono and Taiho Pharmaceutical; and personal fees 
from Asahi Kasei, Daiichi Sankyo, Medicon, Novartis, and Mochida Pharmaceutical, 
outside the submitted work. None of the remaining authors have any conflicts of 
interest to declare.


136. Med Care. 2008 Oct;46(10):1108-15. doi: 10.1097/MLR.0b013e3181862565.

Comparison of cancer diagnosis and treatment in Medicare fee-for-service and 
managed care plans.

Riley GF(1), Warren JL, Potosky AL, Klabunde CN, Harlan LC, Osswald MB.

Author information:
(1)Office of Research, Development, and Information, Centers for Medicare and 
Medicaid Services, Baltimore, Maryland 21244, USA. Gerald.riley@cms.hhs.gov

OBJECTIVE: To compare the Medicare managed care (MC) and fee-for-service (FFS) 
sectors on stage at diagnosis and treatment patterns for prostate, female 
breast, and colorectal cancers, and to examine patterns across MC plans.
DATA: Surveillance, Epidemiology, and End Results-Medicare linked data.
METHODS: Among cases diagnosed at ages 65-79 between 1998 and 2002, we selected 
all MC enrollees (n = 42,467) and beneficiaries in FFS (n = 82,998) who resided 
in the same counties. MC and FFS samples were compared using logistic 
regression, adjusting for demographic, geographic, and clinical covariates.
RESULTS: The percentage of late stage cases was similar in MC and FFS for 
prostate and colorectal cancers; there were slightly fewer late stage breast 
cancer cases in MC after adjustment (7.3% vs. 8.5%, P < 0.001). Within MC, 
radical prostatectomy was performed less frequently for clinically localized 
prostate cancer (18.3% vs. 22.4%, P < 0.0001), and 12 or more lymph nodes were 
examined less often for resected colon cancer cases (40.9% vs. 43.0%, P < 0.05). 
Treatment patterns for early stage breast cancer were similar in MC and FFS. 
Analyses of treatment patterns at the individual plan level revealed significant 
variation among plans, as well as within the FFS sector, for all 3 types of 
cancer.
CONCLUSIONS: On average, there are few significant differences in cancer 
diagnosis and treatment between MC and FFS. Such comparisons, however, mask the 
wide variability among MC plans, as well as FFS providers. Observed variation in 
patterns of care may be related to patient selection, but can potentially lead 
to outcome differences. These findings support the need for quality measures to 
evaluate plan practices and performance.

DOI: 10.1097/MLR.0b013e3181862565
PMID: 18815533 [Indexed for MEDLINE]


137. Sci Rep. 2019 May 21;9(1):7665. doi: 10.1038/s41598-019-43492-0.

Analytical Validation of Multiplex Biomarker Assay to Stratify Colorectal Cancer 
into Molecular Subtypes.

Ragulan C(1)(2), Eason K(1), Fontana E(1)(2), Nyamundanda G(1)(2), Tarazona 
N(3), Patil Y(1)(2), Poudel P(1), Lawlor RT(4)(5), Del Rio M(6), Koo SL(7), Tan 
WS(8), Sclafani F(9), Begum R(9), Teixeira Mendes LS(2), Martineau P(6), Scarpa 
A(4)(5), Cervantes A(3), Tan IB(8)(10)(11), Cunningham D(2)(9), Sadanandam 
A(12)(13).

Author information:
(1)Division of Molecular Pathology, The Institute of Cancer Research, London, 
United Kingdom.
(2)Centre for Molecular Pathology, The Royal Marsden NHS Foundation Trust, 
London, United Kingdom.
(3)CIBERONC, Department of Medical Oncology, Biomedical Research Institute 
INCLIVA, University of Valencia, Valencia, Spain.
(4)ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust 
of Verona, Verona, Italy.
(5)Department of Pathology and Diagnostics, University and Hospital Trust of 
Verona, Verona, Italy.
(6)Institut de Recherche en Cancérologie de Montpellier, Institut National de la 
Santé et de la Recherche Médicale, U896, Université Montpellier, Centre Régional 
de Lutte contre le Cancer Val d'Aurelle Paul Lamarque, Montpellier, France.
(7)National Cancer Centre Singapore, Singapore, Singapore.
(8)Singapore General Hospital, Singapore, Singapore.
(9)Department of Medicine, The Royal Marsden NHS Foundation Trust, London, 
United Kingdom.
(10)Genome Institute of Singapore, Singapore, Singapore.
(11)Duke-NUS Medical School, Singapore, Singapore.
(12)Division of Molecular Pathology, The Institute of Cancer Research, London, 
United Kingdom. anguraj.sadanandam@icr.ac.uk.
(13)Centre for Molecular Pathology, The Royal Marsden NHS Foundation Trust, 
London, United Kingdom. anguraj.sadanandam@icr.ac.uk.

Previously, we classified colorectal cancers (CRCs) into five CRCAssigner (CRCA) 
subtypes with different prognoses and potential treatment responses, later 
consolidated into four consensus molecular subtypes (CMS). Here we demonstrate 
the analytical development and validation of a custom NanoString nCounter 
platform-based biomarker assay (NanoCRCA) to stratify CRCs into subtypes. To 
reduce costs, we switched from the standard nCounter protocol to a custom 
modified protocol. The assay included a reduced 38-gene panel that was selected 
using an in-house machine-learning pipeline. We applied NanoCRCA to 413 samples 
from 355 CRC patients. From the fresh frozen samples (n = 237), a subset had 
matched microarray/RNAseq profiles (n = 47) or formalin-fixed paraffin-embedded 
(FFPE) samples (n = 58). We also analyzed a further 118 FFPE samples. We 
compared the assay results with the CMS classifier, different platforms 
(microarrays/RNAseq) and gene-set classifiers (38 and the original 786 genes). 
The standard and modified protocols showed high correlation (> 0.88) for gene 
expression. Technical replicates were highly correlated (> 0.96). NanoCRCA 
classified fresh frozen and FFPE samples into all five CRCA subtypes with 
consistent classification of selected matched fresh frozen/FFPE samples. We 
demonstrate high and significant subtype concordance across protocols (100%), 
gene sets (95%), platforms (87%) and with CMS subtypes (75%) when evaluated 
across multiple datasets. Overall, our NanoCRCA assay with further validation 
may facilitate prospective validation of CRC subtypes in clinical trials and 
beyond.

DOI: 10.1038/s41598-019-43492-0
PMCID: PMC6529539
PMID: 31113981 [Indexed for MEDLINE]

Conflict of interest statement: A.Sa. has ownership interest as a patent 
inventor for a patent entitled “Colorectal cancer classification with 
differential prognosis and personalized therapeutic responses” (patent number 
PCT/IB2013/060416). A.Sa. receives research funding from Bristol-Myers Squibb 
Merck KGaA and Pierre Fabre. D.C. receives research funding from – Amgen, 
Sanofi, Merrimack, AstraZeneca, Celgene, MedImmune, Bayer, 4SC, Clovis, Eli 
Lilly, Janssen, and Merck. The remaining authors declare no competing interests.


138. J Surg Res. 2019 Apr;236:30-36. doi: 10.1016/j.jss.2018.09.073. Epub 2018 Dec 4.

Variation in Physician-Specific Episode Payments for Major Cancer Surgery and 
Implications for the Merit-Based Incentive Program.

Kaye DR(1), Dunn RL(2), Li J(2), Herrel LA(2), Dupree JM(2), Miller DC(2), 
Ellimoottil C(2).

Author information:
(1)Dow Division of Health Services Research, Department of Urology, University 
of Michigan, Ann Arbor, Michigan. Electronic address: kayed@med.umich.edu.
(2)Dow Division of Health Services Research, Department of Urology, University 
of Michigan, Ann Arbor, Michigan.

BACKGROUND: Nearly 1.5 million clinicians in the United States will be affected 
by Centers for Medicare and Medicaid Services' (CMS) new payment program, the 
Merit-based Incentive Program (MIPS), where clinicians will be penalized or 
rewarded based on the health care expenditures of their patients. We therefore 
examined expenditures for major cancer surgery to understand physician-specific 
variation in episode payments.
METHODS: We used Surveillance, Epidemiology and End Results-Medicare data to 
identify patients aged 66-99 y who underwent a prostatectomy, nephrectomy, lung, 
or colorectal resection for cancer from 2008 to 2012. We calculated 90-d episode 
payments, attributed each episode to a physician, and evaluated physician-level 
payment variation. Next, we determined which component (index admission, 
readmission, physician services, postacute care, hospice) drove differences in 
payments. Finally, we evaluated payments by geographic region, number of 
comorbidities, and cancer stage.
RESULTS: We identified 39,109 patients who underwent surgery by 1 of 7182 
providers. There was wide variation in payments for each procedure 
(prostatectomy: $7046-$40,687; nephrectomy: $8855-$82,489; lung resection: 
$11,167-$223,467; colorectal resection: $9711-$199,480). The largest component 
difference in episode payments varied by condition: physician payments for 
prostatectomy (29%), postacute care for nephrectomy (38%) and colorectal 
resections (38%), and index hospital admission for lung resections (43%) but 
were fairly stable across region, comorbidity number, and cancer stage.
CONCLUSIONS: For patients undergoing major cancer surgery, 90-d episode payments 
vary widely across surgeons. The components driving such variation differ by 
condition but remain stable across region, number of comorbidities, and cancer 
stage. These data suggest that programs to reduce specific component payments 
may have advantages over those targeting individual physicians for decreasing 
health care expenditures.

Copyright © 2018 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.jss.2018.09.073
PMCID: PMC6377848
PMID: 30694769 [Indexed for MEDLINE]

Conflict of interest statement: Conflicts of Interest: JMD, DCM: Grant contract 
from the Blue Cross Blue Shield of Michigan (BCBSM) for the Michigan Value 
Collaborative (MVC) and the Michigan Urological Surgery Improvement 
Collaborative (MUSIC)


139. Mod Pathol. 2022 Feb;35(2):240-248. doi: 10.1038/s41379-021-00894-8. Epub 2021 
Sep 2.

Image-based assessment of extracellular mucin-to-tumor area predicts consensus 
molecular subtypes (CMS) in colorectal cancer.

Nguyen HG(1), Lundström O(2)(3), Blank A(4), Dawson H(1), Lugli A(1), Anisimova 
M(3)(5), Zlobec I(6).

Author information:
(1)Institute of Pathology, University of Bern, Bern, Switzerland.
(2)Science of Life Laboratory, Department of Biochemistry and Biophysics, 
Stockholm University, Stockholm, Sweden.
(3)Institute of Applied Simulations, School of Life Sciences und Facility 
Management, Zürich University of Applied Sciences, Wädenswil, Switzerland.
(4)Institute of Clinical Pathology, City Hospital Triemli, Zurich, Switzerland.
(5)SIB Swiss Institute of Bioinformatics, Quartier Sorge, Lausanne, Switzerland.
(6)Institute of Pathology, University of Bern, Bern, Switzerland. 
inti.zlobec@pathology.unibe.ch.

The backbone of all colorectal cancer classifications including the consensus 
molecular subtypes (CMS) highlights microsatellite instability (MSI) as a key 
molecular pathway. Although mucinous histology (generally defined as >50% 
extracellular mucin-to-tumor area) is a "typical" feature of MSI, it is not 
limited to this subgroup. Here, we investigate the association of CMS 
classification and mucin-to-tumor area quantified using a deep learning 
algorithm, and  the expression of specific mucins in predicting CMS groups and 
clinical outcome. A weakly supervised segmentation method was developed to 
quantify extracellular mucin-to-tumor area in H&E images. Performance was 
compared to two pathologists' scores, then applied to two cohorts: (1) TCGA 
(n = 871 slides/412 patients) used for mucin-CMS group correlation and (2) Bern 
(n = 775 slides/517 patients) for histopathological correlations and 
next-generation Tissue Microarray construction. TCGA and CPTAC (n = 85 patients) 
were used to further validate mucin detection and CMS classification by gene and 
protein expression analysis for MUC2, MUC4, MUC5AC and MUC5B. An excellent 
inter-observer agreement between pathologists' scores and the algorithm 
was obtained (ICC = 0.92). In TCGA, mucinous tumors were predominantly CMS1 
(25.7%), CMS3 (24.6%) and CMS4 (16.2%). Average mucin in CMS2 was 1.8%, 
indicating negligible amounts. RNA and protein expression of MUC2, MUC4, MUC5AC 
and MUC5B were low-to-absent in CMS2. MUC5AC protein expression correlated with 
aggressive tumor features (e.g., distant metastases (p = 0.0334), BRAF mutation 
(p < 0.0001), mismatch repair-deficiency (p < 0.0001), and unfavorable 5-year 
overall survival (44% versus 65% for positive/negative staining). MUC2 
expression showed the opposite trend, correlating with less lymphatic 
(p = 0.0096) and venous vessel invasion (p = 0.0023), no impact on survival.The 
absence of mucin-expressing tumors in CMS2 provides an important 
phenotype-genotype correlation. Together with MSI, mucinous histology may help 
predict CMS classification using only histopathology and should be considered in 
future image classifiers of molecular subtypes.

© 2021. The Author(s).

DOI: 10.1038/s41379-021-00894-8
PMCID: PMC8786661
PMID: 34475526 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


140. Br J Cancer. 2020 Oct;123(8):1262-1270. doi: 10.1038/s41416-020-1015-3. Epub 
2020 Jul 31.

Integrated clinico-molecular profiling of appendiceal adenocarcinoma reveals a 
unique grade-driven entity distinct from colorectal cancer.

Raghav K(1), Shen JP(2), Jácome AA(2), Guerra JL(2), Scally CP(3), Taggart 
MW(4), Foo WC(4), Matamoros A(5), Shaw KR(6), Fournier K(3), Overman MJ(2), Eng 
C(2).

Author information:
(1)Department of Gastrointestinal Medical Oncology, The University of Texas MD 
Anderson Cancer Center, Houston, TX, USA. kpraghav@mdanderson.org.
(2)Department of Gastrointestinal Medical Oncology, The University of Texas MD 
Anderson Cancer Center, Houston, TX, USA.
(3)Department of Surgical Oncology, The University of Texas MD Anderson Cancer 
Center, Houston, TX, USA.
(4)Department of Pathology, The University of Texas MD Anderson Cancer Center, 
Houston, TX, USA.
(5)Department of Diagnostic Radiology, The University of Texas MD Anderson 
Cancer Center, Houston, TX, USA.
(6)Institute for Personalized Cancer Therapy, The University of Texas MD 
Anderson Cancer Center, Houston, TX, USA.

BACKGROUND: Appendiceal adenocarcinoma (AA) is an orphan disease with unique 
clinical attributes but often treated as colorectal cancer (CRC). Understanding 
key molecular differences between AA and CRC is critical.
METHODS: We performed retrospective analyses of AA patients (N = 266) with 
tumour and/or blood next-generation sequencing (NGS) (2013-2018) with in-depth 
clinicopathological annotation. Overall survival (OS) was examined. For 
comparison, CRC cohorts annotated for sidedness, consensus molecular subtypes 
(CMS) and mutations (N = 3283) were used.
RESULTS: Blood-NGS identified less RAS/GNAS mutations compared to tissue-NGS 
(4.2% vs. 60.9%, P < 0.0001) and showed poor concordance with tissue for 
well-/moderately differentiated tumours. RAS (56.2%), GNAS (28.1%) and TP53 
(26.9%) were most frequent mutations. Well/moderately differentiated tumours 
harboured more RAS (69.2%/64.0% vs. 40.5%) and GNAS (48.7%/32.0% vs. 10.1%) 
while moderate/poorly differentiated tumours had more TP53 (26.0%/27.8% vs. 
7.7%) mutations. Appendiceal adenocarcinoma (compared to CRC) harboured 
significantly fewer APC (9.1% vs. 55.4%) and TP53 (26.9% vs. 67.5%) and more 
GNAS mutations (28.1% vs. 2.0%) (P < 0.0001). Appendiceal adenocarcinoma 
mutation profile did not resemble either right-sided CRC or any of the four CMS 
in CRC. High grade, but no mutation, was independently predictive of survival.
CONCLUSION: Integrated clinico-molecular profiling of AA identified key 
molecular drivers distinct from CRC. Appendiceal adenocarcinoma has a 
predominantly grade-driven biology that trumps mutations.

DOI: 10.1038/s41416-020-1015-3
PMCID: PMC7553941
PMID: 32733093 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


141. J Womens Health (Larchmt). 2011 May;20(5):765-9. doi: 10.1089/jwh.2010.2538. 
Epub 2011 Mar 31.

The association between arterial stiffness and colorectal adenomatous polyp in 
women.

Kim HB(1), Lee HR, Shim JY, Na HY, Park BJ, Jung DH, Lee YJ.

Author information:
(1)Department of Family Medicine, Yonsei University College of Medicine, 
Yongin-city, Gyeonggi-do, Korea.

BACKGROUND: Colorectal adenomatous polyp is a precancerous lesion, and some 
studies have documented its link with cardiovascular risk factors. This study 
aimed to investigate the association between arterial stiffness and colorectal 
adenomatous polyp.
METHODS: Among 388 Korean women, we examined the association between 
brachial-ankle pulse wave velocity (baPWV) as a measurement of arterial 
stiffness and the presence of colorectal adenomatous polyp as determined by 
colonoscopy. baPWV values were categorized separately as follows: ≤1199 cm/s, 
1200-1399 cm/s, 1400-1599 cm/s and ≥1600 cm/s. The odds ratios (ORs) and 95% 
confidence intervals (CIs) for colorectal adenomatous polyp were calculated 
across each group of PWVs.
RESULTS: The prevalence of colorectal adenomatous polyp was 9.5%. After 
adjusting for age, body mass index (BMI), cigarette smoking, blood pressure, 
fasting plasma glucose, and triglycerides, the ORs (95% CIs) for colorectal 
adenomatous polyp according to each of the four groups of baPWV were 1.00, 2.89 
(0.52-15.98), 3.27 (0.48-22.24), and 11.17 (1.17-106.99).
CONCLUSIONS: A higher level of baPWV was found to be independently associated 
with the presence of colorectal adenomatous polyp, regardless of classic 
cardiovascular risk factors and other components of metabolic syndrome in women.

DOI: 10.1089/jwh.2010.2538
PMID: 21453035 [Indexed for MEDLINE]


142. Oncoimmunology. 2015 Apr 2;4(3):e976052. doi: 10.4161/2162402X.2014.976052. 
eCollection 2015 Mar.

An immunogenomic stratification of colorectal cancer: Implications for 
development of targeted immunotherapy.

Lal N(1), Beggs AD(1), Willcox BE(1), Middleton GW(1).

Author information:
(1)Cancer Immunology and Immunotherapy Centre; School of Cancer Sciences; 
University of Birmingham ; Birmingham, UK.

Although tumor infiltrating lymphocyte (TIL) density is prognostic and 
predictive in colorectal cancer (CRC), the impact of tumor genetics upon 
colorectal immunobiology is unclear. Identification of genetic factors that 
influence the tumor immunophenotype is essential to improve the effectiveness of 
stratified immunotherapy approaches. We carried out a bioinformatics analysis of 
CRC data in The Cancer Genome Atlas (TCGA) involving two-dimensional 
hierarchical clustering to define an immune signature that we used to 
characterize the immune response across key patient groups. An immune signature 
termed The Co-ordinate Immune Response Cluster (CIRC) comprising 28 genes was 
coordinately regulated across the patient population. Four patient groups were 
delineated on the basis of cluster expression. Group A, which was heavily 
enriched for patients with microsatellite instability (MSI-H) and POL mutations, 
exhibited high CIRC expression, including the presence of several inhibitory 
molecules: CTLA4, PDL1, PDL2, LAG3, and TIM3. In contrast, RAS mutation was 
enriched in patient groups with lower CIRC expression. This work links the 
genetics and immunobiology of colorectal tumorigenesis, with implications for 
the development of stratified immunotherapeutic approaches. Microsatellite 
instability and POL mutations are linked with high mutational burden and high 
immune infiltration, but the coordinate expression of inhibitory pathways 
observed suggests combination checkpoint blockade therapy may be required to 
improve efficacy. In contrast, RAS mutant tumors predict for a relatively poor 
immune infiltration and low inhibitory molecule expression. In this setting, 
checkpoint blockade may be less efficacious, highlighting a requirement for 
novel strategies in this patient group.

DOI: 10.4161/2162402X.2014.976052
PMCID: PMC4404815
PMID: 25949894


143. Int J Cancer. 2019 Jun 1;144(11):2843-2853. doi: 10.1002/ijc.31998. Epub 2019 
Jan 12.

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal 
cancer cell-intrinsic properties.

Eide PW(1)(2)(3), Eilertsen IA(1)(2)(3), Sveen A(1)(2)(3), Lothe RA(1)(2)(3).

Author information:
(1)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, Oslo, Norway.
(2)K.G.Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, 
Norway.
(3)Institute for Clinical Medicine, University of Oslo, Oslo, Norway.

Elevated miR-31 expression is associated with poor outcome in colorectal cancer 
(CRC). Whether the prognostic information is independent of known molecular 
subgroups and gene expression-based consensus molecular subtypes (CMS) is 
currently unknown. To investigate this, we analyzed nearly 2000 CRC biopsies and 
preclinical models. The expression of miR-31-5p and its host transcript, long 
noncoding RNA MIR31HG, was strongly correlated (Spearman's ρ > 0.80). MIR31HG 
outlier expression was observed in 158/1265 (12%) of pCRCs and was associated 
with depletion of CMS2-canonical subgroup (odds ratio = 0.21 [0.11-0.35]) and 
shorter relapse-free survival (RFS) in multivariable analysis (adjusted hazard 
ratio = 2.2 [1.6-3.0]). For stage II disease, 5-year RFS for patients with 
MIR31HG outlier status was 49% compared to 77% for those with normal-like 
expression. MIR31HG outlier status was associated with inferior outcome also 
within clinical high risk groups and within the poor prognostic CMS4-mesenchymal 
gene expression subtype specifically. Preclinical models with MIR31HG outlier 
expression were characterized by reduced expression of MYC targets as well as 
elevated epithelial-mesenchymal transition, TNF-α/NFκB, TGF-β, and IFN-α/γ gene 
expression signatures, indicating cancer cell-intrinsic properties resembling 
the CMS4 subgroup-associations which were recapitulated in patient biopsies. 
Moreover, the prognostic value of MIR31HG outlier status was independent of 
cytotoxic T lymphocyte and fibroblast infiltration. We here present evidence 
that MIR31HG expression provides clinical stratification beyond major gene 
expression phenotypes and tumor immune and stromal cell infiltration and propose 
a model where increased expression is an indicator of a cellular state 
conferring intrinsic invasive and/or immuno-evasive capabilities.

© 2018 The Authors. International Journal of Cancer published by John Wiley & 
Sons Ltd on behalf of UICC.

DOI: 10.1002/ijc.31998
PMCID: PMC6590447
PMID: 30447009 [Indexed for MEDLINE]


144. Mod Pathol. 2020 Dec;33(12):2626-2636. doi: 10.1038/s41379-020-0598-9. Epub 2020 
Jun 24.

Associations of non-pedunculated T1 colorectal adenocarcinoma outcome with 
consensus molecular subtypes, immunoscore, and microsatellite status: a 
multicenter case-cohort study.

Haasnoot KJC(#)(1), Backes Y(#)(1), Moons LMG(1), Kranenburg O(2), Trinh A(3), 
Vermeulen L(4)(5), Noë M(6), Tuynman JB(7), van Lent AUG(8), van Ginneken R(1), 
Seldenrijk CA(9), Raicu MG(9), Trumpi K(2), Ubink I(2), Milne AN(9), Boonstra 
JJ(10), Groen JN(11), Schwartz MP(12), Wolfhagen FHJ(13), Geesing JMJ(14), Ter 
Borg F(15), Brosens LAA(16), van Bergeijk J(17), Spanier BWM(18), de Vos Tot 
Nederveen Cappel WH(19), Kessels K(20), Seerden TCJ(21), Vleggaar FP(1), 
Offerhaus GJA(16), Siersema PD(22), Elias SG(23), Laclé MM(24); Dutch T1 CRC 
Working Group.

Author information:
(1)Department of Gastroenterology & Hepatology, University Medical Center 
Utrecht, Utrecht, the Netherlands.
(2)Department of Surgical Oncology, UMC Utrecht Cancer Center, University 
Medical Center Utrecht, Utrecht, the Netherlands.
(3)Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 
Boston, MA, USA.
(4)Laboratory for Experimental Oncology and Radiobiology, Center for 
Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam 
Gastroenterology and Metabolism, Amsterdam University Medical Centers, 
Amsterdam, the Netherlands.
(5)Oncode Institute, Amsterdam, the Netherlands.
(6)Department of Pathology, The Johns Hopkins University School of Medicine, 
Baltimore, MD, USA.
(7)Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical 
Centers, Amsterdam, the Netherlands.
(8)Department of Gastroenterology & Hepatology, Onze Lieve Vrouwe Gasthuis, 
Amsterdam, the Netherlands.
(9)Pathology DNA, Sint Antonius Hospital, Nieuwegein, the Netherlands.
(10)Department of Gastroenterology & Hepatology, Leiden University Medical 
Center, Leiden, the Netherlands.
(11)Department of Gastroenterology & Hepatology, Sint Jansdal, Harderwijk, the 
Netherlands.
(12)Department of Gastroenterology & Hepatology, Meander Medical Center, 
Amersfoort, the Netherlands.
(13)Department of Gastroenterology & Hepatology, Albert Schweitzer Hospital, 
Dordrecht, the Netherlands.
(14)Department of Gastroenterology & Hepatology, Diakonessenhuis, Utrecht, the 
Netherlands.
(15)Department of Gastroenterology & Hepatology, Deventer Hospital, Deventer, 
the Netherlands.
(16)Department of Pathology, University Medical Center Utrecht, Utrecht, the 
Netherlands.
(17)Department of Gastroenterology & Hepatology, Gelderse Vallei, Ede, the 
Netherlands.
(18)Department of Gastroenterology & Hepatology, Rijnstate Hospital, Arnhem, the 
Netherlands.
(19)Department of Gastroenterology & Hepatology, Isala Clinics, Zwolle, the 
Netherlands.
(20)Department of Gastroenterology & Hepatology, Sint Antonius Hospital, 
Nieuwegein, the Netherlands.
(21)Department of Gastroenterology & Hepatology, Amphia Hospital, Breda, the 
Netherlands.
(22)Department of Gastroenterology & Hepatology, Radboud University Medical 
Center, Nijmegen, the Netherlands.
(23)Julius Center for Health Sciences and Primary Care, University Medical 
Center Utrecht, Utrecht, the Netherlands.
(24)Department of Pathology, University Medical Center Utrecht, Utrecht, the 
Netherlands. M.M.Lacle@umcutrecht.nl.
(#)Contributed equally

Advanced colorectal cancer (CRC) consensus molecular subtype 4 (CMS4) or CRC 
with a low immunoscore is associated with shorter survival times. Non-metastatic 
CRC with microsatellite instability (MSI) is associated with a lower risk of 
recurrence. We evaluated outcome (lymph node metastases [LNM] or cancer 
recurrence) in these tumor subtypes in patients with surgically-removed 
non-pedunculated T1 CRC by performing a multicenter case-cohort study. We 
included all patients in 13 hospitals in the Netherlands from 2000-2014 
(n = 651). We randomly selected a subgroup of patients (n = 223) and all 
patients with LNM or recurrence (n = 63), and median follow-up of 44 months. We 
centrally reviewed tumor-slides, and constructed and immunostained tissue 
microarrays determining MSI, CMS (MSI/CMS1, CMS2/3, or CMS4), and immunoscore 
(I-low/I-high). We used weighted Cox proportional hazard models to evaluate the 
association of MSI, CMS, and immunoscore with LNM or recurrence, adjusting for 
conventional histologic risk factors. In the randomly selected subgroup of 
patients, 7.1% of tumors were MSI/CMS1, 91.0% CMS2/3, 1.8% CMS4, and 25% I-low. 
In the case-cohort, patients with CMS4 tumors had an increased risk for LNM or 
recurrence compared with patients with tumors of other CMSs (adjusted hazard 
ratio [HR], 3.97; 95% CI, 1.12-14.06; P = 0.03). Albeit not significant, tumors 
with MSI had a lower risk for LNM or recurrence than other tumor subtypes 
(adjusted HR, 0.52; 95% CI, 0.12-2.30; P = 0.39), whereas tumors with a low 
immunoscore had an increased risk for LNM or recurrence (adjusted HR, 1.30; 95% 
CI, 0.68-2.48; P = 0.43). In conclusion, in a case-cohort study of patients with 
non-pedunculated T1 CRC, MSI, and immunoscore were not significantly associated 
with adverse outcome after surgery. CMS4 substantially increased the risk of 
adverse outcome. However, CMS4 is rare in T1 CRCs, limiting its value for 
determining the risk in patients.

DOI: 10.1038/s41379-020-0598-9
PMID: 32581367 [Indexed for MEDLINE]


145. Br J Cancer. 2017 Jan 3;116(1):58-65. doi: 10.1038/bjc.2016.382. Epub 2016 Nov 
24.

Expression profiling of budding cells in colorectal cancer reveals an EMT-like 
phenotype and molecular subtype switching.

De Smedt L(1), Palmans S(1), Andel D(1), Govaere O(1), Boeckx B(2)(3), Smeets 
D(2)(3), Galle E(2)(3), Wouters J(1), Barras D(4), Suffiotti M(4), Dekervel 
J(5), Tousseyn T(1)(6), De Hertogh G(1)(6), Prenen H(7), Tejpar S(7), Lambrechts 
D(2)(3), Sagaert X(1)(6).

Author information:
(1)Translational Cell and Tissue Research Unit, Department of Imaging and 
Pathology, KU Leuven, Leuven, Belgium.
(2)Vesalius Research Center, Vlaams instituut voor Biotechnologie (VIB), Leuven, 
Belgium.
(3)Laboratory for Translational Genetics, Department of Oncology, KU Leuven, 
Leuven, Belgium.
(4)Bioinformatics Core Facility, Swiss Institute for Bioinformatics, Lausanne, 
Switzerland.
(5)Laboratory of Hepatology, Department of Clinical and Experimental Medicine, 
University Hospitals Leuven, Leuven, Belgium.
(6)Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
(7)Digestive Oncology Unit, Department of Oncology, University Hospitals Leuven, 
Leuven, Belgium.

BACKGROUND: Tumour budding, described as the presence of single cells or small 
clusters of up to five tumour cells at the invasive margin, is established as a 
prognostic marker in colorectal carcinoma. In the present study, we aimed to 
investigate the molecular signature of tumour budding cells and the 
corresponding tumour bulk.
METHODS: Tumour bulk and budding areas were microdissected and processed for 
RNA-sequencing. As little RNA was obtained from budding cells, a special 
low-input mRNA library preparation protocol was used. Gene expression profiles 
of budding as compared with tumour bulk were investigated for established EMT 
signatures, consensus molecular subtype (CMS), gene set enrichment and pathway 
analysis.
RESULTS: A total of 296 genes were differentially expressed with an FDR <0.05 
and a twofold change between tumour bulk and budding regions. Genes that were 
upregulated in the budding signature were mainly involved in cell migration and 
survival while downregulated genes were important for cell proliferation. 
Supervised clustering according to an established EMT gene signature categorised 
budding regions as EMT-positive, whereas tumour bulk was considered 
EMT-negative. Furthermore, a shift from CMS2 (epithelial) to CMS4 (mesenchymal) 
was observed as tumour cells transit from the tumour bulk to the budding 
regions.
CONCLUSIONS: Tumour budding regions are characterised by a phenotype switch 
compared with the tumour bulk, involving the acquisition of migratory 
characteristics and a decrease in cell proliferation. In particular, most tumour 
budding signatures were EMT-positive and switched from an epithelial subtype 
(CMS2) in the tumour bulk to a mesenchymal subtype (CMS4) in budding cells.

DOI: 10.1038/bjc.2016.382
PMCID: PMC5220148
PMID: 27884016 [Indexed for MEDLINE]


146. Sci Rep. 2017 Sep 14;7(1):11590. doi: 10.1038/s41598-017-11237-6.

Distinct gut microbiome patterns associate with consensus molecular subtypes of 
colorectal cancer.

Purcell RV(1), Visnovska M(2), Biggs PJ(3), Schmeier S(2), Frizelle FA(4).

Author information:
(1)Department of Surgery, University of Otago, Christchurch, New Zealand. 
Rachel.purcell@otago.ac.nz.
(2)Institute of Natural and Mathematical Sciences, Massey University, Auckland, 
New Zealand.
(3)Hopkirk Institute, Institute of Veterinary, Animal and Biomedical Sciences, 
Massey University, Palmerston North, New Zealand.
(4)Department of Surgery, University of Otago, Christchurch, New Zealand.

Colorectal cancer (CRC) is a heterogeneous disease and recent advances in 
subtype classification have successfully stratified the disease using molecular 
profiling. The contribution of bacterial species to CRC development is 
increasingly acknowledged, and here, we sought to analyse CRC microbiomes and 
relate them to tumour consensus molecular subtypes (CMS), in order to better 
understand the relationship between bacterial species and the molecular 
mechanisms associated with CRC subtypes. We classified 34 tumours into CRC 
subtypes using RNA-sequencing derived gene expression and determined relative 
abundances of bacterial taxonomic groups using 16S rRNA amplicon metabarcoding. 
16S rRNA analysis showed enrichment of Fusobacteria and Bacteroidetes, and 
decreased levels of Firmicutes and Proteobacteria in CMS1. A more detailed 
analysis of bacterial taxa using non-human RNA-sequencing reads uncovered 
distinct bacterial communities associated with each molecular subtype. The most 
highly enriched species associated with CMS1 included Fusobacterium hwasookii 
and Porphyromonas gingivalis. CMS2 was enriched for Selenomas and Prevotella 
species, while CMS3 had few significant associations. Targeted quantitative PCR 
validated these findings and also showed an enrichment of Fusobacterium 
nucleatum, Parvimonas micra and Peptostreptococcus stomatis in CMS1. In this 
study, we have successfully associated individual bacterial species to CRC 
subtypes for the first time.

DOI: 10.1038/s41598-017-11237-6
PMCID: PMC5599497
PMID: 28912574 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that they have no competing 
interests.


147. Front Oncol. 2021 Dec 7;11:730854. doi: 10.3389/fonc.2021.730854. eCollection 
2021.

Comprehensive Imaging Characterization of Colorectal Liver Metastases.

Maclean D(1)(2), Tsakok M(3), Gleeson F(4), Breen DJ(1), Goldin R(5), Primrose 
J(6)(7), Harris A(4), Franklin J(2).

Author information:
(1)Department of Radiology, University Hospital Southampton, Southampton, United 
Kingdom.
(2)Department of Medical Imaging, Bournemouth University, Bournemouth, United 
Kingdom.
(3)Department of Radiology, Oxford University Hospitals, Oxford, United Kingdom.
(4)Department of Oncology, Oxford University, Oxford, United Kingdom.
(5)Department of Metabolism, Digestion and Reproduction, Imperial College 
London, London, United Kingdom.
(6)Department of Surgery, University Hospital Southampton, Southampton, United 
Kingdom.
(7)Academic Unit of Cancer Sciences, University of Southampton, Southampton, 
United Kingdom.

Colorectal liver metastases (CRLM) have heterogenous histopathological and 
immunohistochemical phenotypes, which are associated with variable responses to 
treatment and outcomes. However, this information is usually only available 
after resection, and therefore of limited value in treatment planning. Improved 
techniques for in vivo disease assessment, which can characterise the variable 
tumour biology, would support further personalization of management strategies. 
Advanced imaging of CRLM including multiparametric MRI and functional imaging 
techniques have the potential to provide clinically-actionable phenotypic 
characterisation. This includes assessment of the tumour-liver interface, 
internal tumour components and treatment response. Advanced analysis techniques, 
including radiomics and machine learning now have a growing role in assessment 
of imaging, providing high-dimensional imaging feature extraction which can be 
linked to clinical relevant tumour phenotypes, such as a the Consensus Molecular 
Subtypes (CMS). In this review, we outline how imaging techniques could 
reproducibly characterize the histopathological features of CRLM, with several 
matched imaging and histology examples to illustrate these features, and discuss 
the oncological relevance of these features. Finally, we discuss the future 
challenges and opportunities of CRLM imaging, with a focus on the potential 
value of advanced analytics including radiomics and artificial intelligence, to 
help inform future research in this rapidly moving field.

Copyright © 2021 Maclean, Tsakok, Gleeson, Breen, Goldin, Primrose, Harris and 
Franklin.

DOI: 10.3389/fonc.2021.730854
PMCID: PMC8688250
PMID: 34950575

Conflict of interest statement: The authors declare that the research was 
conducted in the absence of any commercial or financial relationships that could 
be construed as a potential conflict of interest.


148. ESMO Open. 2020 Sep;5(5):e000847. doi: 10.1136/esmoopen-2020-000847.

Detection of postoperative plasma circulating tumour DNA and lack of CDX2 
expression as markers of recurrence in patients with localised colon cancer.

Tarazona N(1), Gimeno-Valiente F(2), Gambardella V(1), Huerta M(2), Roselló 
S(1), Zuniga S(3), Calon A(4), Carbonell-Asins JA(5), Fontana E(6), 
Martinez-Ciarpaglini C(7), Eason K(6), Rentero-Garrido P(3), Fleitas T(1), 
Papaccio F(2), Moro-Valdezate D(8), Nyamundanda G(6), Castillo J(1), Espí A(8), 
Sadanandam A(6), Roda D(1), Cervantes A(9).

Author information:
(1)Department of Medical Oncology, Biomedical Research Institute INCLIVA, 
CIBERONC, University of Valencia, Valencia, Spain.
(2)Department of Medical Oncology, Biomedical Research Institute INCLIVA, 
University of Valencia, Valencia, Spain.
(3)Precision Medicine, INCLIVA Heatl, Valencia, Spain.
(4)Cancer Research Programme, Hospital del Mar Research Institute (IMIM), 
Barcelona, Catalunya, Spain.
(5)Bioinformatics and Biostatistics Unit, INCLIVA Biomedical Research Institute, 
Valencia, Spain.
(6)Division of Molecular Pathology, Institute of cancer Research, London, UK.
(7)Department of Pathology, Biomedical Research Institute INCLIVA, CIBERONC, 
University of Valencia, Valencia, Spain.
(8)Department of Surgery, Biomedical Research Institute INCLIVA, University of 
Valencia, Valencia, Spain.
(9)Department of Medical Oncology, Biomedical Research Institute INCLIVA, 
CIBERONC, University of Valencia, Valencia, Spain. Electronic address: 
andres.cervantes@uv.es.

BACKGROUND: Colon cancer (CC) is a heterogeneous disease. Novel prognostic 
factors beyond pathological staging are required to accurately identify patients 
at higher risk of relapse. Integrating these new biological factors, such as 
plasma circulating tumour DNA (ctDNA), CDX2 staining, inflammation-associated 
cytokines and transcriptomic consensus molecular subtypes (CMS) classification, 
into a multimodal approach may improve our accuracy in determining risk of 
recurrence.
METHODS: One hundred and fifty patients consecutively diagnosed with localised 
CC were prospectively enrolled in our study. ctDNA was tracked to detect minimal 
residual disease by droplet digital PCR. CDX2 expression was analysed by 
immunostaining. Plasma levels of cytokines potentially involved in disease 
progression were measured using ELISAs. A 96 custom gene panel for nCounter 
assay was used to classify CC into colorectal cancer assigner and CMS.
RESULTS: Most patients were classified into CMS4 (37%) and CMS2 (28%), followed 
by CMS1 (20%) and CMS3 (15%) groups. CDX2-negative tumours were enriched in CMS1 
and CMS4 subtypes. In univariable analysis, prognosis was influenced by primary 
tumour location, stage, vascular and perineural invasion together with high 
interleukin-6 plasma levels at baseline, tumours belonging to CMS 1 vs CMS2 
+CMS3, ctDNA presence in plasma and CDX2 loss. However, only positive ctDNA in 
plasma samples (HR 13.64; p=0.002) and lack of CDX2 expression (HR 23.12; 
p=0.001) were found to be independent prognostic factors for disease-free 
survival in the multivariable model.
CONCLUSIONS: ctDNA detection after surgery and lack of CDX2 expression 
identified patients at very high risk of recurrence in localised CC.

© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No 
commercial re-use. Published by BMJ on behalf of the European Society for 
Medical Oncology.

DOI: 10.1136/esmoopen-2020-000847
PMCID: PMC7513635
PMID: 32967918 [Indexed for MEDLINE]

Conflict of interest statement: Competing interests: AC declares the following 
disclosures: Consultant or Advisory Role: Merck Serono, Roche, Beigene, Bayer, 
Servier, Lilly, Novartis, Takeda, Astelas.Research Funding: Genentech, Merck 
Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Pierre 
Fabre, Fibrogen, Amcure, Sierra Oncology, Astra Zeneca, Medimmune, BMS, 
MSD.Speaking: Merck Serono, Roche, Angem, Bayer, Servier, Foundation Medicine. 
Grant support: Merck Serono, Roche.Others: Executive Board member of ESMO, Chair 
of Education ESMO, ESMO Education Director, INCLIVA General and Scientific 
Director, Associate Editor: Annals of Oncology and ESMO Open, Editor in chief: 
Cancer Treatment Reviews. AC declares institutional research funding from 
Genentech, Merck Serono, BMS, MSD, Roche, Beigene, Bayer, Servier, Lilly, 
Novartis, Takeda, Astellas and Fibrogen and advisory board or speaker fees from 
Merck Serono, Roche, Servier, Takeda and Astellas in the last five years. All 
remaining authors have declared no conflict of interest. AS has ownership 
interest as an inventor for a patent entitled ‘Colorectal cancer classification 
with differential prognosis and personalised therapeutic responses’ (patent 
number PCT/IB2013/060416). AS-Research Funding-Bristol-Myers Squibb, Merck KGaA 
and Pierre Fabre.


149. Cancers (Basel). 2019 Oct 11;11(10):1540. doi: 10.3390/cancers11101540.

Tumor Expression of Cyclin-Dependent Kinase 5 (Cdk5) Is a Prognostic Biomarker 
and Predicts Outcome of Oxaliplatin-Treated Metastatic Colorectal Cancer 
Patients.

Ruiz de Porras V(1)(2), Bystrup S(3)(4), Cabrero-de Las Heras S(5)(6), Musulén 
E(7)(8), Palomero L(9)(10), Alonso MH(11)(12)(13)(14), Nieto R(15), Arango 
D(16), Moreno V(17)(18)(19)(20), Queralt C(21)(22), Manzano JL(23)(24)(25), 
Layos L(26)(27)(28), Bugés C(29)(30)(31), Martinez-Balibrea E(32)(33).

Author information:
(1)Program of predictive and personalized cancer medicine (PMPPC) Germans Trias 
i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 
Badalona, Spain. vruiz@igtp.cat.
(2)Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of 
Oncology, Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain. 
vruiz@igtp.cat.
(3)Program of predictive and personalized cancer medicine (PMPPC) Germans Trias 
i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 
Badalona, Spain. sbystrup@igtp.cat.
(4)Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of 
Oncology, Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain. 
sbystrup@igtp.cat.
(5)Program of predictive and personalized cancer medicine (PMPPC) Germans Trias 
i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 
Badalona, Spain. scabrero@igtp.cat.
(6)Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of 
Oncology, Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain. 
scabrero@igtp.cat.
(7)Department of Pathology, Hospital Universitari Germans Trias i Pujol, Ctra. 
Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain. emusulen@hotmail.com.
(8)Department of Pathology, Hospital Universitari General de Catalunya, Grupo 
Quirónsalud, Pedro i Pons 1, 08195 Sant Cugat del Valles, Spain. 
emusulen@hotmail.com.
(9)Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of 
Oncology, 08908 L'Hospitalet del Llobregat, Barcelona, Spain. 
lpalomero@iconcologia.net.
(10)ONCOBELL Program, Bellvitge Institute for Biomedical Research, 08908 
L'Hospitalet del Llobregat, Barcelona, Spain. lpalomero@iconcologia.net.
(11)ONCOBELL Program, Bellvitge Institute for Biomedical Research, 08908 
L'Hospitalet del Llobregat, Barcelona, Spain. mhalonso@iconcologia.net.
(12)Oncology Data Analytics Program, Institut Català d'Oncologia (ICO), 08908 
Barcelona, Spain. mhalonso@iconcologia.net.
(13)Consortium for Biomedical Research in Epidemiology and Public Health 
(CIBERESP), 28029 Madrid, Spain. mhalonso@iconcologia.net.
(14)Department of Clinical Sciences, Faculty of Medicine and Health Sciences, 
University of Barcelona, 08907 Barcelona, Spain. mhalonso@iconcologia.net.
(15)Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, 
Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat 
Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain. 
rocio.nieto@vhir.org.
(16)Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, 
Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat 
Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain. 
diego.arango@vhir.org.
(17)ONCOBELL Program, Bellvitge Institute for Biomedical Research, 08908 
L'Hospitalet del Llobregat, Barcelona, Spain. v.moreno@iconcologia.net.
(18)Oncology Data Analytics Program, Institut Català d'Oncologia (ICO), 08908 
Barcelona, Spain. v.moreno@iconcologia.net.
(19)Consortium for Biomedical Research in Epidemiology and Public Health 
(CIBERESP), 28029 Madrid, Spain. v.moreno@iconcologia.net.
(20)Department of Clinical Sciences, Faculty of Medicine and Health Sciences, 
University of Barcelona, 08907 Barcelona, Spain. v.moreno@iconcologia.net.
(21)Program of predictive and personalized cancer medicine (PMPPC) Germans Trias 
i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 
Badalona, Spain. cqueralt@iconcologia.net.
(22)Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute 
of Oncology, Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain. 
cqueralt@iconcologia.net.
(23)Program of predictive and personalized cancer medicine (PMPPC) Germans Trias 
i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 
Badalona, Spain. jmanzano@iconcologia.net.
(24)Medical Oncology Service, Catalan Institute of Oncology (ICO), 08908, Spain. 
jmanzano@iconcologia.net.
(25)B-ARGO group, Germans Trias I Pujol Research Institute (IGTP), Ctra. Can 
Ruti- Camí de les escoles s/n, 08916 Badalona, Spain. jmanzano@iconcologia.net.
(26)Program of predictive and personalized cancer medicine (PMPPC) Germans Trias 
i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 
Badalona, Spain. llayos@iconcologia.net.
(27)Medical Oncology Service, Catalan Institute of Oncology (ICO), 08908, Spain. 
llayos@iconcologia.net.
(28)B-ARGO group, Germans Trias I Pujol Research Institute (IGTP), Ctra. Can 
Ruti- Camí de les escoles s/n, 08916 Badalona, Spain. llayos@iconcologia.net.
(29)Program of predictive and personalized cancer medicine (PMPPC) Germans Trias 
i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 
Badalona, Spain. cbuges@iconcologia.net.
(30)Medical Oncology Service, Catalan Institute of Oncology (ICO), 08908, Spain. 
cbuges@iconcologia.net.
(31)B-ARGO group, Germans Trias I Pujol Research Institute (IGTP), Ctra. Can 
Ruti- Camí de les escoles s/n, 08916 Badalona, Spain. cbuges@iconcologia.net.
(32)Program of predictive and personalized cancer medicine (PMPPC) Germans Trias 
i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 
Badalona, Spain. embalibrea@iconcologia.net.
(33)Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute 
of Oncology, Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain. 
embalibrea@iconcologia.net.

In recent years, an increasing number of studies have shown that elevated 
expression of cyclin dependent kinase (Cdk5) contributes to the oncogenic 
initiation and progression of many types of cancers. In this study, we 
investigated the expression pattern of Cdk5 in colorectal cancer (CRC) cell 
lines and in a large number of tumor samples in order to evaluate its relevance 
in this pathogenesis and possible use as a prognostic marker. We found that Cdk5 
is highly expressed and activated in CRC cell lines and that silencing of the 
kinase decreases their migration ability. In tumor tissues, Cdk5 is 
overexpressed compared to normal tissues due to a copy number gain. In patients 
with localized disease, we found that high Cdk5 levels correlate with poor 
prognosis, while in the metastatic setting, this was only the case for patients 
receiving an oxaliplatin-based treatment. When exploring the Cdk5 levels in the 
consensus molecular subtypes (CMS), we found the lowest levels in subtype 1, 
where high Cdk5 again was associated with a poorer prognosis. In conclusion, we 
confirm that Cdk5 is involved in CRC and disease progression and that it could 
serve as a prognostic and predictive biomarker in this disease.

DOI: 10.3390/cancers11101540
PMCID: PMC6826373
PMID: 31614664

Conflict of interest statement: All authors have read the journal's policy on 
disclosure of potential conflicts of interest. All authors disclose not to have 
neither financial nor personal relationship with organizations that could 
potentially be perceived as influencing the described research.


150. Cancers (Basel). 2022 Mar 2;14(5):1297. doi: 10.3390/cancers14051297.

Prognosis and Sensitivity of Adjuvant Chemotherapy in Mucinous Colorectal 
Adenocarcinoma without Distant Metastasis.

Bong JW(1), Gim JA(2), Ju Y(1), Cheong C(1), Lee SI(1), Oh SC(3), Min BW(1), 
Kang S(1).

Author information:
(1)Department of Surgery, Korea University Guro Hospital, Korea University 
College of Medicine, Seoul 08308, Korea.
(2)Medical Science Research Center, College of Medicine, Korea University Guro 
Hospital, Seoul 08308, Korea.
(3)Department of Oncology, Korea University Guro Hospital, Korea University 
College of Medicine, Seoul 08308, Korea.

In colorectal cancer, whereas mucinous adenocarcinoma (MAC) has several poor 
clinical prognostic factors compared to adenocarcinoma (AC), the prognosis of 
MAC remains controversial. We evaluated the prognosis of MAC without distant 
metastasis and the effects of adjuvant chemotherapy using health insurance 
registry data managed by South Korea. Patients with colorectal cancer between 
January 2014 and December 2016 were included (AC, 22,050 [96.8%]; MAC, 729 
[3.2%]). We observed no difference in overall survival (OS) between AC and MAC 
in stages I and II. However, MAC showed a worse OS than AC in stage III disease, 
especially in patients administered chemotherapy (p &lt; 0.001). These findings 
persisted after propensity score matching of clinical characteristics between AC 
and MAC. In addition, transcriptome analysis of The Cancer Genome Atlas (TCGA) 
data showed increased chemoresistance-associated pathways in MAC compared to AC. 
In consensus molecular subtypes (CMS) classification, unlike in AC, CMSs 1, 3, 
and 4 comprised most of MAC and the proportions of CMSs 3 and 4 increased with 
stage progression. These results suggest clues to overcome resistance to 
chemotherapy and develop targeted treatments in MAC.

DOI: 10.3390/cancers14051297
PMCID: PMC8909839
PMID: 35267605

Conflict of interest statement: The authors declare no conflict of interest.


151. Adv Exp Med Biol. 2018;1110:23-34. doi: 10.1007/978-3-030-02771-1_3.

Targeting KRAS Mutant CMS3 Subtype by Metabolic Inhibitors.

Aguilera O(1), Serna-Blasco R(2).

Author information:
(1)Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz 
University Hospital, Madrid, Spain. oscar.aguilera@FJD.es.
(2)Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz 
University Hospital, Madrid, Spain.

Cancer cells rewire their metabolism in order to boost growth, survival, 
proliferation, and chemoresistance. The common event of this aberrant metabolism 
is the increased glucose uptake and fermentation of glucose to lactate. This 
phenomenon is observed even in the presence of O2 and completely functioning 
mitochondria. This is known as the "Warburg Effect" and it is a hallmark in 
cancer. Up to 40% of all CRC's are known to have a mutated (abnormal) KRAS gene, 
found at differing frequencies in all consensus molecular subtypes (CMS). CMS3 
colon cancer molecular subtype contains the so-called 'metabolic tumours' which 
represents 13% of total CR cases. These tumours display remarkable metabolic 
deregulation, often showing KRAS mutations (68%). Unfortunately, patients 
harbouring mutated KRAS are unlikely to benefit from anti-EGFR therapies. 
Moreover, it remains unclear that patients with KRAS wild-type CRC will 
definitely respond to such therapies. Although some clinically 
designed-strategies to modulate KRAS aberrant activation have been designed, all 
attempts to target KRAS have failed in the clinical assays and KRAS has been 
assumed to be invulnerable to chemotherapeutic attack. Quest for metabolic 
inhibitors with anti-tumour activity may constitute a novel and hopeful approach 
in order to handle KRAS dependent chemoresistance in colon cancer.

DOI: 10.1007/978-3-030-02771-1_3
PMID: 30623364 [Indexed for MEDLINE]


152. Future Sci OA. 2021 May 28;7(7):FSO722. doi: 10.2144/fsoa-2021-0021. eCollection 
2021 Aug.

Consensus molecular subtypes of primary colon tumors and their hepatic 
metastases.

Lau YC(1), Schmeier S(2), Frizelle F(1), Purcell R(1).

Author information:
(1)Department of Surgery, University of Otago Christchurch, Christchurch, New 
Zealand.
(2)School of Natural & Computational Sciences, Massey University, Auckland, New 
Zealand.

AIM: This pilot study aimed to evaluate the congruency in consensus molecular 
subtypes (CMS) of primary colorectal cancer and corresponding hepatic metastasis 
(HM).
MATERIALS & METHODS: RNA was extracted from both primary colorectal cancer and 
HM from ten patients, sequenced to establish gene-expression profiles and 
classified into CMS. Clinical data were collected retrospectively.
RESULTS: Of the ten patients recruited, nine had primary tumors that were 
classifiable: seven were CMS2, one was CMS3 and one was CMS4. Five had 
incongruent classification in the corresponding HM. Three out of the five 
patients with incongruent classification had received adjuvant chemotherapy 
prior to hepatic resection.
CONCLUSION: A change in CMS type between matched primary and metastatic 
colorectal tumors is common and may be attributable to chemotherapy.

© 2021 The Authors.

DOI: 10.2144/fsoa-2021-0021
PMCID: PMC8256330
PMID: 34258029

Conflict of interest statement: Financial & competing interests disclosure YC 
Lau: Richard Stewart Scholarship from the University of Otago; R Purcell: 
Maurice and Phyllis Paykel Trust; Gut Cancer Foundation (NZ), with support from 
the Hugh Green Foundation; Colorectal Surgical Society of Australia and New 
Zealand (CSSANZ); The Health Research Council of New Zealand. The funding bodies 
had no role in the design of the study or collection, analysis and 
interpretation of data or in writing the manuscript. The authors have no other 
relevant affiliations or financial involvement with any organization or entity 
with a financial interest in or financial conflict with the subject matter or 
materials discussed in the manuscript apart from those disclosed. No writing 
assistance was utilized in the production of this manuscript.


153. Cancers (Basel). 2021 Nov 24;13(23):5909. doi: 10.3390/cancers13235909.

A Novel Prognostic Biomarker Panel for Early-Stage Colon Carcinoma.

Azcue P(1), Guerrero Setas D(2)(3)(4)(5), Encío I(1)(6), Ibáñez-Beroiz 
B(1)(6)(7)(8), Mercado M(2), Vera R(5)(6), Gómez-Dorronsoro ML(2)(6).

Author information:
(1)Department of Health Science, Public University of Navarra, 31008 Pamplona, 
Spain.
(2)Department of Pathology, University Hospital of Navarra, 31008 Pamplona, 
Spain.
(3)Campus Arrosadia, Public University of Navarra, 31006 Pamplona, Spain.
(4)Molecular Pathology of Cancer Group-Navarrabiomed, 31008 Pamplona, Spain.
(5)Department of Medical Oncology, University Hospital of Navarra, 31008 
Pamplona, Spain.
(6)Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain.
(7)Unit of Methodology-Navarrabiomed-University Hospital of Navarra, 31008 
Pamplona, Spain.
(8)Research Network on Health Services Research and Chronic Diseases (REDISSEC), 
31008 Pamplona, Spain.

Molecular characterization of colorectal cancer has helped us understand better 
the biology of the disease. However, previous efforts have yet to provide 
significant clinical value in order to be integrated into clinical practice for 
patients with early-stage colon cancer (CC). The purpose of this study was to 
assess PD-L1, GLUT-1, e-cadherin, MUC2, CDX2, and microsatellite instability 
(dMMR) and to propose a risk-panel with prognostic capabilities. Biomarkers were 
immunohistochemically assessed through tissue microarrays in a cohort of 144 
patients with stage II/III colon cancer. A biomarker panel consisting of PD-L1, 
GLUT-1, dMMR, and potentially CDX2 was constructed that divided patients into 
low, medium, and high risk of overall survival or disease-free survival (DFS) in 
equally sized groups. Compared with low-risk patients, medium-risk patients have 
almost twice the risk of death (HR = 2.10 (0.99-4.46), p = 0.054), while 
high-risk patients have almost four times the risk (HR = 3.79 (1.77-8.11), p = 
0.001). The multivariate goodness of fit was 0.756 and was correlated with 
Kaplan-Meier curves (p = 0.002). Consistent results were found for DFS. This 
study provides a critical basis for the future development of an 
immunohistochemical assessment capable of discerning early-stage CC patients as 
a function of their prognosis. This tool may aid with treatment personalization 
in daily clinical practice and improve survival outcomes.

DOI: 10.3390/cancers13235909
PMCID: PMC8656725
PMID: 34885019

Conflict of interest statement: P.A. is an employee of Servier Medical Affairs, 
although there were no affiliations or financial involvement with this or any 
other organization or entity, with financial or scientific interest, or with the 
subject matter or materials discussed in the manuscript. All other authors 
declare no conflicts of interest. The funders had no role in the design of the 
study, in the collection, analyses, or interpretation of data, in the writing of 
the manuscript, or in the decision to publish the results.


154. Cost-Effectiveness of DNA Stool Testing to Screen for Colorectal Cancer 
[Internet].

Zauber AG(1), Lansdorp-Vogelaar I(2), Wilschut J(2), Knudsen AB(3), van 
Ballegooijen M(2), Kuntz KM(4).

Rockville (MD): Agency for Healthcare Research and Quality (US); 2007 Dec 20.
AHRQ Technology Assessments.

Author information:
(1)Memorial Sloan-Kettering Cancer Center
(2)Erasmus MC
(3)Massachusetts General Hospital
(4)University of Minnesota

BACKGROUND: Despite recent declines in both incidence and mortality, colorectal 
cancer (CRC) is the second most common cause of cancer death in the United 
States. CRC screening reduced CRC mortality by 15–33% in randomized controlled 
trials with Hemoccult II fecal occult blood tests (FOBTs). Novel CRC screening 
technologies, such as the DNA stool test have been developed but need to be 
evaluated in terms of their comparability of diagnostic performance (sensitivity 
and specificity) in detecting adenomatous polyps and CRC, acceptability to 
patients, and test-related complications and costs. Accordingly, we conducted a 
cost-effectiveness analysis of the DNA stool test and other currently 
recommended CRC screening strategies.
METHODS: We used two microsimulation models from the National Cancer Institute 
(NCI)-funded Cancer Intervention and Surveillance Modeling Network (CISNET) 
consortium to assess the cost-effectiveness of screening for CRC with the DNA 
stool test in comparison to the currently recommended CRC screening strategies. 
We conducted incremental cost-effectiveness analyses by comparing the 
incremental costs and benefits with the next best strategy after eliminating 
dominated strategies (i.e., strategies that are more costly and less effective 
than another strategy or a combination of other strategies). We conducted a 
literature review of the evidence for the DNA stool test to obtain estimates of 
its sensitivity and specificity for adenomas by size and for CRC. We derived 
direct medical cost estimates using the Centers for Medicare and Medicaid 
Services (CMS) reimbursement for screening and treatment, as well as for 
complications of screening. We also derived direct beneficiary costs and time 
costs associated with screening and treatment to be used in analyses from the 
modified societal perspective. We assumed a per-test cost of $350 for the DNA 
stool test. We performed sensitivity and threshold analyses on the cost, 
diagnostic performance, and relative adherence of the DNA stool test. We 
considered the currently recommended CRC tests of annual Hemoccult II, Hemoccult 
SENSA®, and a fecal immunochemical test (FIT) with composite test 
characteristics of Magstream, HemeSelect, Flexsure, Monohaem, OC-Hemodia, and 
Insure; 5-year flexible sigmoidoscopy with and without biopsy and with and 
without FOBT annually; and 10-year colonoscopy.
RESULTS: The screening benefit for the DNA stool test, measured in terms of 
life-years gained compared with no screening, was lower than that of annual 
Hemoccult II testing except for 3-year testing with version 1.1 (i.e., 
PreGen-Plus™) and with a per-test cost of $350, the overall costs were higher 
than all of the other screening strategies. All DNA stool test strategies 
considered were dominated by other recommended CRC screening tests. Screening 
with the DNA stool test version 1.1 would be cost-effective (i.e., be a 
non-dominated strategy) at per-test cost of $34 to $51 for 5-yearly DNA stool 
test screening and $40 to $60 for 3-yearly DNA stool testing, depending on the 
simulation model used. The threshold costs of the DNA stool test version 1.1 
increased to $163–$187 for 5-yearly DNA stool testing if the test performance 
was at a level that was 50% between base-case values and a perfect test (i.e., 
sensitivity and specificity equal to 1.0) and $329–$364 if a perfect test. The 
threshold costs of the DNA stool test version 1.1 at 3-yearly intervals were 
$140 to $167 if the test performance parameters were 50% of the level between 
base case and a perfect test and $237–$302 if the DNA stool test had perfect 
test parameters. If the DNA stool test version 1.1 was able to increase 
screening adherence to 75%, while adherence for all other strategies remained at 
50%, the threshold costs could increase to $83–$141 at 5-yearly intervals of 
testing and to $314–$391 at 3-yearly interval intervals of testing. With perfect 
adherence per-test costs could be $472–$740 at 5-yearly intervals and $730–$822 
at 3-yearly intervals, assuming an adherence of 50% for all other tests. 
Analyses conducted from a modified societal perspective yielded threshold 
per-test costs that were approximately 2 to 3 times greater than the analyses 
from the CMS perspective.
CONCLUSIONS: These results suggest that screening for CRC with the DNA stool 
test version 1.1 does provide a benefit in terms of life-years gained compared 
with no screening but the cost, relative to the benefit derived and to the 
availability and costs of other CRC screening tests, would need to be in the 
range of $34–$60 to be a non-dominated option. Only if significant improvements 
for the DNA stool test characteristics or relative adherence with DNA stool 
testing compared with other available options can be demonstrated, will stool 
DNA testing at the current costs of $350 be cost-effective. These estimates are 
based on a third-party payer analysis on an unscreened 65-year old cohort. 
Threshold costs are similar for a 50-year old cohort, but can be somewhat higher 
from a modified societal perspective ($88 to $134 for 5-yearly testing and $73 
to $116 for 3-yearly testing).

PMID: 25879132


155. Indian J Radiol Imaging. 2017 Apr-Jun;27(2):200-206. doi: 
10.4103/ijri.IJRI_24_17.

Early outcomes of radiofrequency ablation in unresectable metastatic colorectal 
cancer from a tertiary cancer hospital in India.

Kulkarni S(1), Shetty NS(1), Polnaya AM(1), Patil S(1), Gala K(1), Chivate R(1), 
Ostwal V(2), Ramaswamy A(2), Shrikhande SV(3), Goel M(3), Patkar S(3), Bhandare 
M(3), Rangarajan V(4), Nilendu P(4).

Author information:
(1)Department of Radio-diagnosis, Tata Memorial Centre, Mumbai, Maharashtra, 
India.
(2)Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, 
India.
(3)Department of Surgical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, 
India.
(4)Department of Nuclear Medicine, Tata Memorial Centre, Mumbai, Maharashtra, 
India.

AIMS: The study was carried out to evaluate the early outcomes using 
Radiofrequency Ablation (RFA) for unresectable liver metastases in the 
management of metastatic colorectal cancer (mCRC) from an area of low 
endemicity.
MATERIAL AND METHODS: 60 Patients with unresectable colorectal liver metastases 
had undergone 88 sessions of RFA from January 2007 till December 2013. The 
results were retrospectively analysed to evaluate the outcomes in terms of 
efficacy and survival rates.
RESULTS: The median follow up of patients in our series was 24.8months. 35/52 
(67.3%) patients had complete response at 3 months while 8 patients were lost to 
follow up. Of the 17 patients who had recurrence, 4 (23.5%) were at the ablated 
site while 13 patients (76.4%) progressed elsewhere. Abdominal pain was 
commonest post procedural symptom (20%). There was no procedure related 
mortality or any major complications. Mean disease free interval and Progression 
free survival was 6.7 and 13.1 months. Estimated median survival in patients 
with liver limited disease and those with small lesion (<3cm) was 3.79 years and 
3.45 years respectively. Median survival in patients with lesion size 3-5 cms 
was 1.5 years. Annual survival rates would be 94.5%, 55.2% and 26.2% for 1, 3 
and 5 years.
CONCLUSION: Radiofrequency ablation of unresectable liver metastases is 
effective in treatment of mCRC. Estimated survival rates and Annual survival 
rates at our institute from the low endemic region also follow the global trend. 
Size of the lesion was an important predictor of efficacy of RFA. Presence of 
extrahepatic disease and lesion size >3 cm was associated with decreased 
survival.

DOI: 10.4103/ijri.IJRI_24_17
PMCID: PMC5510318
PMID: 28744081

Conflict of interest statement: There are no conflicts of interest.


156. J Am Board Fam Med. 2016 Sep-Oct;29(5):533-42. doi: 
10.3122/jabfm.2016.05.160109.

A Practice Facilitation and Academic Detailing Intervention Can Improve Cancer 
Screening Rates in Primary Care Safety Net Clinics.

Mader EM(1), Fox CH(1), Epling JW(1), Noronha GJ(1), Swanger CM(1), Wisniewski 
AM(1), Vitale K(1), Norton AL(1), Morley CP(2).

Author information:
(1)From the Department of Family Medicine, State University of New York Upstate 
Medical University, Syracuse (EMM, JWE, ALN, CPM); the Department of Family 
Medicine, State University of New York at Buffalo (CHF, AMW); the Department of 
Public Health & Preventive Medicine, State University of New York Upstate 
Medical University, Syracuse (JWE, CPM); the Center for Primary Care, University 
of Rochester School of Medicine and Dentistry, Rochester, NY (GJN, CMS); the 
Center for Community Health, University of Rochester School of Medicine and 
Dentistry, Rochester (KV); and the Department of Psychiatry & Behavioral 
Sciences, State University of New York Upstate Medical University, Syracuse 
(CPM).
(2)From the Department of Family Medicine, State University of New York Upstate 
Medical University, Syracuse (EMM, JWE, ALN, CPM); the Department of Family 
Medicine, State University of New York at Buffalo (CHF, AMW); the Department of 
Public Health & Preventive Medicine, State University of New York Upstate 
Medical University, Syracuse (JWE, CPM); the Center for Primary Care, University 
of Rochester School of Medicine and Dentistry, Rochester, NY (GJN, CMS); the 
Center for Community Health, University of Rochester School of Medicine and 
Dentistry, Rochester (KV); and the Department of Psychiatry & Behavioral 
Sciences, State University of New York Upstate Medical University, Syracuse 
(CPM). morleycp@upstate.edu.

Comment in
    J Am Board Fam Med. 2016 Sep-Oct;29(5):521-4.

BACKGROUND: Despite the current evidence of preventive screening effectiveness, 
rates of breast, cervical, and colorectal cancer in the United States fall below 
national targets. We evaluated the efficacy and feasibility of combining 
practice facilitation and academic detailing quality improvement (QI) strategies 
to help primary care practices increase breast, cervical, and colorectal cancer 
screening among patients.
METHODS: Practices received a 1-hour academic detailing session addressing 
current cancer screening guidelines and best practices, followed by 6 months of 
practice facilitation to implement evidence-based interventions aimed at 
increasing patient screening. One-way repeated measures analysis of variance 
compared screening rates before and after the intervention, provider surveys, 
and TRANSLATE model scores. Qualitative data were gathered via participant focus 
groups and interviews.
RESULTS: Twenty-three practices enrolled in the project: 4 federally qualified 
health centers, 10 practices affiliated with larger health systems, 4 
physician-owned practices, 4 university hospital clinics, and 1 nonprofit 
clinic. Average screening rates for breast cancer increased by 13% (P = .001), 
and rates for colorectal cancer increased by 5.6% (P = .001). Practices 
implemented a mix of electronic health record data cleaning workflows, provider 
audits and feedback, reminder systems streamlining, and patient education and 
outreach interventions. Practice facilitators assisted practices in tailoring 
interventions to practice-specific priorities and constraints and in connecting 
with community resources. Practices with resource constraints benefited from the 
engagement of all levels of staff in the quality improvement processes and from 
team-based adaptations to office workflows and policies. Many practices aligned 
quality improvement interventions in this project with patient-centered medical 
home and other regulatory reporting targets.
CONCLUSIONS: Combining practice facilitation and academic detailing is 1 method 
through which primary care practices can achieve systems-level changes to better 
manage patient population health.

© Copyright 2016 by the American Board of Family Medicine.

DOI: 10.3122/jabfm.2016.05.160109
PMID: 27613786 [Indexed for MEDLINE]


157. Saudi J Gastroenterol. 2014 Mar-Apr;20(2):134-8. doi: 10.4103/1319-3767.129479.

Correlation of pretreatment hemoglobin and platelet counts with 
clinicopathological features in colorectal cancer in Saudi population.

Al-Saeed EF, Tunio MA(1), Al-Obaid O, Abdulla M, Al-Anazi A, AlShenaifi JY, 
Al-Ameer L, Al-Obaidan T.

Author information:
(1)Radiation Oncology, Comprehensive Cancer Center, King Fahad Medical City, 
Riyadh, Saudi Arabia.

Erratum in
    Saudi J Gastroenterol. 2015 Jan-Feb;21(1):58. Al-Shanifi, Jumanah [corrected 
to AlShenaifi, Jumanah Y].

BACKGROUND/AIMS: In Saudi Arabia, colorectal cancers (CRCs) are registered as 
the second most common cancers. However, no data has been reported about 
correlation of the severity of the anemia and pretreatment platelets level with 
clinicopathological features of CRCs. We aimed to evaluate the association 
between pretreatment hemoglobin and platelets level and the clinicopathological 
features of CRC patients in Saudi Arabia.
MATERIALS AND METHODS: Between September 2005 and November 2011, One hundred and 
fifty-four confirmed CRC patients underwent thorough physical examination, blood 
investigations, endoscopic ultrasonography (EUS), and computed tomography (CT) 
for staging before surgery. Findings of physical assessment, EUS, CT, and 
pathological specimens were correlated with pretreatment hemoglobin and 
platelets levels the Pearson-Kendall tau correlative coefficients.
RESULTS: The mean age of cohort was 56.6 years (range: 26-89). Left-sided CRC 
were predominant (97 patients; 63%). Mean size of primary tumor was 6 cms (1-18) 
SD ± 3.55. Mean values of hemoglobin, red blood cells, hematocrit, white blood 
cells, and platelets were 11.9 SD ± 2.3, 35.5 SD ± 5.7, 4.43 × 10 6 /mL SD ± 
0.6, 7.67 10 6 /mL SD ± 2.44, and 343 × 10 3 /mL SD ± 164.4, respectively. 
Pretreatment hemoglobin was inversely correlated with primary tumor size (R: 
0.71, R2: 1.55, P = 0.0001) and nodal status (R: 0.02, R2: 0.05, P = 0.01). 
Right-sided CRC had significantly low pretreatment hemoglobin levels ( P = 
0.001). Interestingly, pretreatment thrombocytosis was seen only in right-sided 
CRC (P = 0.0001).
CONCLUSION: Pretreatment anemia and thrombocytosis were found mainly in 
right-sided CRCs and advanced primary and nodal stages. Pretreatment hemoglobin 
and thrombocytosis can be considered as useful prognostic markers in CRC 
patients.

DOI: 10.4103/1319-3767.129479
PMCID: PMC3987154
PMID: 24705152 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of Interest: None declared.


158. Genome Med. 2017 May 24;9(1):46. doi: 10.1186/s13073-017-0434-0.

Multilevel genomics of colorectal cancers with microsatellite 
instability-clinical impact of JAK1 mutations and consensus molecular subtype 1.

Sveen A(1)(2)(3)(4), Johannessen B(1)(2)(3)(4), Tengs T(1)(2)(3)(4), Danielsen 
SA(1)(2)(3)(4), Eilertsen IA(1)(2)(4), Lind GE(1)(2)(4), Berg KCG(1)(2)(4), 
Leithe E(1)(2)(4), Meza-Zepeda LA(3)(5)(6), Domingo E(7), Myklebost O(3)(5), 
Kerr D(8), Tomlinson I(7), Nesbakken A(2)(3)(4)(9), Skotheim RI(1)(2)(3)(4), 
Lothe RA(10)(11)(12)(13).

Author information:
(1)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway.
(2)K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, 
P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway.
(3)Norwegian Cancer Genomics Consortium, Oslo University Hospital, P.O. Box 
4953, Nydalen, NO-0424, Oslo, Norway.
(4)Centre for Cancer Biomedicine, Institute for Clinical Medicine, University of 
Oslo, P.O. Box 4950, Nydalen, NO-0424, Oslo, Norway.
(5)Department of Tumor Biology, Institute for Cancer Research, Oslo University 
Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway.
(6)Genomics Core Facility, Department of Core Facilities, Institute for Cancer 
Research, Oslo University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, 
Norway.
(7)Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt 
Drive, Oxford, OX3 7BN, UK.
(8)Department of Oncology, University of Oxford, Roosevelt Drive, Oxford, OX3 
7DQ, UK.
(9)Department of Gastrointestinal Surgery, Oslo University Hospital, P.O. Box 
4950, Nydalen, NO-0424, Oslo, Norway.
(10)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway. 
rlothe@rr-research.no.
(11)K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, 
P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway. rlothe@rr-research.no.
(12)Norwegian Cancer Genomics Consortium, Oslo University Hospital, P.O. Box 
4953, Nydalen, NO-0424, Oslo, Norway. rlothe@rr-research.no.
(13)Centre for Cancer Biomedicine, Institute for Clinical Medicine, University 
of Oslo, P.O. Box 4950, Nydalen, NO-0424, Oslo, Norway. rlothe@rr-research.no.

Comment in
    Genome Med. 2017 May 24;9(1):45.

BACKGROUND: Approximately 15% of primary colorectal cancers have DNA mismatch 
repair deficiency, causing a complex genome with thousands of small 
mutations-the microsatellite instability (MSI) phenotype. We investigated 
molecular heterogeneity and tumor immunogenicity in relation to clinical 
endpoints within this distinct subtype of colorectal cancers.
METHODS: A total of 333 primary MSI+ colorectal tumors from multiple cohorts 
were analyzed by multilevel genomics and computational modeling-including 
mutation profiling, clonality modeling, and neoantigen prediction in a subset of 
the tumors, as well as gene expression profiling for consensus molecular 
subtypes (CMS) and immune cell infiltration.
RESULTS: Novel, frequent frameshift mutations in four cancer-critical genes were 
identified by deep exome sequencing, including in CRTC1, BCL9, JAK1, and PTCH1. 
JAK1 loss-of-function mutations were validated with an overall frequency of 20% 
in Norwegian and British patients, and mutated tumors had up-regulation of 
transcriptional signatures associated with resistance to anti-PD-1 treatment. 
Clonality analyses revealed a high level of intra-tumor heterogeneity; however, 
this was not associated with disease progression. Among the MSI+ tumors, the 
total mutation load correlated with the number of predicted neoantigens 
(P = 4 × 10-5), but not with immune cell infiltration-this was dependent on the 
CMS class; MSI+ tumors in CMS1 were highly immunogenic compared to MSI+ tumors 
in CMS2-4. Both JAK1 mutations and CMS1 were favorable prognostic factors 
(hazard ratios 0.2 [0.05-0.9] and 0.4 [0.2-0.9], respectively, P = 0.03 and 
0.02).
CONCLUSIONS: Multilevel genomic analyses of MSI+ colorectal cancer revealed 
molecular heterogeneity with clinical relevance, including tumor immunogenicity 
and a favorable patient outcome associated with JAK1 mutations and the 
transcriptomic subgroup CMS1, emphasizing the potential for prognostic 
stratification of this clinically important subtype. See related research 
highlight by Samstein and Chan 10.1186/s13073-017-0438-9.

DOI: 10.1186/s13073-017-0434-0
PMCID: PMC5442873
PMID: 28539123 [Indexed for MEDLINE]


159. Aging (Albany NY). 2019 Oct 9;11(19):8587-8603. doi: 10.18632/aging.102349. Epub 
2019 Oct 9.

A molecular sub-cluster of colon cancer cells with low VDR expression is 
sensitive to chemotherapy, BRAF inhibitors and PI3K-mTOR inhibitors treatment.

Wang H(1)(2), Wang X(1)(2), Xu L(1)(2), Zhang J(3), Cao H(1)(2).

Author information:
(1)Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian 
Provincial Maternity and Children's Hospital, Affiliated Hospital of Fujian 
Medical University, FuZhou, FuJian 350001, China.
(2)Key Laboratory of Technical Evaluation of Fertility Regulation for Non-human 
Primate, National Health and Family Planning Commission, FuZhou, FuJian 350001, 
China.
(3)State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, 
Rui-Jin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong 
University, Shanghai 200025, China.

Gene expression based consensus molecular subtypes (CMS) and non-negative matrix 
factorization (NMF) sub-clusters are robust colon cancer classification systems. 
Although, the molecular features are clear, colon cancer subgroups based 
interventions are limited. To address this problem, we analyze the CMS and NMF 
subgroup guided drug sensitivity in colon cancer cell lines. CMS3 subtype cells 
are sensitive to 5-Fluorouracil, while, CMS4 subtype cells are sensitive to 
cisplatin treatment. In NMF classification, a sub-cluster is specifically 
sensitive to chemotherapy, BRAF inhibitors, PI3K-mTOR inhibitors and NOTCH 
inhibitor treatment. This sub-cluster has low frequency of TP53, POLE, PIK3CA 
and BRAF mutation. Transcriptional analysis demonstrates low NOTCH signaling 
activity, low CDX2 and VDR expression in this sub-cluster. CDX2 and VDR are 
significantly associated with the sensitivity of chemotherapy, BRAF inhibitors 
and PI3K-mTOR inhibitors. Moreover, a positive correlation between VDR and CDX2 
is identified. VDR and CDX2 mediated regulatory networks are constructed. At 
last, three or four sub-clusters classification is validated in colon cancer 
patients. Overall, our results suggest a molecular sub-cluster of colon cancer 
cells with low CDX2 and VDR expression is sensitive to chemotherapy, BRAF 
inhibitors and PI3K-mTOR inhibitors treatment and provide an example of 
translation of cancer classification to subgroup guided therapies.

DOI: 10.18632/aging.102349
PMCID: PMC6814605
PMID: 31596728 [Indexed for MEDLINE]

Conflict of interest statement: CONFLICTS OF INTEREST: The authors have no 
conflicts of interest to declare.


160. ESMO Open. 2019 Mar 8;4(2):e000489. doi: 10.1136/esmoopen-2019-000489. 
eCollection 2019.

Benefit from anti-EGFRs in RAS and BRAF wild-type metastatic transverse colon 
cancer: a clinical and molecular proof of concept study.

Cremolini C(1)(2), Benelli M(3), Fontana E(4)(5), Pagani F(6), Rossini D(1)(2), 
Fucà G(6), Busico A(7), Conca E(7), Di Donato S(8), Loupakis F(9), Schirripa 
M(9), Lonardi S(9), Borelli B(1)(2), Ongaro E(1)(2)(10), Eason K(4), Morano 
F(6), Casagrande M(10), Fassan M(11), Sadanandam A(4)(5), de Braud F(6)(12), 
Falcone A(1)(2), Pietrantonio F(6)(12).

Author information:
(1)Unit of Medical Oncology 2, Azienda Ospedaliero Universitaria Pisana, Pisa, 
Italy.
(2)Department of Translational Research and New Technologies in Medicine and 
Surgery, University of Pisa, Pisa, Italy.
(3)Bioinformatics Unit, Oncology Department, Hospital of Prato, Prato, Italy.
(4)Division of Molecular Pathology, The Institute of Cancer Research, London, 
UK.
(5)Centre for Molecular Pathology, Royal Marsden NHS Foundation Trust, London, 
UK.
(6)Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 
Milano, Italy.
(7)Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS 
Istituto Nazionale dei Tumori, Milan, Italy.
(8)Medical Oncology Unit, Oncology Department, Hospital of Prato, Prato, Italy.
(9)Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, 
IRCCS Istituto Oncologico Veneto, Padova, Italy.
(10)Department of Oncology, Azienda Sanitaria Universitaria Integrata di Udine, 
Udine, Italy.
(11)Unit of Surgical Pathology, Department of Medicine, University of Padova, 
Padova, Italy.
(12)Department of Oncology and Hemato-oncology, University of Milan, Milan, 
Italy.

OBJECTIVE: Primary tumour location is regarded as a reliable surrogate of 
colorectal cancer biology. Sensitivity to anti-EGFRs (Epidermal Growth Factor 
Receptor) of metastatic transverse colon cancers (mTCCs) has usually been 
assumed similar to right-sided tumours; however, evidence about the clinical 
behaviour of mTCC is limited. Thus, to verify sensitivity of mTCC to anti-EGFRs 
we conducted the present study.
METHODS: Patients with RAS/BRAF wild-type microsatellite stable (MSS) mTCC 
receiving anti-EGFR monotherapy, or in combination with irinotecan if clearly 
irinotecan-refractory, were included. Hypothesising an overall response rate 
(ORR) of 35%, 11 patients, of whom at least 3 were responders, were necessary to 
be able to reject the null hypothesis of an ORR of 5%, with α and β errors of 
0.05 and 0.20. PRESSING panel and consensus molecular subtypes (CMS) were 
assessed on tumour samples, whereas in-silico data were obtained from TCGA 
dataset.
RESULTS: Among nine eligible patients, four and three achieved response and 
disease stabilisation (ORR 44%). At a median follow-up of 23.1 months, median 
progression-free survival and overall survival were 7.3 (95% CI 3.9 to NA) and 
15.0 months (95% CI 10.0 to NA), respectively. A MET amplification and an ERBB4 
S303F substitution were detected in patients with rapid disease progression, 
while others had PRESSING panel-negative tumours with CMS2 or CMS4 subtypes.
CONCLUSIONS: RAS/BRAF wild-type MSS mTCCs may be sensitive to anti-EGFRs, as 
confirmed by molecular analyses.

DOI: 10.1136/esmoopen-2019-000489
PMCID: PMC6435314
PMID: 30962964

Conflict of interest statement: Competing interests: None declared.


161. J Natl Cancer Inst. 2022 Apr 11;114(4):503-516. doi: 10.1093/jnci/djab106.

Clinical Value of Consensus Molecular Subtypes in Colorectal Cancer: A 
Systematic Review and Meta-Analysis.

Ten Hoorn S(1)(2), de Back TR(1)(2), Sommeijer DW(1)(3)(4), Vermeulen 
L(1)(2)(3).

Author information:
(1)Amsterdam University Medical Centers (UMC), University of Amsterdam, Lab. for 
Experimental Oncology and Radiobiology, Center for Experimental and Molecular 
Medicine, Cancer Center Amsterdam, Amsterdam, the Netherlands.
(2)Oncode Institute, Amsterdam UMC, Amsterdam, the Netherlands.
(3)Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, 
Amsterdam, the Netherlands.
(4)Flevohospital, Department of Internal Medicine, Almere, the Netherlands.

BACKGROUND: The consensus molecular subtypes (CMSs) of colorectal cancer (CRC) 
capture tumor heterogeneity at the gene-expression level. Currently, a 
restricted number of molecular features are used to guide treatment for CRC. We 
summarize the evidence on the clinical value of the CMSs.
METHODS: We systematically identified studies in Medline and Embase that 
evaluated the prognostic and predictive value of CMSs in CRC patients. A 
random-effect meta-analysis was performed on prognostic data. Predictive data 
were summarized.
RESULTS: In local disease, CMS4 tumors were associated with worse overall 
survival (OS) compared with CMS1 (hazard ratio [HR] = 3.28, 95% confidence 
interval = 1.27 to 8.47) and CMS2 cancers (HR = 2.60, 95% confidence interval = 
1.93 to 3.50). In metastatic disease, CMS1 consistently had worse survival than 
CMS2-4 (OS HR range = 0.33-0.55; progression-free survival HR range = 
0.53-0.89). Adjuvant chemotherapy in stage II and III CRC was most beneficial 
for OS in CMS2 and CMS3 (HR range = 0.16-0.45) and not effective in CMS4 tumors. 
In metastatic CMS4 cancers, an irinotecan-based regimen improved outcome 
compared with oxaliplatin (HR range = 0.31-0.72). The addition of bevacizumab 
seemed beneficial in CMS1, and anti-epidermal growth factor receptor therapy 
improved outcome for KRAS wild-type CMS2 patients.
CONCLUSIONS: The CMS classification holds clear potential for clinical use in 
predicting both prognosis and response to systemic therapy, which seems to be 
independent of the classifier used. Prospective studies are warranted to support 
implementation of the CMS taxonomy in clinical practice.

© The Author(s) 2021. Published by Oxford University Press.

DOI: 10.1093/jnci/djab106
PMCID: PMC9002278
PMID: 34077519 [Indexed for MEDLINE]


162. Nat Commun. 2018 Oct 5;9(1):4112. doi: 10.1038/s41467-018-06567-6.

Copy number load predicts outcome of metastatic colorectal cancer patients 
receiving bevacizumab combination therapy.

Smeets D(1)(2), Miller IS(3), O'Connor DP(4)(5), Das S(4)(5), Moran B(5), Boeckx 
B(1)(2), Gaiser T(6), Betge J(7), Barat A(3), Klinger R(5), van Grieken NCT(8), 
Cremolini C(9), Prenen H(10)(11), Mazzone M(1)(12), Depreeuw J(1)(2)(13), Bacon 
O(3), Fender B(14), Brady J(15), Hennessy BT(16), McNamara DA(16), Kay E(17), 
Verheul HM(18), Maarten N(18), Gallagher WM(5)(14), Murphy V(19), Prehn JHM(3), 
Koopman M(20), Punt CJA(21), Loupakis F(22), Ebert MPA(7), Ylstra B(8), 
Lambrechts D(23)(24), Byrne AT(3)(5).

Author information:
(1)VIB Center for Cancer Biology, VIB, Herestraat 49, 3000, Leuven, Belgium.
(2)Department of Human Genetics, University of Leuven (KULeuven), Herestraat 49, 
3000, Leuven, Belgium.
(3)Department of Physiology & Medical Physics, Royal College of Surgeons in 
Ireland, 31A York Street, Dublin, D2, Ireland.
(4)Department of Molecular and Cellular Therapeutics, Royal College of Surgeons 
in Ireland, 123 St.Stephen's Green, Dublin, D2, Ireland.
(5)UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, 
University College Dublin, Dublin, D4, Ireland.
(6)Institute of Pathology, University Medical Center Mannheim, University of 
Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
(7)Department of Medicine II, University Hospital Mannheim, Heidelberg 
University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
(8)Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije 
Universiteit Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
(9)Department of Translational Research and New Technologies in Medicine and 
Surgery, University of Pisa, Istituto Toscano Tumori, Lungarno Antonio 
Pacinotti, 43, 56126, Pisa, Italy.
(10)Department of Oncology, University Hospital Antwerp, Edegem, 2650, Belgium.
(11)Center for Oncological Research, Antwerp University, 2650, Edegem, Belgium.
(12)Department of Oncology, University of Leuven (KULeuven), Herestraat 49, 
3000, Leuven, Belgium.
(13)Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 
University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
(14)OncoMark Limited, NovaUCD, Belfield Innovation Park, Dublin, D4, Ireland.
(15)Veterinary Pathobiology, School of Veterinary Medicine, University College 
Dublin, Stillorgan Rd, Belfield, Dublin, D4, Ireland.
(16)Department of Surgery, Beaumont Hospital, Beaumont Rd, Beaumont, Dublin, D9, 
Ireland.
(17)Department of Pathology, Beaumont Hospital, Beaumont Rd, Beaumont, Dublin, 
D9, Ireland.
(18)Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, 
Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The 
Netherlands.
(19)Cancer Trials Ireland, Innovation House, Old Finglas Road, Dublin, D9, 
Ireland.
(20)Department of Medical Oncology, University Medical Center Utrecht, Utrecht 
University, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
(21)Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, 
Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
(22)Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura 
a Carattere Scientifico, IRCCS, Via Gattamelata, 64, 35128, Padova, Italy.
(23)VIB Center for Cancer Biology, VIB, Herestraat 49, 3000, Leuven, Belgium. 
Diether.Lambrechts@kuleuven.vib.be.
(24)Department of Human Genetics, University of Leuven (KULeuven), Herestraat 
49, 3000, Leuven, Belgium. Diether.Lambrechts@kuleuven.vib.be.

Increased copy number alterations (CNAs) indicative of chromosomal instability 
(CIN) have been associated with poor cancer outcome. Here, we study CNAs as 
potential biomarkers of bevacizumab (BVZ) response in metastatic colorectal 
cancer (mCRC). We cluster 409 mCRCs in three subclusters characterized by 
different degrees of CIN. Tumors belonging to intermediate-to-high instability 
clusters have improved outcome following chemotherapy plus BVZ versus 
chemotherapy alone. In contrast, low instability tumors, which amongst others 
consist of POLE-mutated and microsatellite-instable tumors, derive no further 
benefit from BVZ. This is confirmed in 81 mCRC tumors from the phase 2 MoMa 
study involving BVZ. CNA clusters overlap with CRC consensus molecular subtypes 
(CMS); CMS2/4 xenografts correspond to intermediate-to-high instability clusters 
and respond to FOLFOX chemotherapy plus mouse avastin (B20), while CMS1/3 
xenografts match with low instability clusters and fail to respond. Overall, we 
identify copy number load as a novel potential predictive biomarker of BVZ 
combination therapy.

DOI: 10.1038/s41467-018-06567-6
PMCID: PMC6173768
PMID: 30291241 [Indexed for MEDLINE]

Conflict of interest statement: D.L., D.S., and A.T.B. are named as inventors on 
a patent related to this work (WO 2017/182656). The remaining authors declare no 
competing interests.


163. Clin Colorectal Cancer. 2018 Dec;17(4):e699-e709. doi: 
10.1016/j.clcc.2018.07.005. Epub 2018 Jul 17.

Prognostic Implications of Mucinous Differentiation in Metastatic Colorectal 
Carcinoma Can Be Explained by Distinct Molecular and Clinicopathologic 
Characteristics.

Khan M(1), Loree JM(2), Advani SM(3), Ning J(4), Li W(4), Pereira AAL(2), Lam 
M(2), Raghav K(2), Morris VK(2), Broaddus R(5), Maru D(5), Overman MJ(2), Kopetz 
S(6).

Author information:
(1)Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
Houston, TX.
(2)Department of Gastrointestinal Medical Oncology, The University of Texas MD 
Anderson Cancer Center, Houston, TX.
(3)Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, 
Georgetown University, Washington, DC.
(4)Department of Biostatistics, The University of Texas MD Anderson Cancer 
Center, Houston, TX.
(5)Department of Pathology, The University of Texas MD Anderson Cancer Center, 
Houston, TX.
(6)Department of Gastrointestinal Medical Oncology, The University of Texas MD 
Anderson Cancer Center, Houston, TX. Electronic address: SKopetz@mdanderson.org.

BACKGROUND: The mucinous histologic subtype accounts for 5% to 20% of colorectal 
cancer (CRC) cases but remains poorly characterized. The present study 
characterized the baseline characteristics, mutational profile, and clinical 
outcomes of patients diagnosed with mucinous CRC.
MATERIALS AND METHODS: We identified 1877 patients with metastatic CRC with 
available histologic findings and molecular profiling and summarized the 
baseline clinical and pathologic characteristics and overall survival (OS) 
stratified by the histologic type. The data from separate cohorts with consensus 
molecular subtype (CMS) and CpG island methylator information were also 
summarized.
RESULTS: The mucinous histologic type was found in 277 of the 1877 patients 
(14.8%) and was associated with an increased prevalence of microsatellite 
instability (P < .001) and a right-sided primary (P < .001). An increased 
frequency of CMS1 (microsatellite instability immune) and lower rates of CMS2 
(canonical) were identified, with mucinous compared with nonmucinous 
adenocarcinoma (P < .0001). Mutations in SMAD4 (P < .001), GNAS (P < .001), 
ERBB2 (P = .02), BRAF (P < .001), and KRAS (P < .001) occurred at greater 
frequencies in the mucinous CRC cases, and TP53 (P < .001), APC (P < .001), and 
NRAS mutations (P = .03) were less common. Univariate (hazard ratio [HR], 1.38; 
95% confidence interval [CI], 1.17-1.63; P < .001) and multivariate analysis 
(HR, 1.36; 95% CI, 1.12-1.64; P = .002) demonstrated that the mucinous 
histologic type is associated with worse OS. The features associated with the 
mucinous histologic subtype were independent predictors for shorter OS, 
including BRAF (HR, 1.74; 95% CI, 1.35-2.25; P < .001) and KRAS (HR, 1.42; 95% 
CI, 1.22-1.65; P < .001) mutations, right-sided location (HR, 1.20; 95% CI, 
1.04-1.39; P = .01), and synchronous metastases (HR, 2.92; 95% CI, 2.49-3.42; 
P < .001).
CONCLUSION: Compared with nonmucinous adenocarcinoma, the mucinous histologic 
type is associated with a worse prognosis, even when controlling for known 
prognostic features. This unique biologic behavior should be considered in the 
treatment and prognostic assessment of patients with CRC.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.clcc.2018.07.005
PMCID: PMC6588353
PMID: 30205948 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of Interest: None


164. J Clin Lab Anal. 2022 Jan;36(1):e24141. doi: 10.1002/jcla.24141. Epub 2021 Nov 
24.

Predictive molecular markers for the treatment with immune checkpoint inhibitors 
in colorectal cancer.

Du F(1), Liu Y(1).

Author information:
(1)Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, 
Harbin, China.

Colorectal cancer is one of the most common malignant tumors and, hence, has 
become one of the most important public health issues in the world. Treatment 
with immune checkpoint inhibitors (ICIs) successfully improves the survival rate 
of patients with melanoma, non-small-cell lung cancer, and other malignancies, 
and its application in metastatic colorectal cancer is being actively explored. 
However, a few patients develop drug resistance. Predictive molecular markers 
are important tools to precisely screen patient groups that can benefit from 
treatment with ICIs. The current article focused on certain important predictive 
molecular markers for ICI treatment in colorectal cancer, including not only 
some of the mature molecular markers, such as deficient mismatch repair (d-MMR), 
microsatellite instability-high (MSI-H), tumor mutational burden (TMB), 
programmed death-ligand-1 (PD-L1), tumor immune microenvironment (TiME), and 
tumor-infiltrating lymphocytes (TILs), but also some of the novel molecular 
markers, such as DNA polymerase epsilon (POLE), polymerase delta 1 (POLD1), 
circulating tumor DNA (ctDNA), and consensus molecular subtypes (CMS). We have 
reviewed these markers in-depth and presented the results from certain important 
studies, which suggest their applicability in CRC and indicate their advantages 
and disadvantages. We hope this article is helpful for clinicians and 
researchers to systematically understand these markers and can guide the 
treatment of colorectal cancer.

© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley 
Periodicals LLC.

DOI: 10.1002/jcla.24141
PMCID: PMC8761449
PMID: 34817097 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflicts of interest.


165. Medicina (Kaunas). 2022 Jan 10;58(1):100. doi: 10.3390/medicina58010100.

Global Impact of COVID-19 on Colorectal Cancer Screening: Current Insights and 
Future Directions.

Kopel J(1), Ristic B(2), Brower GL(3), Goyal H(4).

Author information:
(1)Department of Medicine, Texas Tech University Health Sciences Center, 
Lubbock, TX 79430, USA.
(2)Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 
Lubbock, TX 79430, USA.
(3)Department of Medication Education, Texas Tech University Health Sciences 
Center, Lubbock, TX 79430, USA.
(4)The Wright Center for Graduate Medical Education, Scranton, PA 18501, USA.

The coronavirus disease 2019 (COVID-19) pandemic has brought significant 
challenges to many aspects of healthcare delivery since the first reported case 
in early December 2019. Once in the body, SARS-CoV-2 can spread to other 
digestive organs, such as the liver, because of the presence of ACE2 receptors. 
Colorectal cancer (CRC) remains the second-leading cause of death in the United 
States (US). Therefore, individuals are routinely screened using either 
endoscopic methods (i.e., flexible sigmoidoscopy and colonoscopy) or stool-based 
tests, as per the published guidelines. At the beginning of the COVID-19 
pandemic, the Centers for Medicare and Medicaid Services (CMS) recommended that 
all non-urgent surgical and medical procedures, including screening 
colonoscopies, be delayed until the pandemic stabilization. This article aims to 
review the impact of COVID-19 on CRC screening.

DOI: 10.3390/medicina58010100
PMCID: PMC8778776
PMID: 35056408 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflict of interest.


166. Sci Rep. 2020 Jul 21;10(1):12123. doi: 10.1038/s41598-020-69083-y.

ColoType: a forty gene signature for consensus molecular subtyping of colorectal 
cancer tumors using whole-genome assay or targeted RNA-sequencing.

Buechler SA(1), Stephens MT(2), Hummon AB(3), Ludwig K(4), Cannon E(5), Carter 
TC(6), Resnick J(7), Gökmen-Polar Y(8), Badve SS(8)(9).

Author information:
(1)Department of Applied and Computational Mathematics and Statistics, Harper 
Cancer Research Institute, University of Notre Dame, 102B Crowley Hall, Notre 
Dame, IN, 46556, USA. steve@nd.edu.
(2)Genomics and Bioinformatics Core Facility, University of Notre Dame, Notre 
Dame, IN, USA.
(3)Department of Chemistry and Biochemistry, Comprehensive Cancer Center, The 
Ohio State University, Columbus, OH, USA.
(4)Functional Genetics Section, Genetics Branch, Center for Cancer Research, 
National Cancer Institute, Bethesda, MD, USA.
(5)Department of Applied and Computational Mathematics and Statistics, Harper 
Cancer Research Institute, University of Notre Dame, 102B Crowley Hall, Notre 
Dame, IN, 46556, USA.
(6)Center for Precision Medicine Research, Marshfield Clinic, Marshfield, WI, 
USA.
(7)Department of Pathology, Marshfield Clinic, Marshfield, WI, USA.
(8)Department of Pathology and Laboratory Medicine, Indiana University School of 
Medicine, Indianapolis, IN, USA.
(9)Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 
USA.

Colorectal cancer (CRC) tumors can be partitioned into four biologically 
distinct consensus molecular subtypes (CMS1-4) using gene expression. Evidence 
is accumulating that tumors in different subtypes are likely to respond 
differently to treatments. However, to date, there is no clinical diagnostic 
test for CMS subtyping. In this study, we used novel methodology in a 
multi-cohort training domain (n = 1,214) to develop the ColoType scores and 
classifier to predict CMS1-4 based on expression of 40 genes. In three 
validation cohorts (n = 1,744, in total) representing three distinct 
gene-expression measurement technologies, ColoType predicted gold-standard CMS 
subtypes with accuracies 0.90, 0.91, 0.88, respectively. To accommodate for 
potential intratumoral heterogeneity and tumors of mixed subtypes, ColoType was 
designed to report continuous scores measuring the prevalence of each of CMS1-4 
in a tumor, in addition to specifying the most prevalent subtype. For analysis 
of clinical specimens, ColoType was also implemented with targeted 
RNA-sequencing (Illumina AmpliSeq). In a series of formalin-fixed, 
paraffin-embedded CRC samples (n = 49), ColoType by targeted RNA-sequencing 
agreed with subtypes predicted by two independent methods with accuracies 0.92, 
0.82, respectively. With further validation, ColoType by targeted 
RNA-sequencing, may enable clinical application of CMS subtyping with 
widely-available and cost-effective technology.

DOI: 10.1038/s41598-020-69083-y
PMCID: PMC7374173
PMID: 32694712 [Indexed for MEDLINE]

Conflict of interest statement: The University of Notre Dame has filed a patent 
application for ColoType with SAB as inventor. SAB is a founder of Claris 
GenomiX, Inc which is has obtained a license for this technology. Other authors 
reported no competing interests.


167. Cell Death Dis. 2020 Nov 30;11(11):1020. doi: 10.1038/s41419-020-03232-z.

Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic 
Birinapant.

Fichtner M(1), Bozkurt E(1)(2), Salvucci M(1), McCann C(3), McAllister KA(3), 
Halang L(1), Düssmann H(1), Kinsella S(1)(4), Crawford N(3), Sessler T(3), 
Longley DB(3), Prehn JHM(5).

Author information:
(1)Department of Physiology and Medical Physics, Centre for Systems Medicine, 
Royal College of Surgeons in Ireland, Dublin, Ireland.
(2)Department of Genetics and Bioengineering, Faculty of Engineering, Izmir 
University of Economics, Balcova, Izmir, Turkey.
(3)Centre for Cancer Research and Cell Biology, Queen's University Belfast, 
Belfast, UK.
(4)Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer 
Research Center, Seattle, WA, USA.
(5)Department of Physiology and Medical Physics, Centre for Systems Medicine, 
Royal College of Surgeons in Ireland, Dublin, Ireland. prehn@rcsi.ie.

Colorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic 
chemotherapy in the adjuvant or palliative setting vary greatly between 
patients, and colorectal cancer cells often resist chemotherapy by evading 
apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore 
defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by 
inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these 
targets, responses to IAP antagonist may differ between molecularly distinct 
colon cancer cells. In this study, responses to the IAP antagonist Birinapant 
and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell 
lines, representing the consensus molecular subtypes (CMS). Treatment with 
Birinapant alone did not result in a substantial increase in apoptotic cells in 
this cell line panel. Annexin-V/PI assays quantified by flow cytometry and 
high-content screening showed that Birinapant increased responses of CMS1 and 
partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not 
effectively sensitized. FRET-based imaging of caspase-8 and -3 activation 
validated these differences at the single-cell level, with CMS1 cells displaying 
sustained activation of caspase-8-like activity during Birinapant and 
oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial 
apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects 
in combination with TNFα, suggesting that Birinapant can restore extrinsic 
apoptosis signaling in the context of inflammatory signals in this subtype. To 
explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with 
peripheral blood mononuclear cells. We observed increased cell death during 
Birinapant single treatment in these co-cultures, which was abrogated by 
anti-TNFα-neutralizing antibodies. Collectively, our study demonstrates that IAP 
inhibition is a promising modulator of response to oxaliplatin/5-FU in 
colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 
subtype, suggesting that molecular subtyping may aid as a patient stratification 
tool for IAP antagonists in this disease.

DOI: 10.1038/s41419-020-03232-z
PMCID: PMC7705699
PMID: 33257690 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that they have no conflict 
of interest.


168. Int J Mol Sci. 2020 Oct 30;21(21):8135. doi: 10.3390/ijms21218135.

ROS-Dependent ER Stress and Autophagy Mediate the Anti-Tumor Effects of 
Tributyltin (IV) Ferulate in Colon Cancer Cells.

Celesia A(1), Morana O(2), Fiore T(3)(4), Pellerito C(3)(4), D'Anneo A(2), 
Lauricella M(1), Carlisi D(1), De Blasio A(2), Calvaruso G(2), Giuliano M(2), 
Emanuele S(1).

Author information:
(1)Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), 
Biochemistry Building, University of Palermo, Via del Vespro 129, 90127 Palermo, 
Italy.
(2)Laboratory of Biochemistry, Department of Biological, Chemical and 
Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via 
del Vespro 129, 90127 Palermo, Italy.
(3)Department of Physics and Chemistry "Emilio Segrè" (DiFC), University of 
Palermo, Viale delle Scienze, Building 17, 90128 Palermo, Italy.
(4)Inter-University Consortium for Research on the Chemistry of Metal Ions in 
Biological Systems (C.I.R.C.M.S.B.), Piazza Umberto I, 1-70121 Bari, Italy.

Organotin compounds represent potential cancer therapeutics due to their 
pro-apoptotic action. We recently synthesized the novel organotin ferulic acid 
derivative tributyltin (IV) ferulate (TBT-F) and demonstrated that it displays 
anti-tumor properties in colon cancer cells related with autophagic cell death. 
The purpose of the present study was to elucidate the mechanism of TBT-F action 
in colon cancer cells. We specifically show that TBT-F-dependent autophagy is 
determined by a rapid generation of reactive oxygen species (ROS) and correlated 
with endoplasmic reticulum (ER) stress. TBT-F evoked nuclear factor erythroid-2 
related factor 2 (Nrf2)-mediated antioxidant response and Nrf2 silencing by RNA 
interference markedly increased the anti-tumor efficacy of the compound. 
Moreover, as a consequence of ROS production, TBT-F increased the levels of 
glucose regulated protein 78 (Grp78) and C/EBP homologous protein (CHOP), two ER 
stress markers. Interestingly, Grp78 silencing produced significant decreasing 
effects on the levels of the autophagic proteins p62 and LC3-II, while only p62 
decreased in CHOP-silenced cells. Taken together, these results indicate that 
ROS-dependent ER stress and autophagy play a major role in the TBT-F action 
mechanism in colon cancer cells and open a new perspective to consider the 
compound as a potential candidate for colon cancer treatment.

DOI: 10.3390/ijms21218135
PMCID: PMC7663760
PMID: 33143349 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflict of interest.


169. Trends Cancer. 2016 Mar;2(3):121-133. doi: 10.1016/j.trecan.2016.02.004. Epub 
2016 Mar 5.

The Immune Biology of Microsatellite-Unstable Cancer.

Kloor M(1), von Knebel Doeberitz M(2).

Author information:
(1)Department of Applied Tumor Biology, Institute of Pathology, University 
Hospital Heidelberg, Clinical Cooperation Unit (CCU 105) of the German Cancer 
Research Center and Molecular Medicine Partner Unit (MMPU) of the European 
Molecular Biology Laboratory, Im Neuenheimer Feld 224, 69120 Heidelberg, 
Germany. Electronic address: matthias.kloor@med.uni-heidelberg.de.
(2)Department of Applied Tumor Biology, Institute of Pathology, University 
Hospital Heidelberg, Clinical Cooperation Unit (CCU 105) of the German Cancer 
Research Center and Molecular Medicine Partner Unit (MMPU) of the European 
Molecular Biology Laboratory, Im Neuenheimer Feld 224, 69120 Heidelberg, 
Germany. Electronic address: Magnus.Knebel-Doeberitz@med.uni-heidelberg.de.

Deficient DNA mismatch repair (MMR) boosts the accumulation of frameshift 
mutations in genes encompassing coding microsatellites (cMS). This results in 
the translation of proteins with mutation-induced frameshift peptides 
(neoantigens) rendering microsatellite-unstable (MSI) cancers highly 
immunogenic. MSI cancers express a defined set of neoantigens resulting from 
functionally relevant driver mutations, which are shared by most MSI cancers. 
Patients with MSI cancers and healthy individuals affected by Lynch syndrome, an 
inherited predisposition for MSI cancers, develop specific immune responses 
against these neoantigens. In this review, we summarize our current 
understanding of the immune biology of MSI cancers and outline new concepts and 
research directions to develop not only therapeutic treatments, but also 
preventive vaccines based on the MSI cancer genome landscapes.

Copyright © 2016 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.trecan.2016.02.004
PMID: 28741532 [Indexed for MEDLINE]


170. BMC Health Serv Res. 2019 Jan 21;19(1):54. doi: 10.1186/s12913-018-3864-5.

Does a transition to accountable care in Medicaid shift the modality of 
colorectal cancer testing?

Davis MM(1), Shafer P(2), Renfro S(3), Hassmiller Lich K(2), Shannon J(4), 
Coronado GD(5), McConnell KJ(3), Wheeler SB(6).

Author information:
(1)Department of Family Medicine, OHSU-PSU School of Public Health, and Oregon 
Rural Practice-based Research Network, Oregon Health & Science University, 3181 
SW Sam Jackson Park Road, Mail Code L222, Portland, OR, 97239, USA. 
davismel@ohsu.edu.
(2)Department of Health Policy & Management, University of North Carolina at 
Chapel Hill, Chapel Hill, NC, USA.
(3)Center for Health Systems Effectiveness, Oregon Health & Science University, 
3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
(4)OHSU-PSU School of Public Health, Oregon Health & Science University, 3181 SW 
Sam Jackson Park Road, Portland, OR, 97239, USA.
(5)Center for Health Research Northwest, Kaiser Permanente, 3800 N. Interstate 
Avenue, Portland, OR, 97227-1098, USA.
(6)Department of Health Policy & Management, Lineberger Comprehensive Cancer 
Center, and Center for Health Promotion & Disease Prevention, University of 
North Carolina at Chapel Hill, Chapel Hill, NC, USA.

BACKGROUND: Health care reform is changing preventive services delivery. This 
study explored trajectories in colorectal cancer (CRC) testing over a 5-year 
period that included implementation of 16 Medicaid Accountable Care 
Organizations (ACOs, 2012) and Medicaid expansion (2014) - two provisions of the 
Affordable Care Act (ACA) - within the state of Oregon, USA.
METHODS: Retrospective analysis of Oregon's Medicaid claims for enrollee's 
eligible for CRC screening (50-64 years) spanning January 2010 through December 
2014. Our analysis was conducted and refined April 2016 through June 2018. The 
analysis assessed the annual probability of patients receiving CRC testing and 
the modality used (e.g., colonoscopy, fecal testing) relative to a baseline year 
(2010). We hypothesized that CRC testing would increase following Medicaid ACO 
formation - called Coordinated Care Organizations (CCOs).
RESULTS: A total of 132,424 unique Medicaid enrollees (representing 255,192 
person-years) met inclusion criteria over the 5-year study. Controlling for 
demographic and regional factors, the predicted probability of CRC testing was 
significantly higher in 2014 (+ 1.4 percentage points, p < 0.001) compared to 
the 2010 baseline but not in 2012 or 2013. Increased fecal testing using Fecal 
Occult Blood Tests (FOBT) or Fecal Immunochemical Tests (FIT) played a prominent 
role in 2014. The uptick in statewide fecal testing appears driven primarily by 
a subset of CCOs.
CONCLUSIONS: Observed CRC testing did not immediately increase following the 
transition to CCOs in 2012. However increased testing in 2014, may reflect a 
delay in implementation of interventions to increase CRC screening and/or a 
strong desire by newly insured Medicaid CCO members to receive preventive care.

DOI: 10.1186/s12913-018-3864-5
PMCID: PMC6341697
PMID: 30665396 [Indexed for MEDLINE]

Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The 
study was approved by the Oregon Health & Science University Institutional 
Review Board with a waiver of informed consent (IRB #8865). CONSENT FOR 
PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they 
have no competing interests. PUBLISHER’S NOTE: Springer Nature remains neutral 
with regard to jurisdictional claims in published maps and institutional 
affiliations.


171. Sci Rep. 2017 Nov 30;7(1):16618. doi: 10.1038/s41598-017-16747-x.

CMScaller: an R package for consensus molecular subtyping of colorectal cancer 
pre-clinical models.

Eide PW(1)(2)(3), Bruun J(1)(2), Lothe RA(1)(2)(3), Sveen A(4)(5).

Author information:
(1)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, Oslo, NO-0424, Norway.
(2)K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, 
Oslo, NO-0424, Norway.
(3)Institute for Clinical Medicine, University of Oslo, Oslo, NO-0318, Norway.
(4)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, Oslo, NO-0424, Norway. anita.sveen@rr-research.no.
(5)K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, 
Oslo, NO-0424, Norway. anita.sveen@rr-research.no.

Colorectal cancers (CRCs) can be divided into four gene expression-based 
biologically distinct consensus molecular subtypes (CMS). This classification 
provides a potential framework for stratified treatment, but to identify novel 
CMS-drug associations, translation of the subtypes to pre-clinical models is 
essential. The currently available classifier is dependent on gene expression 
signals from the immune and stromal compartments of tumors and fails to identify 
the poor-prognostic CMS4-mesenchymal group in immortalized cell lines, 
patient-derived organoids and xenografts. To address this, we present a novel 
CMS classifier based on a filtered set of cancer cell-intrinsic, 
subtype-enriched gene expression markers. This new classifier, referred to as 
CMScaller, recapitulated the subtypes in both in vitro and in vivo models 
(551 in total). Importantly, by analyzing public drug response data from 
patient-derived xenografts and cell lines, we show that the subtypes are 
predictive of response to standard CRC drugs. CMScaller is available as an R 
package.

DOI: 10.1038/s41598-017-16747-x
PMCID: PMC5709354
PMID: 29192179 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that they have no competing 
interests.


172. Cancers (Basel). 2022 Mar 11;14(6):1451. doi: 10.3390/cancers14061451.

Ras Pathway Activation and MEKi Resistance Scores Predict the Efficiency of MEKi 
and SRCi Combination to Induce Apoptosis in Colorectal Cancer.

Davis TB(1), Gupta S(1), Yang M(1), Pflieger L(2), Rajan M(1), Wang H(1), Thota 
R(3), Yeatman TJ(1)(4), Pledger WJ(1)(4).

Author information:
(1)Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA.
(2)Precision Genomics Translational Science Center, Intermountain Healthcare, 
Murray, UT 84107, USA.
(3)Oncology Clinical Program, Intermountain Healthcare, Murray, UT 84107, USA.
(4)Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Colorectal cancer (CRC) is the second leading cause of cancer death in the 
United States. The RAS pathway is activated in more than 55% of CRC and has been 
targeted for therapeutic intervention with MEK inhibitors. Unfortunately, many 
patients have de novo resistance, or can develop resistance to this new class of 
drugs. We have hypothesized that much of this resistance may pass through SRC as 
a common signal transduction node, and that inhibition of SRC may suppress MEK 
inhibition resistance mechanisms. CRC tumors of the Consensus Molecular Subtype 
(CMS) 4, enriched in stem cells, are difficult to successfully treat and have 
been suggested to evade traditional chemotherapy agents through resistance 
mechanisms. Here, we evaluate targeting two pathways simultaneously to produce 
an effective treatment by overcoming resistance. We show that combining 
Trametinib (MEKi) with Dasatinib (SRCi) provides enhanced cell death in 8 of the 
16 tested CRC cell lines compared to treatment with either agent alone. To be 
able to select sensitive cells, we simultaneously evaluated a validated 18-gene 
RAS pathway activation signature score along with a 13-gene MEKi resistance 
signature score, which we hypothesize predict tumor sensitivity to this dual 
targeted therapy. We found the cell lines that were sensitive to the dual 
treatment were predominantly CMS4 and had both a high 18-gene and a high 13-gene 
score, suggesting these cell lines had potential for de novo MEKi sensitivity 
but were subject to the rapid development of MEKi resistance. The 13-gene score 
is highly correlated to a score for SRC activation, suggesting resistance is 
dependent on SRC. Our data show that gene expression signature scores for RAS 
pathway activation and for MEKi resistance may be useful in determining which 
CRC tumors will respond to the novel drug combination of MEKi and SRCi.

DOI: 10.3390/cancers14061451
PMCID: PMC8945886
PMID: 35326598

Conflict of interest statement: The authors declare no conflict of interest.


173. Carcinogenesis. 2020 Sep 24;41(9):1219-1228. doi: 10.1093/carcin/bgaa072.

Evaluation of an aldo-keto reductase gene signature with prognostic significance 
in colon cancer via activation of epithelial to mesenchymal transition and the 
p70S6K pathway.

Demirkol Canlı S(1), Seza EG(2), Sheraj I(2), Gömçeli I(3), Turhan N(4), 
Carberry S(5), Prehn JHM(5), Güre AO(6), Banerjee S(2)(7).

Author information:
(1)Molecular Pathology Application and Research Center, Hacettepe University, 
Ankara, Turkey.
(2)Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, 
Turkey.
(3)Department of Gastroenterological Surgery, Antalya Education and Research 
Hospital, Antalya, Turkey.
(4)Department of Pathology, Ankara City Hospital, University of Health Science, 
Ankara, Turkey.
(5)Department of Physiology and Medical Physics, Centre for Systems Medicine, 
Royal College of Surgeons in Ireland, Dublin, Ireland.
(6)Department of Molecular Biology and Genetics, Bilkent University, Ankara, 
Turkey.
(7)Cancer Systems Biology Laboratory (CanSyl) Orta Dogu Teknik Universitesi, 
Ankara, Turkey.

AKR1B1 and AKR1B10, members of the aldo-keto reductase family of enzymes that 
participate in the polyol pathway of aldehyde metabolism, are aberrantly 
expressed in colon cancer. We previously showed that high expression of AKR1B1 
(AKR1B1HIGH) was associated with enhanced motility, inflammation and poor 
clinical outcome in colon cancer patients. Using publicly available datasets and 
ex vivo gene expression analysis (n = 51, Ankara cohort), we have validated our 
previous in silico finding that AKR1B1HIGH was associated with worse overall 
survival (OS) compared with patients with low expression of AKR1B1 (AKR1B1LOW) 
samples. A combined signature of AKR1B1HIGH and AKR1B10LOW was significantly 
associated with worse recurrence-free survival (RFS) in microsatellite stable 
(MSS) patients and in patients with distal colon tumors as well as a higher 
mesenchymal signature when compared with AKR1B1LOW/AKR1B10HIGH tumors. When the 
patients were stratified according to consensus molecular subtypes (CMS), 
AKR1B1HIGH/AKR1B10LOW samples were primarily classified as CMS4 with 
predominantly mesenchymal characteristics while AKR1B1LOW/AKR1B10HIGH samples 
were primarily classified as CMS3 which is associated with metabolic 
deregulation. Reverse Phase Protein Array carried out using protein samples from 
the Ankara cohort indicated that AKR1B1HIGH/AKR1B10LOW tumors showed aberrant 
activation of metabolic pathways. Western blot analysis of AKR1B1HIGH/AKR1B10LOW 
colon cancer cell lines also suggested aberrant activation of nutrient-sensing 
pathways. Collectively, our data suggest that the AKR1B1HIGH/AKR1B10LOW 
signature may be predictive of poor prognosis, aberrant activation of metabolic 
pathways, and can be considered as a novel biomarker for colon cancer 
prognostication.

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. 
For Permissions, please email: journals.permissions@oup.com.

DOI: 10.1093/carcin/bgaa072
PMID: 32628753 [Indexed for MEDLINE]


174. Cancers (Basel). 2021 Apr 17;13(8):1943. doi: 10.3390/cancers13081943.

PD-L1 as a Prognostic Factor in Early-Stage Colon Carcinoma within the 
Immunohistochemical Molecular Subtype Classification.

Azcue P(1), Encío I(1)(2), Guerrero Setas D(3)(4)(5)(6), Suarez Alecha J(7), 
Galbete A(2)(4)(8), Mercado M(3), Vera R(2)(6), Gomez-Dorronsoro ML(2)(3).

Author information:
(1)Department of Health Science, Public University of Navarra (UPNA), 31008 
Pamplona, Spain.
(2)Institute for Health Research Navarra (IdISNA), 31008 Pamplona, Spain.
(3)Department of Molecular Pathology, Hospital Complex of Navarra (CHN), 31008 
Pamplona, Spain.
(4)Campus Arrosadia, Public University of Navarra (UPNA), 31006 Pamplona, Spain.
(5)Molecular Pathology of Cancer Group-Navarrabiomed, 31008 Pamplona, Spain.
(6)Department of Medical Oncology, Hospital Complex of Navarra (CHN), 31008 
Pamplona, Spain.
(7)Department of Surgery, Hospital Complex of Navarra (CHN), 31008 Pamplona, 
Spain.
(8)Navarrabiomed-Hospital Complex of Navarra (CHN), Redissec, 31008 Pamplona, 
Spain.

BACKGROUND: There is a patent need to better characterize early-stage colorectal 
cancer (CRC) patients. PD-1 ligand (PD-L1) expression has been proposed as a 
prognostic factor but yields mixed results in different settings. The Consensus 
Molecular Subtype (CMS) classification has yet to be integrated into clinical 
practice. We sought to evaluate the prognostic value of PD-L1 expression overall 
and within CMS in early-stage colon cancer patients, in the hope of assisting 
treatment choice in this setting.
METHODS: Tissue-microarrays were constructed from tumor samples of 162 stage 
II/III CRC patients. They underwent automatic immunohistochemical staining for 
PD-L1 and the proposed CMS panel. Primary endpoints were overall survival (OS) 
and disease-free survival (DFS).
RESULTS: PD-L1 expression was significantly and independently associated with 
better prognosis (HR = 0.46 (0.26-0.82), p = 0.009) and was mostly seen in 
immune cells of the tumor-related stroma. CMS4 five-folds the risk of 
mortalitycompared with CMS1 (HR = 5.58 (1.36, 22.0), p = 0.034). In the subgroup 
CMS2/CMS3 analysis, PD-L1 expression significantly differentiated individuals 
with better OS (p = 0.004) and DFS (p < 0.001).
CONCLUSIONS: Our study suggests that PD-L1 expression is an independent 
prognostic factor in patients with stage II/III colon cancer. Additionally, it 
successfully differentiates patients with better prognosis in the CMS2/CMS3 
group and may prove significant for the clinical relevance of the CMS 
classification.

DOI: 10.3390/cancers13081943
PMCID: PMC8073668
PMID: 33920689

Conflict of interest statement: P.A. is an employee of Servier Medical Affairs, 
although there were no affiliations or financial involvement with this or any 
other organization or entity, with financial or scientific interest, with the 
subject matter or materials discussed in the manuscript. All other authors 
declare no conflicts of interest. The funders had no role in the design of the 
study, in the collection, analyses, or interpretation of data, in the writing of 
the manuscript, or in the decision to publish the results.


175. Exp Mol Med. 2019 Oct 2;51(10):1-12. doi: 10.1038/s12276-019-0319-y.

A prognostic index based on an eleven gene signature to predict systemic 
recurrences in colorectal cancer.

Kim SK(#)(1)(2), Kim SY(#)(3), Kim CW(2)(4), Roh SA(2)(4), Ha YJ(2)(4), Lee 
JL(2)(4), Heo H(1), Cho DH(2)(5), Lee JS(6), Kim YS(7)(8), Kim JC(9)(10).

Author information:
(1)Personalized Genomic Medicine Research Center, Korea Research Institute of 
Bioscience and Biotechnology, Daejeon, 34141, Korea.
(2)Department of Cancer Research, Institute of Innovative Cancer Research and 
Asan Institute for Life Sciences, Asan Medical Center, Seoul, 05505, Korea.
(3)Genome Editing Research Center, Korea Research Institute of Bioscience and 
Biotechnology, Daejeon, 34141, Korea.
(4)Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea.
(5)Graduate School of Life Sciences, Kyungpook National University, 41566, 
Daegu, Korea.
(6)Department of Systems Biology, Division of Cancer Medicine, The University of 
Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
(7)Department of Cancer Research, Institute of Innovative Cancer Research and 
Asan Institute for Life Sciences, Asan Medical Center, Seoul, 05505, Korea. 
yongsung@kribb.re.kr.
(8)Genome Editing Research Center, Korea Research Institute of Bioscience and 
Biotechnology, Daejeon, 34141, Korea. yongsung@kribb.re.kr.
(9)Department of Cancer Research, Institute of Innovative Cancer Research and 
Asan Institute for Life Sciences, Asan Medical Center, Seoul, 05505, Korea. 
jckim@amc.seoul.kr.
(10)Department of Surgery, University of Ulsan College of Medicine, Seoul, 
Korea. jckim@amc.seoul.kr.
(#)Contributed equally

Approximately half of colorectal cancer (CRC) patients experience disease 
recurrence and metastasis, and these individuals frequently fail to respond to 
treatment due to their clinical and biological diversity. Here, we aimed to 
identify a prognostic signature consisting of a small gene group for precisely 
predicting CRC heterogeneity. We performed transcriptomic profiling using 
RNA-seq data generated from the primary tissue samples of 130 CRC patients. A 
prognostic index (PI) based on recurrence-associated genes was developed and 
validated in two larger independent CRC patient cohorts (n = 795). The 
association between the PI and prognosis of CRC patients was evaluated using 
Kaplan-Meier plots, log-rank tests, a Cox regression analysis and a RT-PCR 
analysis. Transcriptomic profiling in 130 CRC patients identified two distinct 
subtypes associated with systemic recurrence. Pathway enrichment and RT-PCR 
analyses revealed an eleven gene signature incorporated into the PI system, 
which was a significant prognostic indicator of CRC. Multivariate and subset 
analyses showed that PI was an independent risk factor (HR = 1.812, 95% 
CI = 1.342-2.448, P < 0.001) with predictive value to identify low-risk stage II 
patients who responded the worst to adjuvant chemotherapy. Finally, a 
comparative analysis with previously reported Consensus Molecular Subgroup 
(CMS), high-risk patients classified by the PI revealed a distinct molecular 
property similar to CMS4, associated with a poor prognosis. This novel PI 
predictor based on an eleven gene signature likely represents a surrogate 
diagnostic tool for identifying high-risk CRC patients and for predicting the 
worst responding patients for adjuvant chemotherapy.

DOI: 10.1038/s12276-019-0319-y
PMCID: PMC6802642
PMID: 31578316 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that they have no conflict 
of interest.


176. Int J Cancer. 2020 Oct 1;147(7):2007-2018. doi: 10.1002/ijc.32993. Epub 2020 May 
22.

Molecular description of ANGPT2 associated colorectal carcinoma.

Jary M(1)(2)(3), Hasanova R(1), Vienot A(1)(2), Asgarov K(1), Loyon R(1)(2), 
Tirole C(2), Bouard A(1), Orillard E(1)(2), Klajer E(2), Kim S(2)(3), Viot 
J(1)(2), Colle E(4), Adotevi O(1)(2), Bouché O(5), Lecomte T(6)(7), Borg 
C(1)(2)(3), Feugeas JP(1).

Author information:
(1)INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, 
Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, 
France.
(2)Department of Medical Oncology, University Hospital of Besançon, Besançon, 
France.
(3)Clinical Investigation Center in Biotherapy, INSERM CIC-BT1431, University 
Hospital of Besançon, Besançon, France.
(4)University Hospital St-Antoine, Paris, France.
(5)Department of Hepato-Gastroenterology and Digestive Oncology, University 
Hospital Robert Debré, Reims, France.
(6)Department of Hepato-Gastroenterology and Digestive Oncology, CHRU de Tours, 
Tours Cedex 09, France.
(7)University of Tours, Tours Cedex 01, France.

Angiopoietin-2 (ANGPT2) is a prognostic factor in metastatic colorectal cancer 
(CRC). Nevertheless, it remains to be elucidated which molecular characteristics 
make up the ANGPT2-related poor-prognosis CRC subset. Public transcriptomic 
datasets were collected from Gene Expression Omnibus GEO and with the 
TCGAbiolinks R-package for the TCGA. After appropriate normalization, 
differential expression analysis was performed using Benjamini and Hochberg 
method for false discovery rate. Plasma from two prospective clinical trials 
were used to investigate the clinical impact of ANGPT2-related biomarkers. In 
the 935 samples included in four annotated platforms (GPL) and derived from 
localized CRC, ANGPT2hi expression conferred a worst overall survival (HR = 
1.20; p = 0.02). CRC stage, ANGPT2hi expression but not Consortium Molecular 
Subtype (CMS) predict overall survival in multivariate analysis. ANGPT2 
expression was not correlated with a specific CMS nor to RAS, RAF, MSI, p53, 
CIN, CIMP genomic alterations. Gene expression analysis revealed that ANGPT2hi 
CRC subset is characterized by angiogenesis-related gene expression, presence of 
myeloid cells, stromal organization and resistance to chemotherapy. A prognostic 
model was proposed using seric levels of ANGPT2, STC1 and CD138 in 97 mCRC 
patients. Our results provide evidence that ANGPT2 is a prognostic factor in 
localized CRC and defined a specific CRC subset with potential clinical 
implementation.

© 2020 UICC.

DOI: 10.1002/ijc.32993
PMID: 32222972 [Indexed for MEDLINE]


177. Ann Oncol. 2017 May 1;28(5):1032-1035. doi: 10.1093/annonc/mdx066.

CDX2 prognostic value in stage II/III resected colon cancer is related to CMS 
classification.

Pilati C(1), Taieb J(2), Balogoun R(1), Marisa L(3), de Reyniès A(3), 
Laurent-Puig P(1).

Author information:
(1)Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, INSERM 
UMR-S1147, Université Paris Descartes, Paris.
(2)Department of Hepatogastroenterology and Gastrointestinal Oncology, Georges 
Pompidou Hospital, Assistance Publique-Hopitaux de Paris, Université Paris 
Descartes, Paris.
(3)Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le 
Cancer, Paris, France.

BACKGROUND: Caudal-type homeobox transcription factor 2 (CDX2) is involved in 
colon cancer (CC) oncogenesis and has been proposed as a prognostic biomarker in 
patients with stage II or III CC.
PATIENTS AND METHODS: We analyzed CDX2 expression in a series of 469 CC typed 
for the new international consensus molecular subtype (CMS) classification, and 
we confirmed results in a series of 90 CC.
RESULTS: Here, we show that lack of CDX2 expression is only present in the 
mesenchymal subgroup (CMS4) and in MSI-immune tumors (CMS1) and not in CMS2 and 
CMS3 colon cancer. Although CDX2 expression was a globally independent 
prognostic factor, loss of CDX2 expression is not associated with a worse 
prognosis in the CMS1 group, but is highly prognostic in CMS4 patients for both 
relapse free and overall survival. Similarly, lack of CDX2 expression was a bad 
prognostic factor in MSS patients, but not in MSI.
CONCLUSIONS: Our work suggests that combination of the consensual CMS 
classification and lack of CDX2 expression could be a useful marker to identify 
CMS4/CDX2-negative patients with a very poor prognosis.

© The Author 2017. Published by Oxford University Press on behalf of the 
European Society for Medical Oncology. All rights reserved. For permissions, 
please email: journals.permissions@oup.com.

DOI: 10.1093/annonc/mdx066
PMID: 28328000 [Indexed for MEDLINE]


178. J Natl Cancer Inst. 2010 Aug 18;102(16):1238-52. doi: 10.1093/jnci/djq242. Epub 
2010 Jul 27.

Cost-effectiveness of computed tomographic colonography screening for colorectal 
cancer in the medicare population.

Knudsen AB(1), Lansdorp-Vogelaar I, Rutter CM, Savarino JE, van Ballegooijen M, 
Kuntz KM, Zauber AG.

Author information:
(1)Institute for Technology Assessment, Massachusetts General Hospital, 101 
Merrimac St, 10th Floor, Boston, MA 02114. aknudsen@mgh-ita.org.

Comment in
    J Natl Cancer Inst. 2010 Aug 18;102(16):1212-4.
    J Natl Cancer Inst. 2010 Nov 3;102(21):1676; author reply 1676-7.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) considered 
whether to reimburse computed tomographic colonography (CTC) for colorectal 
cancer screening of Medicare enrollees. To help inform its decision, we 
evaluated the reimbursement rate at which CTC screening could be cost-effective 
compared with the colorectal cancer screening tests that are currently 
reimbursed by CMS and are included in most colorectal cancer screening 
guidelines, namely annual fecal occult blood test (FOBT), flexible sigmoidoscopy 
every 5 years, flexible sigmoidoscopy every 5 years in conjunction with annual 
FOBT, and colonoscopy every 10 years.
METHODS: We used three independently developed microsimulation models to assess 
the health outcomes and costs associated with CTC screening and with currently 
reimbursed colorectal cancer screening tests among the average-risk Medicare 
population. We assumed that CTC was performed every 5 years (using test 
characteristics from either a Department of Defense CTC study or the National 
CTC Trial) and that individuals with findings of 6 mm or larger were referred to 
colonoscopy. We computed incremental cost-effectiveness ratios for the currently 
reimbursed screening tests and calculated the maximum cost per scan (ie, the 
threshold cost) for the CTC strategy to lie on the efficient frontier. 
Sensitivity analyses were performed on key parameters and assumptions.
RESULTS: Assuming perfect adherence with all tests, the undiscounted number 
life-years gained from CTC screening ranged from 143 to 178 per 1000 
65-year-olds, which was slightly less than the number of life-years gained from 
10-yearly colonoscopy (152-185 per 1000 65-year-olds) and comparable to that 
from 5-yearly sigmoidoscopy with annual FOBT (149-177 per 1000 65-year-olds). If 
CTC screening was reimbursed at $488 per scan (slightly less than the 
reimbursement for a colonoscopy without polypectomy), it would be the most 
costly strategy. CTC screening could be cost-effective at $108-$205 per scan, 
depending on the microsimulation model used. Sensitivity analyses showed that if 
relative adherence to CTC screening was 25% higher than adherence to other 
tests, it could be cost-effective if reimbursed at $488 per scan.
CONCLUSIONS: CTC could be a cost-effective option for colorectal cancer 
screening among Medicare enrollees if the reimbursement rate per scan is 
substantially less than that for colonoscopy or if a large proportion of 
otherwise unscreened persons were to undergo screening by CTC.

DOI: 10.1093/jnci/djq242
PMCID: PMC2923219
PMID: 20664028 [Indexed for MEDLINE]


179. J Agric Food Chem. 2017 Sep 13;65(36):7966-7981. doi: 10.1021/acs.jafc.7b03093. 
Epub 2017 Aug 29.

Chitosan-Coated Cinnamon/Oregano-Loaded Solid Lipid Nanoparticles to Augment 
5-Fluorouracil Cytotoxicity for Colorectal Cancer: Extract Standardization, 
Nanoparticle Optimization, and Cytotoxicity Evaluation.

Kamel KM, Khalil IA(1), Rateb ME(2)(3), Elgendy H, Elhawary S(4).

Author information:
(1)Nanomaterials Lab., Center of Material Science (CMS), Zewail City of Science 
and Technology , 6th of October, Giza 12588, Egypt.
(2)School of Science & Sport, University of the West of Scotland , Paisley PA1 
2BE, Scotland U.K.
(3)Pharmacognosy Department, Faculty of Pharmacy, Beni-Suef University , 
Beni-Suef 62511, Egypt.
(4)Pharmacognosy Department, Faculty of Pharmacy, Cairo University , Cairo, 
Egypt.

This study aimed to coat lipid-based nanocarriers with chitosan to encapsulate 
nutraceuticals, minimize opsonization, and facilitate passive-targeting. Phase 
one was concerned with standardization according to the World Health 
Organization. Qualitative analysis using liquid chromatography-high-resolution 
mass spectrometry (LC-HRMS/MS) investigated the active constituents, especially 
reported cytotoxic agents. Cinnamaldehyde and rosmarinic acid were selected to 
be quantified using high-performance liquid chromatography. Phase two was aimed 
to encapsulate both extracts in solid lipid nanoparticles (core) and chitosan 
(shell) to gain the advantages of both materials properties. The developed 
experimental model suggested an optimum formulation with 2% lipid, 2.3% 
surfactant, and 0.4% chitosan to achieve a particle size of 254.77 nm, 
polydispersity index of 0.28, zeta potential of +15.26, and entrapment 
efficiency percentage of 77.3% and 69.1% for cinnamon and oregano, respectively. 
Phase three was focused on the evaluation of cytotoxic activity 
unencapsulated/encapsulated cinnamon and oregano extracts with/without 
5-fluorouracil on HCT-116 cells. This study confirmed the success of the 
suggested combination with 5-fluorouracil for treating human colon carcinoma 
with a low dose leading to decreasing side effects and allowing uninterrupted 
therapy.

DOI: 10.1021/acs.jafc.7b03093
PMID: 28813148 [Indexed for MEDLINE]


180. Br J Cancer. 2022 Mar 16. doi: 10.1038/s41416-022-01748-z. Online ahead of 
print.

Fibroblast activation protein identifies Consensus Molecular Subtype 4 in 
colorectal cancer and allows its detection by (68)Ga-FAPI-PET imaging.

Strating E(1), Wassenaar E(1)(2), Verhagen M(3), Rauwerdink P(1)(2), van 
Schelven S(1), de Hingh I(4), Rinkes IB(1), Boerma D(2), Witkamp A(1), Lacle 
M(5), Fodde R(3), Volckmann R(6), Koster J(6), Stedingk K(6), Giesel F(7)(8), de 
Roos R(9), Poot A(9), Bol G(10), Lam M(11), Elias S(12), Kranenburg O(13)(14).

Author information:
(1)Department of Surgical Oncology, Lab Translational Oncology, University 
Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
(2)Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.
(3)Department of Pathology, Erasmus MC, Rotterdam, Netherlands.
(4)Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands.
(5)Department of Pathology, University Medical Center Utrecht, Utrecht 
University, Utrecht, The Netherlands.
(6)Department of Oncogenomics, Amsterdam University Medical Center, Amsterdam, 
The Netherlands.
(7)Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, 
Germany.
(8)Department of Nuclear Medicine, Medical Faculty, Heinrich-Heine-University, 
University Hospital Dusseldorf, Dusseldorf, Germany.
(9)Department of Radiology, University Medical Center Utrecht, Utrecht 
University, Utrecht, The Netherlands.
(10)Department of Medical Oncology, University Medical Center Utrecht, Utrecht 
University, Utrecht, The Netherlands.
(11)Department of Radiology, University Medical Center Utrecht, Utrecht 
University, Utrecht, The Netherlands. m.lam@umcutrecht.nl.
(12)Department of Epidemiology, Julius Center for Health Sciences and Primary 
Care, University Medical Center Utrecht, Utrecht University, Utrecht, The 
Netherlands. s.elias@umcutrecht.nl.
(13)Department of Surgical Oncology, Lab Translational Oncology, University 
Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 
o.kranenburg@umcutrecht.nl.
(14)Utrecht Platform for Organoid Technology, Utrecht University, Utrecht, The 
Netherlands. o.kranenburg@umcutrecht.nl.

BACKGROUND: In colorectal cancer (CRC), the consensus molecular subtype 4 (CMS4) 
is associated with therapy resistance and poor prognosis. Clinical diagnosis of 
CMS4 is hampered by locoregional and temporal variables influencing CMS 
classification. Diagnostic tools that comprehensively detect CMS4 are therefore 
urgently needed.
METHODS: To identify targets for molecular CMS4 imaging, RNA sequencing data of 
3232 primary CRC patients were explored. Heterogeneity of marker expression in 
relation to CMS4 status was assessed by analysing 3-5 tumour regions and 91.103 
single-tumour cells (7 and 29 tumours, respectively). Candidate marker 
expression was validated in CMS4 peritoneal metastases (PM; n = 59). Molecular 
imaging was performed using the 68Ga-DOTA-FAPI-46 PET tracer.
RESULTS: Fibroblast activation protein (FAP) mRNA identified CMS4 with very high 
sensitivity and specificity (AUROC > 0.91), and was associated with 
significantly shorter relapse-free survival (P = 0.0038). Heterogeneous 
expression of FAP among and within tumour lesions correlated with CMS4 
heterogeneity (AUROC = 1.00). FAP expression was homogeneously high in PM, a 
near-homogeneous CMS4 entity. FAPI-PET identified focal and diffuse PM that were 
missed using conventional imaging. Extra-peritoneal metastases displayed 
extensive heterogeneity of tracer uptake.
CONCLUSION: FAP expression identifies CMS4 CRC. FAPI-PET may have value in the 
comprehensive detection of CMS4 tumours in CRC. This is especially relevant in 
patients with PM, for whom effective imaging tools are currently lacking.

© 2022. The Author(s).

DOI: 10.1038/s41416-022-01748-z
PMID: 35296803


181. Mol Oncol. 2022 Mar 17. doi: 10.1002/1878-0261.13210. Online ahead of print.

Development of a miRNA-based classifier for detection of colorectal cancer 
molecular subtypes.

Adam RS(1)(2), Poel D(3), Ferreira Moreno L(1)(2), Spronck JMA(1)(2), de Back 
TR(1)(2), Torang A(1)(2), Gomez Barila PM(1)(2), Ten Hoorn S(1)(2), Markowetz 
F(4), Wang X(5)(6), Verheul HMW(3), Buffart TE(1)(7), Vermeulen L(1)(2).

Author information:
(1)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental and Molecular Medicine (CEMM), Cancer Center Amsterdam and 
Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, 
The Netherlands.
(2)Oncode Institute, Amsterdam, The Netherlands.
(3)Department of Medical Oncology, Radboud University Medical Center, Nijmegen, 
The Netherlands.
(4)Cancer Research UK Cambridge Institute, University of Cambridge, UK.
(5)Department of Biomedical Sciences, City University of Hong Kong, Kowloon 
Tong, Hong Kong.
(6)Shenzhen Research Institute, City University of Hong Kong, Shenzhen, China.
(7)Department of Gastrointestinal Oncology, Netherlands Cancer Institute, 
Amsterdam, The Netherlands.

Previously, colorectal cancer (CRC) has been classified into four distinct 
molecular subtypes based on transcriptome data. These consensus molecular 
subtypes (CMSs) have implications for our understanding of tumor heterogeneity 
and the prognosis of patients. So far, this classification has been based on the 
use of messenger RNAs (mRNAs), although microRNAs (miRNAs) have also been shown 
to play a role in tumor heterogeneity and biological differences between CMSs. 
In contrast to mRNAs, miRNAs have a smaller size and increased stability, 
facilitating their detection. Therefore, we built a miRNA-based CMS classifier 
by converting the existing mRNA-based CMS classification using machine learning 
(training dataset of n = 271). The performance of this miRNA-assigned CMS 
classifier (CMS-miRaCl) was evaluated in several datasets, achieving an overall 
accuracy of ~ 0.72 (0.6329-0.7987) in the largest dataset (n = 158). To gain 
insight into the biological relevance of CMS-miRaCl, we evaluated the most 
important features in the classifier. We found that miRNAs previously reported 
to be relevant in microsatellite-instable CRCs or Wnt signaling were important 
features for CMS-miRaCl. Following further studies to validate its robustness, 
this miRNA-based alternative might simplify the implementation of CMS 
classification in clinical workflows.

© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on 
behalf of Federation of European Biochemical Societies.

DOI: 10.1002/1878-0261.13210
PMID: 35298091


182. Support Care Cancer. 2012 Sep;20(9):2089-96. doi: 10.1007/s00520-011-1318-2. 
Epub 2011 Dec 11.

Hematologic outcomes and blood utilization in cancer patients with 
chemotherapy-induced anemia (CIA) pre- and post-national coverage determination 
(NCD): results from a multicenter chart review.

Henry DH(1), Langer CJ, McKenzie RS, Piech CT, Senbetta M, Schulman KL, 
Stepanski EJ.

Author information:
(1)Joan Karnell Cancer Center, Pennsylvania Hospital, Philadelphia, PA 19106, 
USA. dhhenry@juno.com

PURPOSE: In July 2007, the Centers for Medicare and Medicaid Services (CMS) 
limited coverage of erythropoiesis-stimulating agents (ESAs) in cancer patients 
with chemotherapy-induced anemia (CIA) through a National Coverage Determination 
(NCD). The primary objective of this study was to compare transfusion rates in 
patients with CIA with lung, breast, or colorectal cancer before and after the 
NCD.
METHODS: Adult Medicare patients with CIA treated at 49 community oncology 
clinics were selected from two time periods based on clinics' NCD implementation 
date. Chart data were abstracted for 12 weeks post-CIA episode start, defined as 
hemoglobin (Hb) level <11 g/dL while receiving chemotherapy or within 60 days of 
the last chemotherapy dose. Multivariate analyses were used to calculate the 
odds of transfusion and to assess the units of blood transfused, controlling for 
differences in demographics, clinical history, and chemotherapy.
RESULTS: Eight hundred pre-NCD and 994 post-NCD patients from 49 sites were 
selected. Of the patients, 56% used ESAs post-NCD vs. 88% pre-NCD (p < 0.0001). 
The duration of ESA use decreased in the post-NCD (32.1 days) vs. pre-NCD (48.4 
days, p < 0.0001) group. The post-NCD group reported significantly lower Hb 
levels, higher odds of receiving a transfusion (odds ratio: 1.41, 95% CI 
1.05-1.89, p = 0.0238) and increased blood utilization of 53% (units transfused: 
OR 1.53, 95% CI 1.15-2.04, p = 0.0034).
CONCLUSIONS: Decreased frequency and duration of ESA administration were 
reported in the post-NCD vs. pre-NCD period. Findings were accompanied by a 
modest but statistically significant increase in transfusions and a decrease in 
Hb values.

DOI: 10.1007/s00520-011-1318-2
PMID: 22160485 [Indexed for MEDLINE]


183. Sci Rep. 2016 Nov 16;6:37169. doi: 10.1038/srep37169.

Colon cancer subtypes: concordance, effect on survival and selection of the most 
representative preclinical models.

Sztupinszki Z(1)(2), Győrffy B(1)(2).

Author information:
(1)MTA TTK Lendület Cancer Biomarker Research Group, 1117, Budapest, Hungary.
(2)2nd Dept. of Pediatrics, Semmelweis University, 1094, Budapest, Hungary.

Multiple gene-expression-based subtypes have been proposed for the molecular 
subdivision of colon cancer in the last decade. We aimed to cross-validate these 
classifiers to explore their concordance and their power to predict survival. A 
gene-chip-based database comprising 2,166 samples from 12 independent datasets 
was set up. A total of 22 different molecular subtypes were re-trained including 
the CCHS, CIN25, CMS, ColoGuideEx, ColoGuidePro, CRCassigner, MDA114, Meta163, 
ODXcolon, Oncodefender, TCA19, and V7RHS classifiers as well as subtypes 
established by Budinska, Chang, DeSousa, Marisa, Merlos, Popovici, Schetter, 
Yuen, and Watanabe (first authors). Correlation with survival was assessed by 
Cox proportional hazards regression for each classifier using relapse-free 
survival data. The highest efficacy at predicting survival in stage 2-3 patients 
was achieved by Yuen (p = 3.9e-05, HR = 2.9), Marisa (p = 2.6e-05, HR = 2.6) and 
Chang (p = 9e-09, HR = 2.35). Finally, 61 colon cancer cell lines from four 
independent studies were assigned to the closest molecular subtype.

DOI: 10.1038/srep37169
PMCID: PMC5111107
PMID: 27849044 [Indexed for MEDLINE]


184. Oncogene. 2016 Nov 17;35(46):6026-6037. doi: 10.1038/onc.2016.134. Epub 2016 May 
9.

A multidimensional network approach reveals microRNAs as determinants of the 
mesenchymal colorectal cancer subtype.

Fessler E(1)(2), Jansen M(3), De Sousa E Melo F(1)(2), Zhao L(4), Prasetyanti 
PR(1)(2), Rodermond H(1)(2), Kandimalla R(1)(2), Linnekamp JF(1)(2), Franitza 
M(5)(6), van Hooff SR(1)(2), de Jong JH(1)(2), Oppeneer SC(7), van Noesel CJ(3), 
Dekker E(7), Stassi G(8), Wang X(4), Medema JP(1)(2), Vermeulen L(1).

Author information:
(1)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 
University of Amsterdam, Amsterdam, The Netherlands.
(2)Cancer Genomics Center, Utrecht, The Netherlands.
(3)Department of Pathology, AMC, University of Amsterdam, Amsterdam, The 
Netherlands.
(4)Department of Biomedical Sciences, City University of Hong Kong, Kowloon 
Tong, Hong Kong.
(5)Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
(6)Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated 
Diseases (CECAD), University of Cologne, Cologne, Germany.
(7)Department of Gastroenterology, AMC, University of Amsterdam, Amsterdam, The 
Netherlands.
(8)Cellular and Molecular Pathophysiology Laboratory, Department of Surgical and 
Oncological Sciences, University of Palermo, Palermo, Italy.

Colorectal cancer (CRC) is a heterogeneous disease posing a challenge for 
accurate classification and treatment of this malignancy. There is no common 
genetic molecular feature that would allow for the identification of patients at 
risk for developing recurrences and thus selecting patients who would benefit 
from more stringent therapies still poses a major clinical challenge. Recently, 
an international multicenter consortium (CRC Subtyping Consortium) was 
established aiming at the classification of CRC patients in biologically 
homogeneous CRC subtypes. Four consensus molecular subtypes (CMSs) were 
identified, of which the mesenchymal CMS4 presented with worse prognosis 
signifying the importance of identifying these patients. Despite the large 
number of samples analyzed and their clear association with unifying biological 
programs and clinical features, single-driver mutations could not be identified 
and patients are heterogeneous with regard to currently used clinical markers. 
We therefore set out to define the regulatory mechanisms underlying the distinct 
gene expression profiles using a network-based approach involving multiple 
molecular modalities such as gene expression, methylation levels and microRNA 
(miR) expression. The miR-200 family presented as the most powerful determinant 
of CMS4-specific gene expression, tuning the majority of genes differentially 
expressed in the poor prognosis subtype, including genes associated with the 
epithelial-mesenchymal transition program. Furthermore, our data show that two 
epigenetic marks, namely the methylation of the two miR-200 promoter regions, 
can identify tumors belonging to the mesenchymal subtype and is predictive of 
disease-free survival in CRC patients. Importantly, epigenetic silencing of the 
miR-200 family is also detected in epithelial CRC cell lines that belong to the 
mesenchymal CMS. We thus show that determining regulatory networks is a powerful 
strategy to define drivers of distinct cancer subtypes, which possess the 
ability to identify subtype affiliation and to shed light on biological 
behavior.

DOI: 10.1038/onc.2016.134
PMCID: PMC5116560
PMID: 27157610 [Indexed for MEDLINE]


185. An Med Interna. 2003 Oct;20(10):521-5.

[Prognostic significance and clinic utility of serum and immunohistochemical 
cathepsin B levels in colorectal cancer].

[Article in Spanish]

Padilla D(1), Cubo T, Molina JM, García M, De la Osa G, Palomino T, Pardo R, 
Martín J, Arévalo E, Hernández Calvo J.

Author information:
(1)Servicio de Cirugía General y del Aparato Digestivo. Complejo Hospitalario de 
Ciudad Real. Spain. maynona@terra.es

BACKGROUND: Aproximately one third of node-negative colorectal cancer recur 
suggesting the presence of micrometastasis not detected by conventional 
histopathologic methods. We think that the role of enzymes like Cathepsin B play 
in the process of invasion and metastasis in colorectal cancer might identify at 
earlier stages patients with high risk of shorter survival and who need more 
aggressive treatment. Our porpuse is to evaluate the prognostic significance of 
preoperative serum and inmunohistochemical levels of cathepsin B to identify 
colorectal carcinomas with worse prognostic.
METHODS: Fifty five patients undergoing surgical treatment for colorectal cancer 
from 1998 to 2000. As a control group sera from 23 patients with acute 
appendicitis. Serum levels of cathepsin B were obtained preoperatively (KRKA, 
Novo Slovenia;ng/ml); cathepsin B inmunoreactivity was determinated after 
surgical treatment, (C-19, Santa Cruz Biotechnology). Serum levels of CEA 
(Inmulit 2000 CEA), and CA 19,9 (Inmulite Gi-Ma, Diagnostic Products 
Corporation, Los Angeles, CA), and p53 expression (Dako) were determinated in 
patients with colorectal cancer. Survival analysis was realized using Cox and 
Kaplan-Meier methods (SPSS 10.0 for Windows).
RESULTS: The mean age of patients with colorectal cancer was 68 years (range 
39-87 years). 29 males and 26 females. Tumor size was 4.6 cms., range 1-12. 
Rectal localization, 32.2%. Moderately differentiated, 49.1%. The median serum 
and inmunohistochemical levels of cathepsin B were 5.74 ng/ml and 29.56% in 
patients with acute appendicitis respectively. Preoperative serum levels in 
patients with colorectal cancer were: CEA, 46.04 ng/ml (range 0.21-7.32 ); CA 
19,9, 110.52 UI/ml, (range 2.5-1920); and Cathepsin B, 6.94 ng/ml, range 
3.57-11.6). Inmunohistochemical results were: p53, 44.36%, (range 0-95); 
Cathepsin B, 66.9% (range 10-90). Serum and inmunhistochemical values were 
significantly increased in patients with colorectal cancer when compared with 
control group, p=0,011 and p=0,000. High serum levels of cathepsib B were 
significantly associated wiyh shorter survival of patients with colorectal 
cancer in univariate and multivariate methods, p=0.041;HR 1.281 95%CI 
(1.043-1.716) and p= 0.022; HR 1.338.955 CI (1.043-1.716).
CONCLUSIONS: Cathepsin B can be used like an independent prognostic tumoral 
marker in colorectal cancer. Preoperative serum levels over 6.94 ng/ml, are 
associated with worse prognostic and shorter survival.

PMID: 14585038 [Indexed for MEDLINE]


186. Br J Cancer. 2005 May 23;92(10):1825-9. doi: 10.1038/sj.bjc.6602582.

The use of radiofrequency in cancer.

Gillams AR(1).

Author information:
(1)Department of Medical Imaging, The Middlesex Hospital, Mortimer Street, 
London W1T 3AA, UK. a.gillams@medphys.ucl.ac.uk

Radiofrequency ablation (RFA) provides an effective technique for minimally 
invasive tissue destruction. An alternating current delivered via a needle 
electrode causes localised ionic agitation and frictional heating of the tissue 
around the needle. Image-guided, percutaneous ablation techniques have been 
developed in most parts of the body, but the most widely accepted applications 
are for the treatment of hepatocellular carcinoma (HCC) in early cirrhosis, 
limited but inoperable colorectal liver metastases, inoperable renal cell 
carcinoma and inoperable primary or secondary lung tumours. The procedures are 
well tolerated and the complication rates low. Patients with coexistent 
morbidity who are not suitable for surgery are often able to undergo RFA. Most 
treatments in the lung, kidney and for HCC are performed under conscious 
sedation with an overnight hospital stay or as a day-case. Larger more 
complicated ablations, for example, in hepatic metastases may require general 
anaesthesia. Limitations of RFA include the volume of tissue that can be ablated 
in a timely fashion, that is, most centres will treat 3-5 tumours up to 4-5 cms 
in diameter. Early series reporting technical success and complications are 
available for lung and renal ablation. Liver ablation is better established and 
5-year survival figures are available from several centres. In patients with 
limited but inoperable colorectal metastases, the 5-year survival ranges from 26 
to 30% and for HCC it is just under 50%. In summary, RFA provides the 
opportunity for localised tissue destruction of limited volumes of tumour; it 
can be offered to nonsurgical candidates and used in conjunction with systemic 
therapy.

DOI: 10.1038/sj.bjc.6602582
PMCID: PMC2361772
PMID: 15870717 [Indexed for MEDLINE]


187. Cancers (Basel). 2021 Oct 27;13(21):5394. doi: 10.3390/cancers13215394.

APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular 
Subtypes.

Thota R(1), Yang M(2), Pflieger L(3), Schell MJ(4), Rajan M(2), Davis TB(2), 
Wang H(2), Presson A(5), Pledger WJ(2)(6), Yeatman TJ(2)(6).

Author information:
(1)Oncology Clinical Program, Intermountain Healthcare, Murray, UT 84107, USA.
(2)Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA.
(3)Precision Genomics Translational Science Center, Intermountain Healthcare, 
Murray, UT 84107, USA.
(4)Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & 
Research Institute, Tampa, FL 33612, USA.
(5)Department of Internal Medicine, Division of Epidemiology, University of 
Utah, Salt Lake City, UT 84132, USA.
(6)Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Recently, it was suggested that consensus molecular subtyping (CMS) may aide in 
predicting response to EGFR inhibitor (cetuximab) therapies. We recently 
identified that APC and TP53 as two tumor suppressor genes, when mutated, may 
enhance cetuximab sensitivity and may represent easily measured biomarkers in 
tumors or blood. Our study aimed to use APC and TP53 mutations (AP) to refine 
the CMS classification to better predict responses to cetuximab. In total, 433 
CRC tumors were classified into CMS1-4 subtypes. The cetuximab sensitivity 
(CTX-S) signature scores of AP vs. non-AP tumors were determined across each of 
the CMS classes. Tumors harboring combined AP mutations were predominantly 
enriched in the CMS2 class, and to a lesser degree, in the CMS4 class. On the 
other hand, AP mutated CRCs had significantly higher CTX-S scores compared to 
non-AP CRCs across all CMS classes. Similar results were also obtained in 
independent TCGA tumor collections (n = 531) and in PDMR PDX/PDO/PDC models (n = 
477). In addition, the in vitro cetuximab growth inhibition was preferentially 
associated with the CMS2 cell lines harboring A/P genotypes. In conclusion, the 
AP mutation signature represents a convenient biomarker that refines the CMS 
classification to identify CRC subpopulations predicted to be sensitive to EGFR 
targeted therapies.

DOI: 10.3390/cancers13215394
PMCID: PMC8582550
PMID: 34771559

Conflict of interest statement: The authors declare no conflict of interest.


188. Oncotarget. 2017 Jul 18;8(44):76290-76304. doi: 10.18632/oncotarget.19350. 
eCollection 2017 Sep 29.

Molecular signatures reflecting microenvironmental metabolism and 
chemotherapy-induced immunogenic cell death in colorectal liver metastases.

Østrup O(#)(1)(2), Dagenborg VJ(#)(1)(3), Rødland EA(1)(2), Skarpeteig V(2), 
Silwal-Pandit L(2), Grzyb K(4), Berstad AE(5), Fretland ÅA(6)(7)(3), Mælandsmo 
GM(1)(8), Børresen-Dale AL(2)(3), Ree AH(9)(3), Edwin B(6)(7)(3), Nygaard 
V(#)(1), Flatmark K(#)(1)(10)(3).

Author information:
(1)Department of Tumor Biology, Institute for Cancer Research, Oslo University 
Hospital, The Norwegian Radium Hospital, Oslo, Norway.
(2)Department of Cancer Genetics, Institute for Cancer Research, Oslo University 
Hospital, The Norwegian Radium Hospital, Oslo, Norway.
(3)Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 
Oslo, Norway.
(4)Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, 
Norway.
(5)Department of Radiology, Oslo University Hospital, The Norwegian Radium 
Hospital, Oslo, Norway.
(6)Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, 
Rikshospitalet, Oslo, Norway.
(7)The Intervention Centre, Oslo University Hospital, Rikshospitalet, Oslo, 
Norway.
(8)Department of Pharmacy, University of Tromsø - The Arctic University of 
Norway, Tromsø, Norway.
(9)Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
(10)Department of Gastroenterological Surgery, Oslo University Hospital, The 
Norwegian Radium Hospital, Oslo, Norway.
(#)Contributed equally

BACKGROUND: Metastatic colorectal cancer (CRC) is associated with highly 
variable clinical outcome and response to therapy. The recently identified 
consensus molecular subtypes (CMS1-4) have prognostic and therapeutic 
implications in primary CRC, but whether these subtypes are valid for metastatic 
disease is unclear. We performed multi-level analyses of resectable CRC liver 
metastases (CLM) to identify molecular characteristics of metastatic disease and 
evaluate the clinical relevance.
METHODS: In this ancillary study to the Oslo-CoMet trial, CLM and tumor-adjacent 
liver tissue from 46 patients were analyzed by profiling mutations (targeted 
sequencing), genome-wide copy number alteration (CNAs), and gene expression.
RESULTS: Somatic mutations and CNAs detected in CLM were similar to reported 
primary CRC profiles, while CNA profiles of eight metastatic pairs suggested 
intra-patient divergence. A CMS classifier tool applied to gene expression data, 
revealed the cohort to be highly enriched for CMS2. Hierarchical clustering of 
genes with highly variable expression identified two subgroups separated by high 
or low expression of 55 genes with immune-related and metabolic functions. 
Importantly, induction of genes and pathways associated with immunogenic cell 
death (ICD) was identified in metastases exposed to neoadjuvant chemotherapy 
(NACT).
CONCLUSIONS: The uniform classification of CLM by CMS subtyping may indicate 
that novel class discovery approaches need to be explored to uncover clinically 
useful stratification of CLM. Detected gene expression signatures support the 
role of metabolism and chemotherapy in shaping the immune microenvironment of 
CLM. Furthermore, the results point to rational exploration of immune modulating 
strategies in CLM, particularly by exploiting NACT-induced ICD.

DOI: 10.18632/oncotarget.19350
PMCID: PMC5652706
PMID: 29100312

Conflict of interest statement: CONFLICTS OF INTEREST All authors declare no 
conflicts of interest.


189. Biomed Res Int. 2018 Dec 19;2018:2954208. doi: 10.1155/2018/2954208. eCollection 
2018.

Challenges in Stratifying the Molecular Variability of Patient-Derived Colon 
Tumor Xenografts.

Cybulska M(1)(2), Olesinski T(3), Goryca K(1), Paczkowska K(1), Statkiewicz 
M(1), Kopczynski M(1), Grochowska A(1)(2), Unrug-Bielawska K(1), Tyl-Bielicka 
A(1), Gajewska M(1), Mroz A(3), Dabrowska M(1), Karczmarski J(1), Paziewska 
A(2), Zając L(3), Bednarczyk M(3), Mikula M(1), Ostrowski J(1)(2).

Author information:
(1)Department of Genetics, Maria Sklodowska-Curie Institute-Oncology Centre, 
02-781 Warsaw, Poland.
(2)Department of Gastroenterology, Hepatology and Clinical Oncology, Medical 
Center for Postgraduate Education, 01-813 Warsaw, Poland.
(3)Department of Gastroenterological Oncology, Maria Sklodowska-Curie 
Institute-Oncology Centre, 02-781 Warsaw, Poland.

Colorectal cancer (CRC) is the second most common cancer in Europe and a leading 
cause of death worldwide. Patient-derived xenograft (PDX) models maintain 
complex intratumoral biology and heterogeneity and therefore remain the platform 
of choice for translational drug discovery. In this study, we implanted 37 
primary CRC tumors and five CRC cell lines into NU/J mice to develop xenograft 
models. Primary tumors and established xenografts were histologically assessed 
and surveyed for genetic variants and gene expression using a panel of 409 
cancer-related genes and RNA-seq, respectively. More than half of CRC tumors (20 
out of 37, 54%) developed into a PDX. Histological assessment confirmed that PDX 
grading, stromal components, inflammation, and budding were consistent with 
those of the primary tumors. DNA sequencing identified an average of 0.14 
variants per gene per sample. The percentage of mutated variants in PDXs 
increased with successive passages, indicating a decrease in clonal 
heterogeneity. Gene Ontology analyses of 4180 differentially expressed 
transcripts (adj. p value < 0.05) revealed overrepresentation of genes involved 
in cell division and catabolic processes among the transcripts upregulated in 
PDXs; downregulated transcripts were associated with GO terms related to 
extracellular matrix organization, immune responses, and angiogenesis. Neither a 
transcriptome-based consensus molecular subtype (CMS) classifier nor three other 
predictors reliably matched PDX molecular subtypes with those of the primary 
tumors. In sum, both genetic and transcriptomic profiles differed between donor 
tumors and PDXs, likely as a consequence of subclonal evolution at the early 
phase of xenograft development, making molecular stratification of PDXs 
challenging.

DOI: 10.1155/2018/2954208
PMCID: PMC6313970
PMID: 30662905 [Indexed for MEDLINE]


190. Ann Ital Chir. 2016;87:23-30.

Use of the circular compression stapler and circular mechanical stapler in the 
end-to-side transanal colorectal anastomosis after left colon and rectal 
resections A single center experience.

Pironi D, Vendettuoli M, Pontone S, Panarese A, Arcieri S, Filippini A, Grimaldi 
G.

AIM: The aim of our study was to compare the efficacy of the circular 
compression stapler and the circular mechanical stapler in transanal colorectal 
anastomosis after left colectomy or anterior rectal resection.
MATERIALS AND METHODS: We performed a retrospective analysis of 10 patients with 
disease of the, sigmoid colon or rectum (carcinoma or diverticular disease) who 
underwent left colectomy or anterior rectal resection with end-to-side transanal 
colorectal anastomosis. A follow-up was planned for all patients at 1, 3 and 6 
months after surgery and the anastomosis was evaluated by colonoscopy at 1 year.
RESULTS: In all patients an end-to-side transanal colorectal anastomosis was 
performed using a circular compression stapler (CCS group) or circular 
mechanical staplers with titanium staples (CMS group). The mean distance of the 
anastomosis from the anal margin was 6.4 ± 1.5 cm in the CCS group and 18.2 ± 
11.2 cm in the CMS group. All patients in the CCS group expelled the ring after 
a mean time of 8.2 postoperative days. At 12 months colonoscopy revealed that 
all CCS patients had a satisfactory anastomosis with mean size of the colic 
lumen at the level of anastomotic line of 26.3 mm.
CONCLUSIONS: In our experience the circular compression stapler a valuable 
alternative to the circular mechanical stapler for the creation of transanal 
colorectal anastomosis, in line with the relevant literature.
KEY WORDS: Anastomotic leakage, Anastomotic stenosis, Circular compression 
stapler, Circular mechanical stapler, Transanal colorectal anastomosis.

Publisher: SCOPO: Lo scopo del nostro studio è confrontare l’efficacia della 
suturatrice circolare a compressione rispetto alla suturatrice circolare 
meccanica negli interventi di emicolectomia sinistra e resezione anteriore del 
retto.
MATERIALI E METODI: È stata effettuata un’analisi retrospettiva di 10 pazienti 
affetti da patologie del colon discendente, sigma o retto (carcinoma o malattia 
diverticolare) sottoposti a emicolectomia sinistra o resezione anteriore del 
retto con anastomosi colorettale transanale termino-laterale. Il follow-up è 
stato effettuato in tutti i pazienti a 1, 3 e 6 mesi dopo l’intervento 
chirurgico e l’anastomosi è stata valutata mediante endoscopia a 1 anno.
RISULTATI: In tutti i pazienti è stata effettuata un’anastomosi colorettale 
transanale termino-laterale utilizzando la suturatrice circolare a compressione 
(gruppo CCS) o la suturatrice meccanica circolare con clip di titanio (gruppo 
CMS). La distanza media dell’anastomosi dal margine anale è di 6.4 ± 1.5 
centimetri nel gruppo CCS e di 18.2 ± 11.2 centimetri nel gruppo CMS. Tutti i 
pazienti del gruppo CCS hanno espulso l’anello dopo un tempo medio di 8.2 giorni 
postoperatori. Un’anastomosi soddisfacente è stata rilevata nei pazienti del 
gruppo CCS valutati endoscopicamente a 12 mesi con calibro medio del lume colico 
a livello della linea anastomotica di 26.3 mm.
CONCLUSIONI: Nella nostra esperienza il dispositivo a compressione si è rivelato 
valido quanto la suturatrice circolare meccanica tradizionale per il 
confezionamento di anastomosi colorettale transanale, in linea con gli studi 
presenti in letteratura.

PMID: 27025236 [Indexed for MEDLINE]


191. EMBO Mol Med. 2016 Jul 1;8(7):745-60. doi: 10.15252/emmm.201606184. Print 2016 
Jul.

TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer 
subtype.

Fessler E(1), Drost J(2), van Hooff SR(1), Linnekamp JF(1), Wang X(3), Jansen 
M(4), De Sousa E Melo F(1), Prasetyanti PR(1), IJspeert JE(5), Franitza M(6), 
Nürnberg P(6), van Noesel CJ(4), Dekker E(5), Vermeulen L(7), Clevers H(2), 
Medema JP(8).

Author information:
(1)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 
University of Amsterdam, Amsterdam, The Netherlands Cancer Genomics Center, 
Amsterdam, The Netherlands.
(2)Cancer Genomics Center, Amsterdam, The Netherlands Hubrecht Institute, Royal 
Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The 
Netherlands.
(3)Department of Biomedical Sciences, City University of Hong Kong, Kowloon 
Tong, Hong Kong.
(4)Department of Pathology, AMC, University of Amsterdam, Amsterdam, The 
Netherlands.
(5)Department of Gastroenterology, AMC, University of Amsterdam, Amsterdam, The 
Netherlands.
(6)Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany 
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated 
Diseases (CECAD), University of Cologne, Cologne, Germany.
(7)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 
University of Amsterdam, Amsterdam, The Netherlands.
(8)Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for 
Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 
University of Amsterdam, Amsterdam, The Netherlands Cancer Genomics Center, 
Amsterdam, The Netherlands j.p.medema@amc.nl.

The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is 
suggested to be a determining factor in the efficacy of adjuvant therapy for 
individual patients. Based on gene expression profiling, CRC is currently 
classified into four consensus molecular subtypes (CMSs), characterized by 
specific biological programs, thus suggesting the existence of unifying 
developmental drivers for each CMS Using human organoid cultures, we 
investigated the role of such developmental drivers at the premalignant stage of 
distinct CRC subtypes and found that TGFβ plays an important role in the 
development of the mesenchymal CMS4, which is of special interest due to its 
association with dismal prognosis. We show that in tubular adenomas (TAs), which 
progress to classical CRCs, the dominating response to TGFβ is death by 
apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment 
prevails in a genetically engineered organoid culture carrying a BRAF(V) (600E) 
mutation, constituting a model system for sessile serrated adenomas (SSAs). Our 
data indicate that TGFβ signaling is already active in SSA precursor lesions and 
that TGFβ is a critical cue for directing SSAs to the mesenchymal, 
poor-prognosis CMS4 of CRC.

© 2016 The Authors. Published under the terms of the CC BY 4.0 license.

DOI: 10.15252/emmm.201606184
PMCID: PMC4931289
PMID: 27221051 [Indexed for MEDLINE]


192. J Manag Care Pharm. 2007 Aug;13(6 Suppl C):S27-9. doi: 
10.18553/jmcp.2007.13.s6-c.27.

Colorectal cancer: complexities and challenges in managed care.

Minkoff NB(1).

Author information:
(1)Network Services and Pharmacy, Harvard Pilgrim Health Care, Wellesley, 
Massachusetts 02481, USA. neil_minkoff@hphc.org

BACKGROUND: Managed care weighs advances and associated costs to determine 
whether the combination of longer life at sometimes significantly increased cost 
represents value. The price of treatment is only 1 factor.
OBJECTIVE: To review treatment decision processes for oncologic agents in 
managed care environments.
SUMMARY: Price can be exceptionally high for individuals. But if the population 
size is low, the per-member-per-month (PMPM) impact can be almost negligible, 
unlike treatments that have moderate costs but are used ubiquitously. Cancer 
therapies have, for the most part, escaped managed care's notice. For 2007, the 
national Cancer Institute projects that antineoplastic agents will consume 
almost a quarter of the overall drug spend. The Medicare population is a unique 
concern with regard to cancer. Traditionally, Medicare reimbursement of 
chemotherapeutic agents was based on average wholesale price (AWP) discounting, 
not the oncologist's purchasing cost. This allowed oncologists to use 
reimbursement for infusions to support their medical practices. The proposed 
plan of the Center for Medicare & Medicaid Services (CMS) to use average sales 
price (ASP) plus 6% to reimburse for drugs used in the office setting leads to 
significant problems. Pharmacy and therapeutics committees will also face 
challenges: fewer data are available for some agents because they have become 
available through the U.S. Food and drug administration's Fast Track, Priority 
review, or accelerated approval processes.
CONCLUSION: Oncology disease management programs must reach out to patients and 
not necessarily deal with oncology issues directly, but address tangential 
issues that impact care, especially depression and pain management.

DOI: 10.18553/jmcp.2007.13.s6-c.27
PMID: 17713992 [Indexed for MEDLINE]


193. J Natl Cancer Inst. 2022 Feb 4:djac027. doi: 10.1093/jnci/djac027. Online ahead 
of print.

Counting Advanced Pre-Cancerous Lesions as True Positives When Determining 
Colorectal Cancer Screening Test Specificity.

Ladabaum U(1), Church TR(2), Feng Z(3), Ransohoff DF(4), Schoen RE(5).

Author information:
(1)Division of Gastroenterology and Hepatology, Department of Medicine, Stanford 
University School of Medicine, Stanford, CA, USA.
(2)Division of Environmental Health Sciences, University of Minnesota School of 
Public Health and Masonic Cancer Center, Minneapolis, MN, USA.
(3)Biostatistics Program, Division of Public Health Sciences, Fred Hutchinson 
Cancer Research Center, Seattle, WA, USA.
(4)Division of Gastroenterology and Hepatology, Department of Medicine, 
University of North Carolina at Chapel Hill, NC, USA.
(5)Departments of Medicine and Epidemiology, Division of Gastroenterology, 
Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA.

The landmark Centers for Medicare & Medicaid Services (CMS) Decision Memo on 
blood-based biomarkers to screen for colorectal cancer (CRC) sets thresholds 
of ≥ 74% for sensitivity and ≥90% for specificity for CRC. This approach does 
not consider detection of advanced precancerous lesions as true positives. We 
contrasted the impact of counting advanced precancerous lesions as true vs. 
false positives, and projected CRC outcomes under contrasting tests in a 
validated model. A test with the threshold performance set by CMS decreased CRC 
incidence by 30% and CRC mortality by 48% in 45-year-olds. If this test also 
detected advanced precancerous lesions with 30% sensitivity, CRC incidence 
decreased by 45% and mortality by 58%, but the test's CRC specificity of only 
88% would not satisfy the CMS threshold. CMS should reconsider its definition of 
threshold specificity for CRC screening biomarkers. Future coverage 
determinations on biomarkers to screen for cancer should consider detection of 
relevant precursor lesions, and projected outcomes.

© The Author(s) 2022. Published by Oxford University Press. All rights reserved. 
For permissions, please email: journals.permissions@oup.com.

DOI: 10.1093/jnci/djac027
PMID: 35134969


194. Drug Dev Ind Pharm. 2018 Jul;44(7):1158-1170. doi: 
10.1080/03639045.2018.1438463. Epub 2018 Feb 19.

Facile development, characterization, and optimization of new metformin-loaded 
nanocarrier system for efficient colon cancer adjunct therapy.

Arafa K(1), Shamma RN(2), El-Gazayerly ON(2), El-Sherbiny IM(3).

Author information:
(1)a Center for Aging and Associated Disease (CAAD) , Zewail City of Science and 
Technology , Giza , Egypt.
(2)b Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy , 
Cairo University , Cairo , Egypt.
(3)c Nanomedicine Group, Center for Materials Science (CMS) , Zewail City of 
Science and Technology , Giza , Egypt.

PURPOSE: Metformin hydrochloride (MF) repurposing as adjuvant anticancer therapy 
for colorectal cancer (CRC) proved effective. Several studies attempted to 
develop MF-loaded nanoparticles (NPs), however the entrapment efficiency (EE%) 
was poor. Thus, the present study aimed at the facile development of a new 
series of chitosan (CS)-based semi-interpenetrating network (semi-IPN) NPs 
incorporating Pluronic® nanomicelles as nanocarriers for enhanced entrapment and 
sustained release of MF for efficient treatment of CRC.
METHODS: The NPs were prepared by ionic gelation and subsequently characterized 
using FTIR, DSC, TEM, and DLS. A full factorial design was also adopted to study 
the effect of various formulation variables on EE%, particle size, and 
zeta-potential of NPs.
RESULTS: NPs had a spherical shape and a mean particle size ranging between 135 
and 220 nm. FTIR and DSC studies results were indicative of successful ionic 
gelation with the drug being dispersed in its amorphous form within CS-Pluronic® 
matrix. Maximum EE% reaching 57.00 ± 12.90% was achieved using Pluronic®-123 
based NPs. NPs exhibited a sustained release profile over 48 h. The MF-loaded 
NPs sensitized RKO CRC cells relative to drug alone.
CONCLUSION: The reported results highlighted the novel utility of the developed 
NPs in the arena of colon cancer treatment.

DOI: 10.1080/03639045.2018.1438463
PMID: 29429370 [Indexed for MEDLINE]


195. JCO Precis Oncol. 2021 Jul 1;5:PO.21.00132. doi: 10.1200/PO.21.00132. 
eCollection 2021.

Underdiagnosis of Hereditary Colorectal Cancers Among Medicare Patients: Genetic 
Testing Criteria for Lynch Syndrome Miss the Mark.

Muller C(1), Nielsen SM(2), Hatchell KE(2), Yang S(2), Michalski ST(2), 
Hamlington B(2), Nussbaum RL(2), Esplin ED(2), Kupfer SS(1).

Author information:
(1)Section of Gastroenterology, Hepatology, and Nutrition, Department of 
Medicine, University of Chicago, Chicago, IL.
(2)Invitae Corporation, San Francisco, CA.

PURPOSE: Strict clinical criteria used by Medicare for germline testing for 
Lynch syndrome (LS) could lead to missed diagnoses of hereditary cancer 
syndromes given variable individual and family phenotypes. The aim of this study 
was to compare rates and spectrum of pathogenic or likely pathogenic (P/LP) 
variants in LS and other hereditary cancer genes on the basis of meeting 
Medicare LS testing criteria.
METHODS: Retrospective review of Medicare beneficiaries who had multigene panel 
testing with an indication of personal or family history of colorectal cancer 
(CRC) was performed. Ordering providers determined if Medicare LS criteria were 
met. The results of genetic testing were compared on the basis of whether or not 
Medicare testing criteria were met.
RESULTS: Among 639 Medicare beneficiaries, 495 (77.5%) met testing criteria. 
Overall rates of P/LP variant identification were similar between those meeting 
and not meeting testing criteria (18.4% v 11.8%; P = .06). LS was diagnosed more 
frequently among those meeting testing criteria (10.1% v 4.9%; P = .05). No 
statistical differences were found in rates of P/LP variant identification for 
non-LS CRC genes (5.3% v 5.6%; P = .89) or non-CRC genes (4.2% v 2.1%; P = .23). 
PMS2, MUTYH, and ATM P/LP variants were found at higher rates among those 
outside of criteria.
CONCLUSION: Among Medicare beneficiaries undergoing genetic testing for 
suspected LS, rates of P/LP variants in actionable cancer genes were similar 
regardless of whether testing criteria were met. Current testing criteria fail 
to identify individuals with P/LP variants in PMS2 and other actionable cancer 
genes. Relaxing LS testing criteria could improve identification of individuals 
with hereditary cancer syndromes among Medicare beneficiaries.

© 2021 by American Society of Clinical Oncology.

DOI: 10.1200/PO.21.00132
PMCID: PMC8462652
PMID: 34585040 [Indexed for MEDLINE]

Conflict of interest statement: Sarah M. Nielsen Employment: Invitae Stock and 
Other Ownership Interests: Invitae Travel, Accommodations, Expenses: Invitae 
Kathryn E. Hatchell Employment: Invitae Stock and Other Ownership Interests: 
Invitae Shan Yang Employment: Invitae Stock and Other Ownership Interests: 
Invitae Travel, Accommodations, Expenses: Invitae Scott T. Michalski Employment: 
Invitae Stock and Other Ownership Interests: Invitae Travel, Accommodations, 
Expenses: Invitae Barbara Hamlington Employment: Invitae, Rocky Mountain Cancer 
Centers Stock and Other Ownership Interests: Invitae Robert L. Nussbaum 
Employment: Invitae Leadership: Invitae Stock and Other Ownership Interests: 
Genome Medical, Maze Therapeutics, Invitae Honoraria: Pfizer Consulting or 
Advisory Role: Genome Medical, Maze Therapeutics, Pfizer Patents, Royalties, 
Other Intellectual Property: Royalties on a patented mouse model for Parkinson 
disease held by the National Institutes of Health and the University of 
California San Francisco Open Payments Link: 
https://openpaymentsdata.cms.gov/physician/603319/summary Edward D. Esplin 
Employment: Invitae Stock and Other Ownership Interests: Invitae Sonia S. Kupfer 
Honoraria: Advance Medical Other Relationship: Invitae No other potential 
conflicts of interest were reported. Sarah M. Nielsen Employment: Invitae Stock 
and Other Ownership Interests: Invitae Travel, Accommodations, Expenses: Invitae 
Kathryn E. Hatchell Employment: Invitae Stock and Other Ownership Interests: 
Invitae Shan Yang Employment: Invitae Stock and Other Ownership Interests: 
Invitae Travel, Accommodations, Expenses: Invitae Scott T. Michalski Employment: 
Invitae Stock and Other Ownership Interests: Invitae Travel, Accommodations, 
Expenses: Invitae Barbara Hamlington Employment: Invitae, Rocky Mountain Cancer 
Centers Stock and Other Ownership Interests: Invitae Robert L. Nussbaum 
Employment: Invitae Leadership: Invitae Stock and Other Ownership Interests: 
Genome Medical, Maze Therapeutics, Invitae Honoraria: Pfizer Consulting or 
Advisory Role: Genome Medical, Maze Therapeutics, Pfizer Patents, Royalties, 
Other Intellectual Property: Royalties on a patented mouse model for Parkinson 
disease held by the National Institutes of Health and the University of 
California San Francisco Open Payments Link: 
https://openpaymentsdata.cms.gov/physician/603319/summary Edward D. Esplin 
Employment: Invitae Stock and Other Ownership Interests: Invitae Sonia S. Kupfer 
Honoraria: Advance Medical Other Relationship: Invitae No other potential 
conflicts of interest were reported.


196. J Cancer Res Clin Oncol. 2022 Mar;148(3):533-545. doi: 
10.1007/s00432-021-03888-w. Epub 2022 Jan 20.

Genomic landscape of colorectal carcinogenesis.

Kim JC(1)(2), Bodmer WF(3).

Author information:
(1)Department of Surgery, University of Ulsan College of Medicine and Asan 
Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea. 
jckim@amc.seoul.kr.
(2)Laboratory of Cancer Biology and Genetics, Asan Institute for Life Sciences, 
Asan Medical Center, Seoul, Korea. jckim@amc.seoul.kr.
(3)Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular 
Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK. 
walter.bodmer@hertford.ox.ac.uk.

PURPOSE: The molecular pathogenesis of solid tumour was first assessed in 
colorectal cancer (CRC). To date, ≤ 100 genes with somatic alterations have been 
found to inter-connectively promote neoplastic transformation through specific 
pathways. The process of colorectal carcinogenesis via genome landscape is 
reviewed on the basis of an adenoma-to-carcinoma sequence, as shown by serial 
histological and epidemiological observations.
METHODS: The relevant literatures from PubMed (1980-2021) have been reviewed for 
this article.
RESULTS: The major routes of CRC development, chromosomal instability (CIN), 
microsatellite instability (MSI), and the serrated route either via CIN or MSI, 
proceed through the respective molecular pathway of colorectal carcinogenesis. 
Particular aspects of CRC carcinogenesis can also be determined by evaluating 
familial CRCs (FCRC) and genotype-phenotype correlations. Specific causative 
gene alterations still leave to be identified in several FCRCs. Otherwise, 
recently verified FCRC can be particularly notable, for example, 
EPCAM-associated Lynch syndrome, polymerase proofreading-associated polyposis, 
RNF43-associated polyposis syndrome or NTHL1 tumour syndrome, and hereditary 
mixed polyposis syndrome. The oncogenic landscape is described, including 
representative pathway genes, the three routes of carcinogenesis, familial CRCs, 
genotype-phenotype correlations, the identification of causative genes, and 
consensus molecular subtypes (CMS).
CONCLUSION: Whole genome research using multi-gene panels (MGPs) has facilitated 
high through-put detection of previously unidentified genes involved in 
colorectal carcinogenesis. New approaches designed to identify rare variants are 
recommended to consider their alterations implicated in the molecular 
pathogenesis.

© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, 
part of Springer Nature.

DOI: 10.1007/s00432-021-03888-w
PMID: 35048197 [Indexed for MEDLINE]


197. Cancer Res. 2005 Jul 15;65(14):6418-24. doi: 10.1158/0008-5472.CAN-05-0044.

Immunoselective pressure and human leukocyte antigen class I antigen machinery 
defects in microsatellite unstable colorectal cancers.

Kloor M(1), Becker C, Benner A, Woerner SM, Gebert J, Ferrone S, von Knebel 
Doeberitz M.

Author information:
(1)Institute of Molecular Pathology, University of Heidelberg, Germany.

In colorectal cancer, the immune response is particularly pronounced against 
tumors displaying the high microsatellite instability (MSI-H) phenotype. MSI-H 
tumors accumulate mutations affecting microsatellites located within protein 
encoding regions (coding microsatellites, cMS), which lead to translational 
shifts of the respective reading frames. Consequently, novel tumor-specific 
frameshift-derived neopeptides (FSP) are generated and presented by MSI-H tumor 
cells, thus eliciting effective cytotoxic immune responses. To analyze whether 
the immunoselective pressure was reflected by the phenotype of MSI-H colorectal 
cancer cells, we compared here the expression of antigen processing machinery 
(APM) components and human leukocyte antigen (HLA) class I antigen subunits in 
20 MSI-H and 20 microsatellite-stable (MSS) colorectal cancer using a panel of 
newly developed APM component-specific monoclonal antibodies. In addition, we 
did a systematic analysis of mutations at cMS located within APM genes and 
beta2-microglobulin (beta2m). Total HLA class I antigen loss was observed in 12 
(60.0%) of the 20 MSI-H lesions compared with only 6 (30.0%) of the 20 MSS 
colorectal cancer lesions. Moreover, total loss of membraneous HLA-A staining 
was significantly more frequent in MSI-H colorectal cancer (P = 0.0024). 
Mutations at cMS of beta2m and genes encoding APM components (TAP1 and TAP2) 
were detected in at least 7 (35.0%) of 20 MSI-H colorectal cancers but in none 
of the MSS colorectal cancers (P = 0.0002). These data show that defects of HLA 
class I antigen processing and presentation seem to be significantly more 
frequent in MSI-H than in MSS colorectal cancer, suggesting that in MSI-H 
colorectal cancer the immunoselective pressure leads to the outgrowth of cells 
with defects of antigen presentation.

DOI: 10.1158/0008-5472.CAN-05-0044
PMID: 16024646 [Indexed for MEDLINE]


198. Tissue Eng Part C Methods. 2020 Jan;26(1):44-55. doi: 10.1089/ten.TEC.2019.0248. 
Epub 2020 Jan 3.

Human Induced Pluripotent Stem-Cardiac-Endothelial-Tumor-on-a-Chip to Assess 
Anticancer Efficacy and Cardiotoxicity.

Weng KC(1), Kurokawa YK(1), Hajek BS(1), Paladin JA(1), Shirure VS(2), George 
SC(2).

Author information:
(1)Department of Biomedical Engineering, Washington University in St. Louis, St. 
Louis, Missouri.
(2)Department of Biomedical Engineering, University of California, Davis, Davis, 
California.

Cancer remains a leading health threat in the United States, and cardiovascular 
drug toxicity is a primary cause to eliminate a drug from FDA approval. As a 
result, the demand to develop new anticancer drugs without cardiovascular 
toxicity is high. Human induced pluripotent stem (iPS) cell-derived tissue chips 
provide potentially a cost-effective preclinical drug testing platform, 
including potential avenues for personalized medicine. We have developed a 
three-dimensional microfluidic device that simultaneously cultures tumor cell 
spheroids with iPS-derived cardiomyocytes (iPS-CMs) and iPS-derived endothelial 
cells (iPS-EC). The iPS-derived cells include a GCaMP6 fluorescence reporter to 
allow real-time imaging to monitor intracellular calcium transients. The 
multiple-chambered tissue chip features electrodes for pacing of the cardiac 
tissue to assess cardiomyocyte function such as the maximum capture rate and 
conduction velocity. We measured the inhibition concentration (IC50) of the 
anticancer drugs, Doxorubicin (0.1 μM) and Oxaliplatin (4.2 μM), on the tissue 
chip loaded with colon cancer cells (SW620). We simultaneously evaluated the 
cardiotoxicity of these anticancer drugs by assessing the drug effect on the 
spontaneous beat frequency and conduction velocity of iPS-derived cardiac 
tissue. Consistent with in vivo observations, Doxorubicin reduced the 
spontaneous beating rate and maximum capture rate at or near the IC50 (0.04 and 
0.22 μM, respectively), whereas the toxicity of Oxaliplatin was only observed at 
concentrations beyond the IC50 (33 and 9.9 μM, respectively). Our platform 
demonstrates the feasibility to simultaneously assess cardiac toxicity and 
antitumor effects of drugs and could be used to enhance personalized drug 
testing safety and efficacy. Impact statement Drug development using murine 
models for preclinical testing is no longer adequate nor acceptable both 
financially for the pharmaceutical industry as well as for generalized or 
personalized assessment of safety and efficacy. Innovative solutions using human 
cells and tissues provide exciting new opportunities. In this study, we report 
on the creation of a 3D microfluidic device that simultaneously cultures human 
tumor cell spheroids with cardiomyocytes and endothelial cells derived from the 
same induced pluripotent stem cell line. The platform provides the opportunity 
to assess efficacy of anticancer agents while simultaneously screening for 
potential cardiovascular toxicity in a format conducive for personalized 
medicine.

DOI: 10.1089/ten.TEC.2019.0248
PMCID: PMC6983745
PMID: 31797733 [Indexed for MEDLINE]

Conflict of interest statement: S.C.G. has equity in Aracari Biosciences, a 
startup company whose core technology involves perfused human microvessels. 
There are no conflicts to declare for all other authors.


199. J Surg Res. 2022 Feb;270:169-177. doi: 10.1016/j.jss.2021.09.007. Epub 2021 Oct 
20.

Cartilage Oligomeric Matrix Protein, COMP may be a Better Prognostic Marker Than 
CEACAM5 and Correlates With Colon Cancer Molecular Subtypes, Tumor 
Aggressiveness and Overall Survival.

Wusterbarth E(1), Chen Y(2), Jecius H(1), Krall E(1), Runyan RB(3), Pandey R(4), 
Nfonsam V(5).

Author information:
(1)Department of Surgery, University of Arizona Medical Center, Tucson, Arizona.
(2)University of Arizona Cancer Center, Tucson, Arizona.
(3)Department of Cellular and Molecular Medicine, University of Arizona Medical 
Center, Tucson, Arizona.
(4)University of Arizona Cancer Center, Tucson, Arizona; Department of Cellular 
and Molecular Medicine, University of Arizona Medical Center, Tucson, Arizona.
(5)Department of Surgery, University of Arizona Medical Center, Tucson, Arizona. 
Electronic address: vnfonsam@surgery.arizona.edu.

BACKGROUND: New tumor biomarkers are needed to improve the management of colon 
cancer (CC), the second leading cause of cancer-related deaths in the United 
States. Carcinoembryonic Antigen (CEA), the translated protein of 
carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) gene, is 
used as a biomarker for CC. Cartilage Oligomeric Matrix Protein (COMP) is 
overexpressed in CC compared to normal colon tissues. This study aims to 
evaluate the expression of COMP by disease stage, consensus molecular subtype 
(CMS), its impact on disease outcomes, and comparison to CEACAM5.
MATERIALS AND METHODS: RNA-seq data from 456 CC The Cancer Genome Atlas samples 
and 41 matching control samples were analyzed for COMP expression 
and CEACAM5 expression. We stratified tumor samples by stage (I-IV), subtype 
(CMS1-CMS4), tumor location, and Kirsten RAt Sarcoma (KRAS) mutant status and 
three quartiles were established based on COMP expression. Kaplan Meier survival 
outcomes were evaluated.
RESULTS: COMP expression was significantly higher in tumor samples, with 
elevation of expression occurring in stage I and significantly increasing in 
stage IV. Increased COMP expression occurs in CMS4 with relatively low 
expression in CMS3. No significant expression difference was attributed to tumor 
location and KRAS mutant status. Compared to CEACAM5, COMP was a stronger 
molecular marker across stages and subtypes. CMS4 was associated with the 
high COMP expression, and higher levels of COMP were associated with poorer 
overall survival, disease-specific survival, and tumor progression-free 
intervals. CMS2 and 3 were associated with low expression and better survival.
CONCLUSION: COMP is a potential molecular biomarker for CC and may be superior 
to CEA as an indicator of CC.

Published by Elsevier Inc.

DOI: 10.1016/j.jss.2021.09.007
PMID: 34687957 [Indexed for MEDLINE]

Conflict of interest statement: Disclosure All authors declare no conflict of 
interest.


200. PLoS One. 2013;8(2):e56964. doi: 10.1371/journal.pone.0056964. Epub 2013 Feb 14.

High prevalence of mucosa-associated E. coli producing cyclomodulin and 
genotoxin in colon cancer.

Buc E(1), Dubois D, Sauvanet P, Raisch J, Delmas J, Darfeuille-Michaud A, Pezet 
D, Bonnet R.

Author information:
(1)UMR 1071 Inserm/Université d'Auvergne, Clermont Université, Clermont-Ferrand, 
France.

Some Escherichia coli strains produce toxins designated cyclomodulins (CMs) 
which interfere with the eukaryotic cell cycle of host cells, suggesting a 
possible link between these bacteria and cancers. There are relatively few data 
available concerning the colonization of colon tumors by cyclomodulin- and 
genotoxic-producing E. coli. We did a qualitative and phylogenetic analysis of 
mucosa-associated E. coli harboring cyclomodulin-encoding genes from 38 patients 
with colorectal cancer (CRC) and 31 with diverticulosis. The functionality of 
these genes was investigated on cell cultures and the genotoxic activity of 
strains devoid of known CM-encoding gene was investigated. Results showed a 
higher prevalence of B2 phylogroup E. coli harboring the colibatin-producing 
genes in biopsies of patients with CRC (55.3%) than in those of patients with 
diverticulosis (19.3%), (p<0.01). Likewise, a higher prevalence of B2 E. coli 
harboring the CNF1-encoding genes in biopsies of patients with CRC (39.5%) than 
in those of patients with diverticulosis (12.9%), (p = 0.01). Functional 
analysis revealed that the majority of these genes were functional. Analysis of 
the ability of E. coli to adhere to intestinal epithelial cells Int-407 
indicated that highly adherent E. coli strains mostly belonged to A and D 
phylogroups, whatever the origin of the strains (CRC or diverticulosis), and 
that most E. coli strains belonging to B2 phylogroup displayed very low levels 
of adhesion. In addition, 27.6% (n = 21/76) E. coli strains devoid of known 
cyclomodulin-encoding genes induced DNA damage in vitro, as assessed by the 
comet assay. In contrast to cyclomodulin-producing E. coli, these strains mainly 
belonged to A or D E. coli phylogroups, and exhibited a non significant 
difference in the distribution of CRC and diverticulosis specimens (22% versus 
32.5%, p = 0.91). In conclusion, cyclomodulin-producing E. coli belonging mostly 
to B2 phylogroup colonize the colonic mucosa of patients with CRC.

DOI: 10.1371/journal.pone.0056964
PMCID: PMC3572998
PMID: 23457644 [Indexed for MEDLINE]

Conflict of interest statement: Competing Interests: The authors have declared 
that no competing interests exist.


201. Colloids Surf B Biointerfaces. 2016 Dec 1;148:674-683. doi: 
10.1016/j.colsurfb.2016.09.044. Epub 2016 Sep 28.

Soluble curcumin amalgamated chitosan microspheres augmented drug delivery and 
cytotoxicity in colon cancer cells: In vitro and in vivo study.

Jyoti K(1), Bhatia RK(1), Martis EAF(2), Coutinho EC(2), Jain UK(1), Chandra 
R(3), Madan J(4).

Author information:
(1)Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Punjab 
140307, India.
(2)Molecular Simulation Group, Department of Pharmaceutical Chemistry, Bombay 
College of Pharmacy Mumbai, India.
(3)Department of Chemistry, University of Delhi, Delhi 110007, India.
(4)Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Punjab 
140307, India. Electronic address: jitenderpharmacy@gmail.com.

In present investigation, initially curcumin was complexed with 2-HP-β-CD 
(curcumin-2-HP-β-CD-complex) in 1:1 ratio and later amalgamated with chitosan 
microspheres (curcumin-2-HP-β-CD-CMs) for selective delivery in colon only 
through oral route of administration. Various analytical, spectral and in-silico 
docking techniques revealed that the curcumin was deeply inserted in the 
2-HP-β-CD cavity with apparent stability constant of 3.35×10-3M. Furthermore, 
the mean particle size of 6.8±2.6μm and +39.2±4.1mV surface charge of 
curcumin-2-HP-β-CD-complex-CMs in addition to encapsulation efficiency of about 
79.8±6.3% exhibited that the tailored microspheres were optimum for colon 
delivery of curcumin. This was also demonstrated in dissolution testing and 
standard cell proliferation assay in which curcumin-2-HP-β-CD-complex-CMs 
exhibited maximum release in simulated colonic fluid (SCF, pH ∼7.0-8.0, almond 
emulsion-β-glucosidase) with improved therapeutic index in HT-29 cells. 
Consistently, curcumin-2-HP-β-CD-complex-CMs successively enhanced the colonic 
bio-distribution of curcumin by ∼8.36 folds as compared to curcumin suspension 
in preclinical pharmacokinetic studies. In conclusion, 
curcumin-2-HP-β-CD-complex-CMs warrant further in vivo tumor regression study to 
establish its therapeutic efficacy in experimental colon cancer.

Copyright © 2016 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.colsurfb.2016.09.044
PMID: 27701049 [Indexed for MEDLINE]


202. J Radiat Res. 2020 Sep 8;61(5):766-775. doi: 10.1093/jrr/rraa041.

Effect of preoperative chemoradiotherapy on the immunological status of rectal 
cancer patients.

Yasui K(1)(2), Kondou R(1), Iizuka A(1), Miyata H(1), Tanaka E(1), Ashizawa 
T(1), Nagashima T(3)(4), Ohshima K(5), Urakami K(3), Kusuhara M(6), Muramatsu 
K(7), Sugino T(7), Yamguchi K(8), Mori K(9), Harada H(2), Nishimura T(2), Kagawa 
H(10), Yamakawa Y(10), Hino H(10), Shiomi A(10), Akiyama Y(1).

Author information:
(1)Immunotherapy Division, Shizuoka Cancer Center Research Institute, 1007 
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
(2)Division of Radiation Oncology, Shizuoka Cancer Center Hospital, 1007 
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
(3)Cancer Diagnostic Research Division, Shizuoka Cancer Center Research 
Institute, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, 
Japan.
(4)SRL Inc., Hachioji, Tokyo 191-0002, Japan.
(5)Medical Genetics Division, Shizuoka Cancer Center Research Institute, 1007 
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
(6)Regional Resources Division, Shizuoka Cancer Center Research Institute, 1007 
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
(7)Division of Pathology, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, 
Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
(8)Office of the President, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, 
Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
(9)Clinical Research Center, Shizuoka Cancer Center Hospital, 1007 
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
(10)Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, 1007 
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.

The aim of the study was to investigate the effect of chemo-radiation on the 
genetic and immunological status of rectal cancer patients who were treated with 
preoperative chemoradiotherapy (CRT). The expression of immune 
response-associated genes was compared between rectal cancer patients treated 
(n = 9) and not-treated (n = 10) with preoperative CRT using volcano plot 
analysis. Apoptosis and epithelial-to-mesenchymal transition (EMT) marker genes 
were analysed by quantitative PCR (qPCR). Other markers associated with the 
tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TIL) and 
immune checkpoint molecules, were investigated using immunohistochemistry (IHC). 
The clinical responses of preoperative CRT for 9 rectal cancer patients were all 
rated as stable disease, while the pathological tumor regression score (TRG) 
revealed 6 cases of grade2 and 3 cases of grade1. According to the genetic 
signature of colon cancers, treated tumors belonged to consensus molecular 
subtype (CMS)4, while not-treated tumors had signatures of CMS2 or 3. 
CRT-treated tumors showed significant upregulation of EMT-associated genes, such 
as CDH2, TGF-beta and FGF, and cancer stem cell-associated genes. Additionally, 
qPCR and IHC demonstrated a suppressive immunological status derived from the 
upregulation of inflammatory cytokines (IL-6, IL-10 and TGF-beta) and immune 
checkpoint genes (B7-H3 and B7-H5) and from M2-type macrophage accumulation in 
the tumor. The induction of EMT and immune-suppressive status in the tumor after 
strong CRT treatment urges the development of a novel combined therapy that 
restores immune-suppression and inhibits EMT, ultimately leading to distant 
metastasis control.

© The Author(s) 2020. Published by Oxford University Press on behalf of The 
Japanese Radiation Research Society and Japanese Society for Radiation Oncology.

DOI: 10.1093/jrr/rraa041
PMCID: PMC7482156
PMID: 32672335 [Indexed for MEDLINE]


203. CA Cancer J Clin. 2014 Sep-Oct;64(5):352-63. doi: 10.3322/caac.21239. Epub 2014 
Jun 27.

Issues with implementing a high-quality lung cancer screening program.

Mulshine JL(1), D'Amico TA.

Author information:
(1)Professor, Department of Internal Medicine, Associate Provost for Research 
and Vice President, Rush University, Chicago, IL.

After a comprehensive review of the evidence, the United States Preventive 
Services Task Force recently endorsed screening with low-dose computed 
tomography as an early detection approach that has the potential to 
significantly reduce deaths due to lung cancer. Prudent implementation of lung 
cancer screening as a high-quality preventive health service is a complex 
challenge. The clinical evaluation and management of high-risk cohorts in the 
absence of symptoms mandates an approach that differs significantly from that of 
symptom-detected lung cancer. As with other cancer screenings, it is essential 
to provide to informed at-risk individuals a safe, high-quality, cost-effective, 
and accessible service. In this review, the components of a successful screening 
program are discussed as we begin to disseminate lung cancer screening as a 
national resource to improve outcomes with this lethal cancer. This information 
about lung cancer screening will assist clinicians with communications about the 
potential benefits and harms of this service for high-risk individuals 
considering participation in the screening process.

© 2014 American Cancer Society.

DOI: 10.3322/caac.21239
PMID: 24976072 [Indexed for MEDLINE]


204. Ann Surg Oncol. 2014 Jun;21(6):1781-91. doi: 10.1245/s10434-014-3631-8. Epub 
2014 Mar 19.

Adjuvant chemotherapy for stage II right-sided and left-sided colon cancer: 
analysis of SEER-medicare data.

Weiss JM(1), Schumacher J, Allen GO, Neuman H, Lange EO, Loconte NK, Greenberg 
CC, Smith MA.

Author information:
(1)Department of Medicine, University of Wisconsin School of Medicine and Public 
Health (UWSMPH), Madison, WI, USA, jmw@medicine.wisc.edu.

Comment in
    Ann Surg Oncol. 2014 Jun;21(6):1765-7.

BACKGROUND: Survival benefit from adjuvant chemotherapy is established for stage 
III colon cancer; however, uncertainty exists for stage II patients. Tumor 
heterogeneity, specifically microsatellite instability (MSI), which is more 
common in right-sided cancers, may be the reason for this observation. We 
examined the relationship between adjuvant chemotherapy and overall 5-year 
mortality for stage II colon cancer by location (right- vs left-side) as a 
surrogate for MSI.
METHODS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, 
we identified Medicare beneficiaries from 1992 to 2005 with AJCC stage II 
(n = 23,578) and III (n = 17,148) primary adenocarcinoma of the colon who 
underwent surgery for curative intent. Overall 5-year mortality was examined 
with Kaplan-Meier survival analysis and Cox proportional hazards regression with 
propensity score weighting.
RESULTS: It was found that 18 % of stage II patients (n = 2941) with right-sided 
cancer and 22 % (n = 1693) with left-sided cancer received adjuvant 
chemotherapy. After adjustment, overall 5-year survival benefit from 
chemotherapy was observed only for stage III patients (right-sided: hazard ratio 
[HR], 0.64; 95 % CI, 0.59-0.68; p < .001 and left-sided: HR, 0.61; 95 % CI, 
0.56-0.68; p < .001). No survival benefit was observed for stage II patients 
with either right-sided (HR, 0.97; 95 % CI, 0.87-1.09; p = .64) or left-sided 
cancer (HR, 0.97; 95 % CI, 0.84-1.12; p = .68).
CONCLUSIONS: Among Medicare patients with stage II colon cancer, a substantial 
number receive adjuvant chemotherapy. Adjuvant chemotherapy did not improve 
overall 5-year survival for either right- or left-sided colon cancers. Our 
results reinforce existing guidelines and should be considered in treatment 
algorithms for older adults with stage II colon cancer.

DOI: 10.1245/s10434-014-3631-8
PMCID: PMC4016118
PMID: 24643898 [Indexed for MEDLINE]

Conflict of interest statement: Disclosures and Research Support: None of the 
authors have conflicts to disclose. This manuscript represents an original work 
of the authors, and has not been previously published. The results were 
presented as a poster at Digestive Disease Week, May 18–21, 2013, Orlando, FL. 
Dr. Weiss was supported by the Agency for Healthcare Research and Quality 
(AHRQ)/National Research Service Award (NRSA) T-32 Institutional Training 
Program Grant Number: 5-T32-HS00083. This project also received funding from the 
University of Wisconsin Carbone Cancer Center (UWCCC) Support Grant from the 
National Cancer Institute, grant number P30 CA014520. This project was also 
supported by the Health Innovation Program, the UW School of Medicine and Public 
Health from The Wisconsin Partnership Program, and the-Community Academic 
Partnerships core of the University of Wisconsin Institute for Clinical and 
Translational Research (UW ICTR) through the National Center for Advancing 
Translational Sciences (NCATS), grant UL1TR000427. The ideas and opinions 
expressed herein are those of the author(s) and endorsement by the State of 
California, Department of Public Health the National Cancer Institute, the 
National Institutes of Health, and the Centers for Disease Control and 
Prevention or their Contractors and Subcontractors is not intended nor should be 
inferred. This study used the linked SEER-Medicare database. The interpretation 
and reporting of these data are the sole responsibility of the authors. The 
collection of the California cancer incidence data used in this study was 
supported by the California Department of Public Health as part of the statewide 
cancer reporting program mandated by California Health and Safety Code Section 
103885; the National Cancer Institute’s Surveillance, Epidemiology and End 
Results Program under contract N01-PC-35136 awarded to the Northern California 
Cancer Center, contract N01-PC-35139 awarded to the University of Southern 
California, and contract N02-PC-15105 awarded to the Public Health Institute; 
and the Centers for Disease Control and Prevention’s National Program of Cancer 
Registries, under agreement #U55/CCR921930-02 awarded to the Public Health 
Institute. The authors acknowledge the efforts of the Applied Research Program, 
NCI; the Office of Research, Development and Information, CMS; Information 
Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End 
Results (SEER) Program tumor registries in the creation of the SEER-Medicare 
database.


205. Nat Commun. 2020 Sep 21;11(1):4740. doi: 10.1038/s41467-020-18514-5.

The shared frameshift mutation landscape of microsatellite-unstable cancers 
suggests immunoediting during tumor evolution.

Ballhausen A(#)(1)(2)(3), Przybilla MJ(#)(1)(2)(3), Jendrusch M(#)(1)(2)(3), 
Haupt S(4), Pfaffendorf E(1)(2)(3), Seidler F(1)(2)(3), Witt J(1)(2)(3), 
Hernandez Sanchez A(1)(2)(3), Urban K(1)(2)(3), Draxlbauer M(1)(2)(3), Krausert 
S(1)(2)(3), Ahadova A(1)(2)(3), Kalteis MS(1)(2)(3), Pfuderer PL(1)(2)(3), Heid 
D(1)(2)(3), Stichel D(1)(5), Gebert J(1)(2)(3), Bonsack M(6)(7)(8), Schott S(9), 
Bläker H(10), Seppälä T(11), Mecklin JP(12)(13), Ten Broeke S(14), Nielsen 
M(14), Heuveline V(4), Krzykalla J(15), Benner A(15), Riemer AB(6)(7), von 
Knebel Doeberitz M(1)(2)(3), Kloor M(16)(17)(18).

Author information:
(1)Department of Applied Tumor Biology, Institute of Pathology, University of 
Heidelberg, Heidelberg, Germany.
(2)Collaboration Unit Applied Tumor Biology, German Cancer Research Center 
(DKFZ), Heidelberg, Germany.
(3)Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital 
and EMBL, Heidelberg, Germany.
(4)Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center 
for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany.
(5)Clinical Cooperation Unit Neuropathology, German Cancer Research Center 
(DKFZ), Heidelberg, Germany.
(6)Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), 
Heidelberg, Germany.
(7)Molecular Vaccine Design, German Center for Infection Research (DZIF), 
partner site Heidelberg, Heidelberg, Germany.
(8)Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
(9)Department of Obstetrics and Gynecology, University Hospital Heidelberg, 
Heidelberg, Germany.
(10)Institute of Pathology, University Hospital Leipzig, Leipzig, Germany.
(11)Department of Gastrointestinal Surgery, Helsinki University Hospital and 
University of Helsinki, Helsinki, Finland.
(12)Department of Education and Research, Central Finland Central Hospital, 
Jyväskylä, Finland.
(13)Department of Sports and Health Sciences, University of Jyväskylä, 
Jyväskylä, Finland.
(14)Department of Clinical Genetics, Leiden University Medical Center, Leiden, 
The Netherlands.
(15)Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, 
Germany.
(16)Department of Applied Tumor Biology, Institute of Pathology, University of 
Heidelberg, Heidelberg, Germany. matthias.kloor@med.uni-heidelberg.de.
(17)Collaboration Unit Applied Tumor Biology, German Cancer Research Center 
(DKFZ), Heidelberg, Germany. matthias.kloor@med.uni-heidelberg.de.
(18)Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital 
and EMBL, Heidelberg, Germany. matthias.kloor@med.uni-heidelberg.de.
(#)Contributed equally

The immune system can recognize and attack cancer cells, especially those with a 
high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA 
mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR 
deficiency leads to insertion/deletion (indel) mutations at coding 
microsatellites (cMS) and to neoantigen-inducing translational frameshifts. 
Here, we develop a tool to quantify frameshift mutations in MSI colorectal and 
endometrial cancer. Our results show that frameshift mutation frequency is 
negatively correlated to the predicted immunogenicity of the resulting peptides, 
suggesting counterselection of cell clones with highly immunogenic frameshift 
peptides. This correlation is absent in tumors with Beta-2-microglobulin 
mutations, and HLA-A*02:01 status is related to cMS mutation patterns. 
Importantly, certain outlier mutations are common in MSI cancers despite being 
related to frameshift peptides with functionally confirmed immunogenicity, 
suggesting a possible driver role during MSI tumor evolution. Neoantigens 
resulting from shared mutations represent promising vaccine candidates for 
prevention of MSI cancers.

DOI: 10.1038/s41467-020-18514-5
PMCID: PMC7506541
PMID: 32958755 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


206. Clin Cancer Res. 2020 Sep 1;26(17):4503-4510. doi: 
10.1158/1078-0432.CCR-19-3517. Epub 2020 Jun 15.

A Frameshift Peptide Neoantigen-Based Vaccine for Mismatch Repair-Deficient 
Cancers: A Phase I/IIa Clinical Trial.

Kloor M(1)(2)(3), Reuschenbach M(4)(2)(3), Pauligk C(5), Karbach J(6), Rafiyan 
MR(6), Al-Batran SE(5), Tariverdian M(7), Jäger E(6), von Knebel Doeberitz 
M(4)(2)(3).

Author information:
(1)Department of Applied Tumor Biology, Institute of Pathology, University 
Hospital Heidelberg, Heidelberg, Germany. matthias.kloor@med.uni-heidelberg.de.
(2)Clinical Cooperation Unit Applied Tumor Biology, DKFZ (German Cancer Research 
Center) Heidelberg, Heidelberg, Germany.
(3)Molecular Medicine Partnership Unit (MMPU), EMBL Heidelberg, Heidelberg, 
Germany.
(4)Department of Applied Tumor Biology, Institute of Pathology, University 
Hospital Heidelberg, Heidelberg, Germany.
(5)Institute of Clinical Cancer Research (IKF), Krankenhaus Nordwest, UCT 
University Cancer Center, Frankfurt, Germany.
(6)Clinic for Oncology and Hematology, Krankenhaus Nordwest, Frankfurt, Germany.
(7)Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.

PURPOSE: DNA mismatch repair (MMR) deficiency is a hallmark of Lynch syndrome, 
the most common inherited cancer syndrome. MMR-deficient cancer cells accumulate 
numerous insertion/deletion mutations at microsatellites. Mutations of coding 
microsatellites (cMS) lead to the generation of immunogenic frameshift peptide 
(FSP) neoantigens. As the evolution of MMR-deficient cancers is triggered by 
mutations inactivating defined cMS-containing tumor suppressor genes, distinct 
FSP neoantigens are shared by most MMR-deficient cancers. To evaluate safety and 
immunogenicity of an FSP-based vaccine, we performed a clinical phase I/IIa 
trial (Micoryx).
PATIENTS AND METHODS: The trial comprised three cycles of four subcutaneous 
vaccinations (FSP neoantigens derived from mutant AIM2, HT001, TAF1B genes) 
mixed with Montanide ISA-51 VG over 6 months. Inclusion criteria were history of 
MMR-deficient colorectal cancer (UICC stage III or IV) and completion of 
chemotherapy. Phase I evaluated safety and toxicity as primary endpoint (six 
patients), phase IIa addressed cellular and humoral immune responses (16 
patients).
RESULTS: Vaccine-induced humoral and cellular immune responses were observed in 
all patients vaccinated per protocol. Three patients developed grade 2 local 
injection site reactions. No vaccination-induced severe adverse events occurred. 
One heavily pretreated patient with bulky metastases showed stable disease and 
stable CEA levels over 7 months.
CONCLUSIONS: FSP neoantigen vaccination is systemically well tolerated and 
consistently induces humoral and cellular immune responses, thus representing a 
promising novel approach for treatment and even prevention of MMR-deficient 
cancer.

©2020 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-19-3517
PMID: 32540851 [Indexed for MEDLINE]


207. Zhonghua Yu Fang Yi Xue Za Zhi. 1993 Sep;27(5):286-9.

[Experimental study on prevention of the colorectal cancer by China medical 
stone and the organgermanium compound].

[Article in Chinese]

Song WS(1).

Author information:
(1)Pearl River Hospital, First Medical University of PLA, Guangzhou.

To compare the effect of cancer prevention of China medical stone (CMS) and 
Ge-132, rats were subcutaneously injected with dimethylhydrazine for 15 weeks 
and orally administered with 10% china medical stone soak and Ge-132 for 27 
weeks. Colorectal cancer incidence in CMS was found significantly lower than in 
Ge-132 and controls (P < 0.05-0.01). In Ge-132 only the mean cancer foci and the 
mean cancer volumes/rat were found significantly less than controls (P < 0.01). 
It was shown by endoscopy that a precancerous lesion of the bowel resulted from 
carcinogen was more mild in CMS and Ge-132 than in controls. Serum 
gamma-interferon titer and NK activity of spleen cells were significantly 
elevated in CMS and Ge-132. Researches explained that the effect of cancer 
prevention of CMS was better than that of Ge-132.

PMID: 8137660 [Indexed for MEDLINE]


208. PLoS Genet. 2022 Apr 21;18(4):e1010163. doi: 10.1371/journal.pgen.1010163. 
eCollection 2022 Apr.

Comparative molecular genomic analyses of a spontaneous rhesus macaque model of 
mismatch repair-deficient colorectal cancer.

Ozirmak Lermi N(1)(2), Gray SB(3), Bowen CM(1), Reyes-Uribe L(1), Dray BK(4), 
Deng N(1), Harris RA(5), Raveendran M(5), Benavides F(6), Hodo CL(3), Taggart 
MW(7), Colbert Maresso K(1), Sinha KM(1), Rogers J(5), Vilar E(1)(8).

Author information:
(1)Department of Clinical Cancer Prevention, The University of Texas MD Anderson 
Cancer Center, Houston, Texas, United States of America.
(2)School of Health Professions, The University of Texas MD Anderson Cancer 
Center, Houston, Texas, United States of America.
(3)Michale E. Keeling Center for Comparative Medicine and Research, The 
University of Texas MD Anderson Cancer Center, Houston, Texas, United States of 
America.
(4)Charles River Laboratories, Ashland, Ohio, United States of America.
(5)Human Genome Sequencing Center and Department of Molecular and Human 
Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
(6)Department of Epigenetics and Molecular Carcinogenesis, The University of 
Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
(7)Department of Pathology, The University of Texas MD Anderson Cancer Center, 
Houston, Texas, United States of America.
(8)Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer 
Center, Houston, Texas, United States of America.

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% 
of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome 
(LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus 
macaques from our institution developed spontaneous mismatch repair deficient 
(MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in 
MLH1 (c.1029C<G, p.Tyr343Ter). Our study aimed to provide a detailed molecular 
characterization of rhesus CRC for cross-comparison with human MMRd CRC. We 
performed PCR-based MSI testing (n = 41), transcriptomics analysis (n = 35), 
reduced-representation bisulfite sequencing (RRBS) (n = 28), and MLH1 DNA 
methylation (n = 10) using next-generation sequencing (NGS) of rhesus CRC. 
Systems biology tools were used to perform gene set enrichment analysis (GSEA) 
for pathway discovery, consensus molecular subtyping (CMS), and somatic mutation 
profiling. Overall, the majority of rhesus tumors displayed high levels of MSI 
(MSI-H) and differential gene expression profiles that were consistent with 
known deregulated pathways in human CRC. DNA methylation analysis exposed 
differentially methylated patterns among MSI-H, MSI-L (MSI-low)/MSS (MS-stable) 
and LS tumors with MLH1 predominantly inactivated among sporadic MSI-H CRCs. The 
findings from this study support the use of rhesus macaques as an alternative 
animal model to mice to study carcinogenesis, develop immunotherapies and 
vaccines, and implement chemoprevention approaches relevant to sporadic MSI-H 
and LS CRC in humans.

DOI: 10.1371/journal.pgen.1010163
PMCID: PMC9064097
PMID: 35446842

Conflict of interest statement: I have read the journal’s policy and the authors 
of this manuscript have the following competing interests: Dr. Vilar has a 
consulting or advisory role with Janssen Research and Development and Recursion 
Pharma. He has received research support from Janssen Research and Development. 
Please, note that these financial relations are not connected to the research 
reported in this manuscript.


209. J Inorg Biochem. 2015 Sep;150:18-27. doi: 10.1016/j.jinorgbio.2015.06.001. Epub 
2015 Jun 5.

Synthesis, chemical characterization, computational studies and biological 
activity of new DNA methyltransferases (DNMTs) specific inhibitor. Epigenetic 
regulation as a new and potential approach to cancer therapy.

Pellerito C(1), Morana O(2), Ferrante F(2), Calvaruso G(3), Notaro A(3), Sabella 
S(3), Fiore T(4).

Author information:
(1)Dipartimento di Fisica e Chimica (DiFC), Università degli Studi di Palermo, 
Viale delle Scienze, Ed. 17-90128 Palermo, Italy; Consorzio Interuniversitario 
di Ricerca in Chimica dei Metalli nei Sistemi Biologici (C.I.R.C.M.S.B.), Piazza 
Umberto I, 1-70121 Bari, Italy. Electronic address: claudia.pellerito@unipa.it.
(2)Dipartimento di Fisica e Chimica (DiFC), Università degli Studi di Palermo, 
Viale delle Scienze, Ed. 17-90128 Palermo, Italy.
(3)Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche 
(STEBICEF), Laboratorio di Biochimica, Policlinico Universitario, Via del 
Vespro, 129-90127 Palermo, Italy.
(4)Dipartimento di Fisica e Chimica (DiFC), Università degli Studi di Palermo, 
Viale delle Scienze, Ed. 17-90128 Palermo, Italy; Consorzio Interuniversitario 
di Ricerca in Chimica dei Metalli nei Sistemi Biologici (C.I.R.C.M.S.B.), Piazza 
Umberto I, 1-70121 Bari, Italy.

This work deals with the synthesis, the chemical characterization of 
dibutyltin(IV) complex of caffeic acid (Bu2Sn(IV)HCAF, caf1) and its cytotoxic 
action on tumor cells. The coordination environment at the tin center was 
investigated by FTIR, (119)Sn{(1)H} cross polarization magic angle spinning, 
electrospray ionization mass spectroscopy in the solid state and UV-vis, 
fluorescence and (1)H, (13)C and (119)Sn NMR spectroscopy in solution phases. 
Density functional theory study confirmed the proposed structures in solution 
phase and indicated the most probably stable conformation. The effects on 
viability of breast cancer MDA-MB231, colorectal cancer HCT116, hepatocellular 
carcinoma HepG2 and Chang liver cells, an immortalized non-tumor hepatic cell 
line, have been investigated. The effect of a variation in structure of caf1 was 
found to lead to a change in the respective antiproliferative properties: caf1 
induces loss of viability in HCT116, MDA-MB-231, and HepG2; the complex shows 
only moderate effects in non-tumor Chang liver cells. caf1 exerts lower 
cytotoxic activity than Bu2SnCl2, suggesting that the binding with H3CAF 
modulates the marked cytotoxic activity exerted by Bu2SnCl2; caf1 displays a 
considerably more pronounced antitumoural effect towards cell lines than caffeic 
acid. It is known that caffeic acid can modulate DNA 
(cytosine-5)-methyltransferases 1 (DNMT1) mediated DNA methylation. In this 
paper we demonstrate that caf1 treatment was able to induce a time-dependent 
reduction of global DNA methylated status. This effect was also confirmed by a 
concomitant reduction DNMT1 expression level. The effect induced by caf1 was 
more evident not only with respect to untreated cells but also compared to H3CAF 
treated cells.

Copyright © 2015 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.jinorgbio.2015.06.001
PMID: 26072325 [Indexed for MEDLINE]


210. Lancet Oncol. 2019 May;20(5):e274-e283. doi: 10.1016/S1470-2045(19)30172-X.

Explaining the unexplainable: discrepancies in results from the CALGB/SWOG 80405 
and FIRE-3 studies.

Aderka D(1), Stintzing S(2), Heinemann V(3).

Author information:
(1)Gastrointestinal Cancer Unit, Division of Oncology, Sheba Medical Centre, 
Ramat-Gan, Israel; Tel-Aviv University, Tel-Aviv, Israel. Electronic address: 
aderkadan@gmail.com.
(2)Medical Department, Division of Oncology and Haematology (Campus Charité 
Mitte), Charité University Hospital Berlin, Berlin, Germany.
(3)Department of Medical Oncology & Comprehensive Cancer Centre, University 
Hospital Grosshadern, Munich, Germany.

We propose a working hypothesis that integrates data from the CALGB/SWOG 80405 
and FIRE-3 studies to explain apparent discrepancies in their results. Both 
trials assessed the combination of either cetuximab or bevacizumab with a 
different chemotherapy backbone: irinotecan in all patients in the FIRE-3 study, 
or oxaliplatin in 75% of the patients in the CALGB/SWOG 80405 study. The 
hypothesis is divided into three parts. Firstly, in addition to the biology or 
microenvironment of the tumour and the selection of the biologically targeted 
agents common to both trials, chemotherapy itself is an important variable that 
determines treatment efficacy because of a complex interplay between the 
biological therapy, the chemotherapy, and the microenvironment. Secondly, the 
tumour microenvironment, as defined by the Consensus Molecular Subtypes (CMS) 
classification, determines the interaction of chemotherapeutic agents with 
biologically targeted agents such as bevacizumab and cetuximab. Whereas 
irinotecan synergises with cetuximab across all CMS subtypes, oxaliplatin might 
have variable effects, synergising with cetuximab in fibroblast-poor 
microenvironments, such as CMS2 and CMS3, but activating fibroblast-rich 
microenvironments, such as CMS1 and CMS4, to release cytokines that might 
antagonise some of the cetuximab effects. Thirdly, the previous assumptions 
integrate into a final concept, which is that overall survival is determined not 
only by the biological therapy or the first-line treatment, but specifically by 
the sequence of first-line and second-line regimens, and the degree of synergism 
between them. In a clinical setting, the optimal first-line combination of 
biological therapy and chemotherapy predetermines the crossover to a specific 
second-line treatment, which affects the overall survival of a patient with a 
specific tumour subtype. Our working hypothesis suggests that the CALGB/SWOG 
80405 and FIRE-3 studies are complementary rather than discrepant, and it 
provides an explanation for their opposing interpretations. In conclusion, 
proper interpretation of the CALGB/SWOG 80405 and FIRE-3 results requires an 
in-depth examination of the complex interplay, not only between the targeted 
biological agents and chemotherapeutic drugs, but also between therapies and the 
tumour biology and microenvironment, for each line of treatment.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30172-X
PMID: 31044725 [Indexed for MEDLINE]


211. Genome Med. 2019 Dec 30;11(1):87. doi: 10.1186/s13073-019-0697-8.

Neoantigen-specific immunity in low mutation burden colorectal cancers of the 
consensus molecular subtype 4.

van den Bulk J(1), Verdegaal EME(2), Ruano D(1), Ijsselsteijn ME(1), Visser 
M(2), van der Breggen R(1), Duhen T(3), van der Ploeg M(1), de Vries NL(4), 
Oosting J(1), Peeters KCMJ(5), Weinberg AD(3)(6), Farina-Sarasqueta A(1), van 
der Burg SH(2), de Miranda NFCC(7).

Author information:
(1)Pathology, LUMC, Postbus 9600, 2300 RC, Leiden, The Netherlands.
(2)Medical Oncology, Oncode Institute, LUMC, Leiden, The Netherlands.
(3)Earle A. Chiles Institute, Portland, USA.
(4)Immunohematology and Blood Transfusion, LUMC, Leiden, The Netherlands.
(5)Surgery, LUMC, Leiden, The Netherlands.
(6)AgonOx, Portland, USA.
(7)Pathology, LUMC, Postbus 9600, 2300 RC, Leiden, The Netherlands. 
N.F.de_Miranda@lumc.nl.

BACKGROUND: The efficacy of checkpoint blockade immunotherapies in colorectal 
cancer is currently restricted to a minority of patients diagnosed with mismatch 
repair-deficient tumors having high mutation burden. However, this observation 
does not exclude the existence of neoantigen-specific T cells in colorectal 
cancers with low mutation burden and the exploitation of their anti-cancer 
potential for immunotherapy. Therefore, we investigated whether autologous 
neoantigen-specific T cell responses could also be observed in patients 
diagnosed with mismatch repair-proficient colorectal cancers.
METHODS: Whole-exome and transcriptome sequencing were performed on cancer and 
normal tissues from seven colorectal cancer patients diagnosed with mismatch 
repair-proficient tumors to detect putative neoantigens. Corresponding 
neo-epitopes were synthesized and tested for recognition by in vitro expanded T 
cells that were isolated from tumor tissues (tumor-infiltrating lymphocytes) and 
from peripheral mononuclear blood cells stimulated with tumor material.
RESULTS: Neoantigen-specific T cell reactivity was detected to several 
neo-epitopes in the tumor-infiltrating lymphocytes of three patients while their 
respective cancers expressed 15, 21, and 30 non-synonymous variants. Cell 
sorting of tumor-infiltrating lymphocytes based on the co-expression of CD39 and 
CD103 pinpointed the presence of neoantigen-specific T cells in the CD39+CD103+ 
T cell subset. Strikingly, the tumors containing neoantigen-reactive TIL were 
classified as consensus molecular subtype 4 (CMS4), which is associated with 
TGF-β pathway activation and worse clinical outcome.
CONCLUSIONS: We have detected neoantigen-targeted reactivity by autologous T 
cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. 
These findings warrant the development of specific immunotherapeutic strategies 
that selectively boost the activity of neoantigen-specific T cells and target 
the TGF-β pathway to reinforce T cell reactivity in this patient group.

DOI: 10.1186/s13073-019-0697-8
PMCID: PMC6938004
PMID: 31888734 [Indexed for MEDLINE]

Conflict of interest statement: T. Duhen and A.D. Weinberg disclose that they 
have submitted a patent regarding therapeutic and diagnostic use of the 
CD39+CD103+ CD8+ T cells in cancer patients. The other authors declare that they 
have no competing interests.


212. J Am Coll Radiol. 2017 Aug;14(8):1013-1019. doi: 10.1016/j.jacr.2017.01.056. 
Epub 2017 May 27.

Variation in Screening Mammography Rates Among Medicare Advantage Plans.

Rosenkrantz AB(1), Fleming M(2), Duszak R Jr(2).

Author information:
(1)Department of Radiology, NYU School of Medicine, NYU Langone Medical Center, 
New York, New York. Electronic address: andrew.rosenkrantz@nyumc.org.
(2)Department of Radiology and Imaging Sciences, Emory University School of 
Medicine, Atlanta, Georgia.

PURPOSE: Prior studies have shown higher screening mammography rates for 
beneficiaries in capitated managed care Medicare Advantage (MA) plans compared 
with traditional fee-for-service Medicare. The aim of this study was to explore 
variation in screening mammography rates at the level of MA managed care plans.
METHODS: Using the 2016 MA Healthcare Effectiveness Data and Information Set 
Public Use File, screening mammography rates were identified for all 385 
reporting MA plans. Associations were explored with a range of plan 
characteristics from this file, as well as from the CMS Part C and Part D 
Medicare Star Ratings Data File, Medicare Advantage Plan Directory, and Medicare 
Monthly Enrollment by Plan File.
RESULTS: Overall MA plan screening rates were high (mean, 72.6 ± 9.4%) but 
varied substantially among plans (range, 14.3%-91.8%). Screening rates were 
higher in nonprofit versus for-profit plans (77.3% versus 71.8%, P < .001), as 
well as in health maintenance organization or local preferred provider 
organization plans versus private fee-for-service or regional preferred provider 
organization plans (71.9%-73.2% versus 65.5%-66.8%, P = .001). Among parent 
organizations with five or more plans, screening rates were highest for Kaiser 
Foundation (median, 88.4%) and lowest for Molina Healthcare (median, 65.3%). 
Screening rates showed small but significant associations with plans' contract 
lengths, enrolled populations, and counties served. Screening rates showed 
strong associations (r = 0.796-0.798) with colorectal cancer screening and 
annual flu vaccine rates and showed moderate associations (r = 0.283-0.365) with 
ambulatory and preventive care visits, osteoporosis screenings, body mass index 
assessments, and nonrecommended prostate-specific antigen screenings after 
age 70.
CONCLUSIONS: Screening mammography rates vary considerably among MA plans. With 
increased federal interest in promoting the MA program, enhanced transparency 
will be necessary to ensure appropriate Medicare beneficiary participation 
decision making.

Copyright © 2017 American College of Radiology. Published by Elsevier Inc. All 
rights reserved.

DOI: 10.1016/j.jacr.2017.01.056
PMID: 28566133 [Indexed for MEDLINE]


213. Med Decis Making. 2016 Jul;36(5):666-79. doi: 10.1177/0272989X16646732.

The Role of Decision Models in Health Care Policy: A Case Study.

John-Baptiste A(1)(2)(3)(4)(5), Schapira MM(6)(7), Cravens C(1), Chambers JD(5), 
Neumann PJ(5), Siegel J(1), Lawrence W(1).

Author information:
(1)Center for Outcomes and Evidence, Agency for Healthcare Research and Quality, 
Department of Health and Human Services, Rockville, MD, USA (AJ-B, CC, JS, WL)
(2)Departments of Anesthesia & Perioperative Medicine, Epidemiology & 
Biostatistics, Interfaculty Program in Public Health, Schulich School of 
Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada 
(AJ-B)
(3)Centre for Medical Evidence, Decision Integrity, Clinical Impact (MEDICI), 
London, Ontario, Canada (AJ-B)
(4)Lawson Health Research Institute, London, Ontario, Canada (AJ-B)
(5)Center for the Evaluation of Value and Risk in Health, Institute for Clinical 
Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA (AJ-B, 
JDC, PJN)
(6)Perelman School of Medicine, University of Pennsylvania, PA, USA (MMS)
(7)Center for Health Equity & Research Program, Philadelphia VA Medical Center, 
PA, USA (MMS)

Erratum in
    Med Decis Making. 2018 Aug;38(6):761.

BACKGROUND: In 2009, the Centers for Medicare and Medicaid Services (CMS) 
underwent a National Coverage Determination on computed tomography colonography 
(CTC) to screen for colorectal cancer. The Cancer Intervention & Surveillance 
Network developed decision models to inform this decision. The purpose of our 
study was to investigate the role of models in this decision.
METHODS: We performed a descriptive case study. We conducted semistructured 
telephone interviews with members of the CMS coverage and analysis group (CAG) 
and Medicare Coverage and Analysis Advisory Committee (MEDCAC) panelists. 
Informed by previously published literature, we developed a coding scheme to 
analyze interview transcripts, MEDCAC meeting transcripts, and the final CMS 
decision memo.
RESULTS: Four members of the CAG and 8 MEDCAC panelists were interviewed. The 
total number of codes across all study documents was 772. We found evidence that 
decision makers believed in the adequacy of models to inform decision making. In 
interview transcripts, the code Models Are Adequate to Inform was more frequent 
than the code Models Are Inadequate to Inform (47 times v. 5). Discussion of 
model conceptualization dominated the MEDCAC meeting (Model Conceptualization 
assigned 113 times) and was frequently discussed during interviews (Model 
Conceptualization assigned 84 times). We also found evidence that the models 
helped to focus the policy discussion. Across study documents, the codes Focus 
on Cost, Focus on Clinical-Health Impact, and Focus on Inadequacy of Evidence 
Base were assigned 99, 98, and 97 times, respectively.
CONCLUSIONS: Decision makers involved in the CTC decision believed in the 
adequacy of models to inform coverage decisions. The model played a role in 
focusing the CTC coverage policy discussion.

© The Authors 2016.

DOI: 10.1177/0272989X16646732
PMID: 27225487 [Indexed for MEDLINE]


214. Clin Cancer Res. 2020 Feb 15;26(4):870-881. doi: 10.1158/1078-0432.CCR-19-1159. 
Epub 2019 Nov 22.

Whole-Slide Image Analysis Reveals Quantitative Landscape of Tumor-Immune 
Microenvironment in Colorectal Cancers.

Yoo SY(1)(2), Park HE(1)(2), Kim JH(1)(2), Wen X(2), Jeong S(2), Cho NY(2), Gwon 
HG(3)(4), Kim K(4), Lee HS(1)(5), Jeong SY(6), Park KJ(6), Han SW(7), Kim TY(7), 
Bae JM(8)(2), Kang GH(8)(2).

Author information:
(1)Department of Pathology, Seoul National University College of Medicine, 
Seoul, South Korea.
(2)Laboratory of Epigenetics, Cancer Research Institute, Seoul National 
University College of Medicine, Seoul, South Korea.
(3)Department of Statistics, Korea University, Seoul, South Korea.
(4)Division of Clinical Bioinformatics, Biomedical Research Institute, Seoul 
National University Hospital, Seoul, South Korea.
(5)Department of Pathology, Seoul National University Bundang Hospital, 
Seongnam, South Korea.
(6)Department of Surgery, Seoul National University College of Medicine, Seoul, 
South Korea.
(7)Department of Internal Medicine, Seoul National University College of 
Medicine, Seoul, South Korea.
(8)Department of Pathology, Seoul National University College of Medicine, 
Seoul, South Korea. ghkang@snu.ac.kr jeongmobae@gmail.com.

PURPOSE: Despite the well-known prognostic value of the tumor-immune 
microenvironment (TIME) in colorectal cancers, objective and readily applicable 
methods for quantifying tumor-infiltrating lymphocytes (TIL) and the 
tumor-stroma ratio (TSR) are not yet available.
EXPERIMENTAL DESIGN: We established an open-source software-based analytic 
pipeline for quantifying TILs and the TSR from whole-slide images obtained after 
CD3 and CD8 IHC staining. Using a random forest classifier, the method 
separately quantified intraepithelial TILs (iTIL) and stromal TILs (sTIL). We 
applied this method to discovery and validation cohorts of 578 and 283 stage III 
or high-risk stage II colorectal cancers patients, respectively, who were 
subjected to curative surgical resection and oxlaliplatin-based adjuvant 
chemotherapy.
RESULTS: Automatic quantification of iTILs and sTILs showed a moderate 
concordance with that obtained after visual inspection by a pathologist. The 
K-means-based consensus clustering of 197 TIME parameters that showed robustness 
against interobserver variations caused colorectal cancers to be grouped into 
five distinctive subgroups, reminiscent of those for consensus molecular 
subtypes (CMS1-4 and mixed/intermediate group). In accordance with the original 
CMS report, the CMS4-like subgroup (cluster 4) was significantly associated with 
a worse 5-year relapse-free survival and proved to be an independent prognostic 
factor. The clinicopathologic and prognostic features of the TIME subgroups have 
been validated in an independent validation cohort.
CONCLUSIONS: Machine-learning-based image analysis can be useful for extracting 
quantitative information about the TIME, using whole-slide histopathologic 
images. This information can classify colorectal cancers into 
clinicopathologically relevant subgroups without performing a molecular analysis 
of the tumors.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-19-1159
PMID: 31757879 [Indexed for MEDLINE]


215. J Am Coll Radiol. 2013 Dec;10(12):937-42. doi: 10.1016/j.jacr.2013.09.014.

The challenges of CT colonography reimbursement.

Dachman AH(1), Yee J.

Author information:
(1)The University of Chicago Medical Center, Chicago, Illinois. Electronic 
address: ahdachma@uchicago.edu.

CT colonography has been shown to be an effective method to screen for 
colorectal cancer. However, at present, full endorsement and reimbursement for 
screening CT colonography, particularly by the US Preventive Services Task Force 
and CMS, respectively, are absent, so this screening option is infrequently 
used, and optical colonoscopy remains the de facto standard screening option. 
The authors summarize the past accomplishments that led to the current state of 
reimbursement and outline the remaining challenges and road to full acceptance 
and reimbursement of screening CT colonography nationally.

Copyright © 2013 American College of Radiology. All rights reserved.

DOI: 10.1016/j.jacr.2013.09.014
PMID: 24295944 [Indexed for MEDLINE]


216. J Clin Med. 2021 Jun 1;10(11):2458. doi: 10.3390/jcm10112458.

Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under 
Regular Colonoscopy Surveillance.

Ahadova A(1), Pfuderer PL(1), Ahtiainen M(2), Ballhausen A(1), Bohaumilitzky 
L(1), Kösegi S(1), Müller N(1), Tang YL(1), Kosmalla K(1), Witt J(1), Endris 
V(3), Stenzinger A(3), von Knebel Doeberitz M(1), Bläker H(4), Renkonen-Sinisalo 
L(5), Lepistö A(5), Böhm J(6), Mecklin JP(2)(7), Seppälä TT(5)(8), Kloor M(1).

Author information:
(1)Department of Applied Tumour Biology, Institute of Pathology, University 
Hospital Heidelberg, Cooperation Unit Applied Tumour Biology, German Cancer 
Research Center (DKFZ), 69120 Heidelberg, Germany.
(2)Department of Education and Research, Central Finland Central Hospital, 40620 
Jyväskylä, Finland.
(3)Department of General Pathology, Institute of Pathology, University Hospital 
Heidelberg, 69120 Heidelberg, Germany.
(4)Institute of Pathology, University Hospital Leipzig, 04103 Leipzig, Germany.
(5)Department of Gastrointestinal Surgery, Helsinki University Hospital, 00290 
Helsinki, Finland.
(6)Department of Pathology, Central Finland Central Hospital, 40620 Jyväskylä, 
Finland.
(7)Faculty of Sports and Health Sciences, University of Jyväskylä, 40014 
Jyväskylä, Finland.
(8)Department of Surgical Oncology, Johns Hopkins University, Baltimore, MD 
21287, USA.

Regular colonoscopy even with short intervals does not prevent all colorectal 
cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether 
cancers detected under regular colonoscopy surveillance (incident cancers) are 
phenotypically different from cancers detected at first colonoscopy (prevalent 
cancers). We analyzed clinical, histological, immunological and mutational 
characteristics, including panel sequencing and high-throughput coding 
microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs (n total 
= 95). Incident cancers presented with lower UICC and T stage compared to 
prevalent cancers (p < 0.0005). The majority of incident cancers (21/28) were 
detected after previous colonoscopy without any pathological findings. On the 
molecular level, incident cancers presented with a significantly lower KRAS 
codon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenic TP53 mutation 
frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 
10/17 (58.8%) incident cancers harbored one or more truncating APC mutations, 
all showing mutational signatures of mismatch repair (MMR) deficiency. The 
proportion of MMR deficiency-related mutational events was significantly higher 
in incident compared to prevalent CRC (p = 0.018). In conclusion, our study 
identifies a set of features indicative of biological differences between 
incident and prevalent cancers in LS, which should further be monitored in 
prospective LS screening studies to guide towards optimized prevention 
protocols.

DOI: 10.3390/jcm10112458
PMCID: PMC8198627
PMID: 34206061

Conflict of interest statement: The authors declare no conflict of interest.


217. Front Immunol. 2021 Sep 24;12:733317. doi: 10.3389/fimmu.2021.733317. 
eCollection 2021.

High-Throughput 3D In Vitro Tumor Vasculature Model for Real-Time Monitoring of 
Immune Cell Infiltration and Cytotoxicity.

Song J(1), Choi H(2), Koh SK(3), Park D(1), Yu J(2), Kang H(2), Kim Y(1), Cho 
D(3)(4), Jeon NL(1)(2)(5).

Author information:
(1)Department of Mechanical Engineering, Seoul National University, Seoul, South 
Korea.
(2)Interdisciplinary Program in Bioengineering, Seoul National University, 
Seoul, South Korea.
(3)Department of Health Sciences and Technology, Samsung Advanced Institute for 
Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, South 
Korea.
(4)Department of Laboratory Medicine and Genetics, Samsung Medical Center, 
Sungkyunkwan University School of Medicine, Seoul, South Korea.
(5)Institute of Advanced Machines and Design (SNU-IAMD), Seoul National 
University, Seoul, South Korea.

Recent advances in anticancer therapy have shown dramatic improvements in 
clinical outcomes, and adoptive cell therapy has emerged as a type of 
immunotherapy that can modulate immune responses by transferring engineered 
immune cells. However, a small percentage of responders and their toxicity 
remain as challenges. Three-dimensional (3D) in vitro models of the tumor 
microenvironment (TME) have the potential to provide a platform for assessing 
and predicting responses to therapy. This paper describes an in vitro 3D tumor 
model that incorporates clusters of colorectal cancer (CRC) cells around 
perfusable vascular networks to validate immune-cell-mediated cytotoxicity 
against cancer cells. The platform is based on an injection-molded 3D co-culture 
model and composed of 28 microwells where separate identical vascularized cancer 
models can be formed. It allows robust hydrogel patterning for 3D culture that 
enables high-throughput experimentation. The uniformity of the devices resulted 
in reproducible experiments that allowed 10× more experiments to be performed 
when compared to conventional polydimethylsiloxane (PDMS)-based microfluidic 
devices. To demonstrate its capability, primary natural killer (NK) cells were 
introduced into the vascularized tumor network, and their activities were 
monitored using live-cell imaging. Extravasation, migration, and cytotoxic 
activity against six types of CRC cell lines were tested and compared. The 
consensus molecular subtypes (CMS) of CRC with distinct immune responses 
resulted in the highest NK cell cytotoxicity against CMS1 cancer cells. These 
results show the potential of our vascularized tumor model for understanding 
various steps involved in the immune response for the assessment of adoptive 
cell therapy.

Copyright © 2021 Song, Choi, Koh, Park, Yu, Kang, Kim, Cho and Jeon.

DOI: 10.3389/fimmu.2021.733317
PMCID: PMC8500473
PMID: 34630415 [Indexed for MEDLINE]

Conflict of interest statement: NJ is a founder and CTO of Qureator which has 
commercialized the chips used in this work. The remaining authors declare that 
the research was conducted in the absence of any commercial or financial 
relationships that could be construed as a potential conflict of interest.


218. Ethn Dis. 2006 Spring;16(2):412-20.

Racial disparities and trends in use of colorectal procedures among Tennessee 
elderly (1996-2000).

Zhao BB(1), Kilbourne B, Stain SC, Van Cain A, Briggs NC, Husaini BA, Levine R.

Author information:
(1)Meharry Medical College, Department of Surgery, 1005 DB Todd Blvd, Nashville, 
TN 37208, USA. bzhao@mmc.edu

BACKGROUND: Blacks are more likely to be diagnosed at a later stage of 
colorectal cancer (CRC), and have poorer survival than Whites. Colorectal cancer 
(CRC) is usually curable when diagnosed at an early stage.
OBJECTIVES: We compare the use of CRC tests for screening between Whites and 
Blacks and compare the use of CRC tests for either screening or diagnosis and 
further check the test results for a diagnosis of CRC.
DATA: The data we use are from physician claims files provided by the Centers 
for Medicare and Medicaid Services (CMS) (1996-2000) for a closed cohort of all 
Tennesseans eligible for Medicare in 1996, age > or = 6.
RESULTS: Half as many Blacks as Whites were screened with fecal occult blood 
testing (FOBT), sigmoidoscopy, and colonoscopy. Significantly fewer Blacks had 
any colorectal procedures, sigmoidoscopy, colonoscopy, and/ or barium enema, for 
screening or diagnosis; however, the test results show that more Blacks were 
diagnosed with CRC than Whites. The use of CRC tests is low regardless of race. 
Only 24% of beneficiaries used at least one of the four procedures during the 
five years. During the five years, FOBT and barium enema use decreased 
significantly for both Blacks and Whites, while colonoscopy use increased 
significantly. Sigmoidoscopy use was highest in 1998, which corresponds to the 
change of Medicare coverage policy in 1998.
CONCLUSIONS: Removal of financial barriers to screening alone has failed to 
substantially improve the use of colorectal procedures. Lack of vigilance and 
lack of access to good quality of care contribute to the fact that Blacks are 
more likely to be diagnosed at a late stage of CRC than Whites.

PMID: 17682243 [Indexed for MEDLINE]


219. J Gen Intern Med. 2015 May;30(5):641-50. doi: 10.1007/s11606-014-3162-9. Epub 
2015 Jan 14.

Unveiling SEER-CAHPS®: a new data resource for quality of care research.

Chawla N(1), Urato M, Ambs A, Schussler N, Hays RD, Clauser SB, Zaslavsky AM, 
Walsh K, Schwartz M, Halpern M, Gaillot S, Goldstein EH, Arora NK.

Author information:
(1)Division of Cancer Control and Population Sciences, Cancer Prevention Fellow, 
National Cancer Institute, 9609 Medical Center Drive, 3E450, Rockville, MD, 
20892, USA, neetu.chawla@nih.gov.

Comment in
    J Gen Intern Med. 2015 May;30(5):655.

BACKGROUND: Since 1990, the National Cancer Institute (NCI) and Centers for 
Medicare and Medicaid Services (CMS) have collaborated to create linked data 
resources to improve our understanding of patterns of care, health care costs, 
and trends in utilization. However, existing data linkages have not included 
measures of patient experiences with care.
OBJECTIVE: To describe a new resource for quality of care research based on a 
linkage between the Medicare Consumer Assessment of Healthcare Providers and 
Systems (CAHPS®) patient surveys and the NCI's Surveillance, Epidemiology and 
End Results (SEER) data.
DESIGN: This is an observational study of CAHPS respondents and includes both 
fee-for-service and Medicare Advantage beneficiaries with and without cancer. 
The data linkage includes: CAHPS survey data collected between 1998 and 2010 to 
assess patient reports on multiple aspects of their care, such as access to 
needed and timely care, doctor communication, as well as patients' global 
ratings of their personal doctor, specialists, overall health care, and their 
health plan; SEER registry data (1973-2007) on cancer site, stage, treatment, 
death information, and patient demographics; and longitudinal Medicare claims 
data (2002-2011) for fee-for-service beneficiaries on utilization and costs of 
care.
PARTICIPANTS: In total, 150,750 respondents were in the cancer cohort and 
571,318 were in the non-cancer cohort.
MAIN MEASURES: The data linkage includes SEER data on cancer site, stage, 
treatment, death information, and patient demographics, in addition to 
longitudinal data from Medicare claims and information on patient experiences 
from CAHPS surveys.
KEY RESULTS: Sizable proportions of cases from common cancers (e.g., breast, 
colorectal, prostate) and short-term survival cancers (e.g., pancreas) by time 
since diagnosis enable comparisons across the cancer care trajectory by MA vs. 
FFS coverage.
CONCLUSIONS: SEER-CAHPS is a valuable resource for information about Medicare 
beneficiaries' experiences of care across different diagnoses and treatment 
modalities, and enables comparisons by type of insurance.

DOI: 10.1007/s11606-014-3162-9
PMCID: PMC4395616
PMID: 25586868 [Indexed for MEDLINE]


220. BMC Cancer. 2022 Mar 10;22(1):256. doi: 10.1186/s12885-022-09344-3.

An integrative gene expression signature analysis identifies CMS4 KRAS-mutated 
colorectal cancers sensitive to combined MEK and SRC targeted therapy.

Yang M(1), Davis TB(1), Pflieger L(2), Nebozhyn MV(3), Loboda A(3), Wang H(1), 
Schell MJ(4), Thota R(5), Pledger WJ(1)(6), Yeatman TJ(7)(8).

Author information:
(1)Department of Surgery & Molecular Medicine, University of South Florida, 
Tampa General Hospital Cancer Institute, 560 Channelside Drive, Tampa, FL, 
33602, USA.
(2)Precision Genomics Translational Science Center, Intermountain Healthcare, 
5026 South State Street, Murray, UT, 84107, USA.
(3)Sharp and Dohme, 770 Sumneytown Pike, Building 53, West Point, P.O. Box 4, 
Merck, PA, 19486, USA.
(4)Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & 
Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
(5)Oncology Clinical Program, Intermountain Healthcare, 5026 South State Street, 
Murray, UT, 84107, USA.
(6)Huntsman Cancer Institute, University of Utah, 2000 Cir of Hope Dr, Salt Lake 
City, UT, 84112, USA.
(7)Department of Surgery & Molecular Medicine, University of South Florida, 
Tampa General Hospital Cancer Institute, 560 Channelside Drive, Tampa, FL, 
33602, USA. yeatman7383@gmail.com.
(8)Huntsman Cancer Institute, University of Utah, 2000 Cir of Hope Dr, Salt Lake 
City, UT, 84112, USA. yeatman7383@gmail.com.

BACKGROUND: Over half of colorectal cancers (CRCs) are hard-wired to 
RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted 
therapeutic inhibitors, has been tempered by disappointing clinical activity, 
likely due to complex resistance mechanisms that are not well understood. This 
study aims to investigate MEK inhibitor-associated resistance signaling and 
identify subpopulation(s) of CRC patients who may be sensitive to 
biomarker-driven drug combination(s).
METHODS: We classified 2250 primary and metastatic human CRC tumors by consensus 
molecular subtypes (CMS). For each tumor, we generated multiple gene expression 
signature scores measuring MEK pathway activation, MEKi "bypass" resistance, SRC 
activation, dasatinib sensitivity, EMT, PC1, Hu-Lgr5-ISC, Hu-EphB2-ISC, Hu-Late 
TA, Hu-Proliferation, and WNT activity. We carried out correlation, survival and 
other bioinformatic analyses. Validation analyses were performed in two 
independent publicly available CRC tumor datasets (n = 585 and n = 677) and a 
CRC cell line dataset (n = 154).
RESULTS: Here we report a central role of SRC in mediating "bypass"-resistance 
to MEK inhibition (MEKi), primarily in cancer stem cells (CSCs). Our integrated 
and comprehensive gene expression signature analyses in 2250 CRC tumors reveal 
that MEKi-resistance is strikingly-correlated with SRC activation (Spearman 
P < 10-320), which is similarly associated with EMT (epithelial to mesenchymal 
transition), regional metastasis and disease recurrence with poor prognosis. 
Deeper analysis shows that both MEKi-resistance and SRC activation are 
preferentially associated with a mesenchymal CSC phenotype. This association is 
validated in additional independent CRC tumor and cell lines datasets. The CMS 
classification analysis demonstrates the strikingly-distinct associations of 
CMS1-4 subtypes with the MEKi-resistance and SRC activation. Importantly, 
MEKi + SRCi sensitivities are predicted to occur predominantly in the KRAS 
mutant, mesenchymal CSC-like CMS4 CRCs.
CONCLUSIONS: Large human tumor gene expression datasets representing CRC 
heterogeneity can provide deep biological insights heretofore not possible with 
cell line models, suggesting novel repurposed drug combinations. We identified 
SRC as a common targetable node--an Achilles' heel--in MEKi-targeted 
therapy-associated resistance in mesenchymal stem-like CRCs, which may help 
development of a biomarker-driven drug combination (MEKi + SRCi) to treat 
problematic subpopulations of CRC.

© 2022. The Author(s).

DOI: 10.1186/s12885-022-09344-3
PMCID: PMC8908604
PMID: 35272617 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


221. J Gastrointest Surg. 2015 Jan;19(1):142-51; discussion 151. doi: 
10.1007/s11605-014-2642-x. Epub 2014 Sep 9.

Prevalence, impact, and risk factors for hospital-acquired conditions after 
major surgical resection for cancer: a NSQIP analysis.

Molena D(1), Mungo B, Stem M, Feinberg RL, Lidor AO.

Author information:
(1)Division of Thoracic Surgery, Department of Surgery, Johns Hopkins University 
School of Medicine, 600 N Wolfe Street, Blalock 240, Baltimore, MD, 21287, USA, 
dmolena2@jhmi.edu.

Comment in
    J Urol. 2016 Oct;196(4):1141-2.

BACKGROUND: The effectiveness of the CMS nonpayment policy for certain 
hospital-acquired conditions (HAC) is debated, since their preventability is 
questionable in several groups of patients. This study aimed to determine the 
rate of the three most common HAC in major surgical resections for cancer: 
surgical site infection (SSI), urinary tract infection (UTI), and venous 
thromboembolism (VTE). Additionally, the association of HAC with patients' 
characteristics and their effect on post-operative outcomes were investigated.
METHODS: Patients who underwent surgical resection for esophageal, gastric, 
hepato-biliary, pancreatic, colorectal, and lung cancer were identified using 
the ACS-NSQIP database (2005-2012). Early surgical outcomes were compared 
between HAC and non-HAC patients. Modified Poisson regression was used to 
identify risk factors for developing HAC.
RESULTS: Seventy-four thousand three hundred eighty-one patients were 
identified, of whom 9,479 (12.74%) developed one or more HAC. HAC patients had 
significantly higher rates of 30-day mortality, return to operating room, 30-day 
readmission, had longer LOS, and were less likely to be discharged home. Several 
peri-operative patients' factors were significantly associated with HAC.
CONCLUSION: Our data show that the development of HAC is strongly associated to 
pre-operative patients' characteristics and not only to sub-optimal 
peri-operative care, therefore suggesting that the nonpayment policy might be 
excessively penalizing.

DOI: 10.1007/s11605-014-2642-x
PMID: 25199948 [Indexed for MEDLINE]


222. J Cell Mol Med. 2022 Jan;26(2):343-353. doi: 10.1111/jcmm.17084. Epub 2021 Nov 
28.

Identification of liver-derived bone morphogenetic protein (BMP)-9 as a 
potential new candidate for treatment of colorectal cancer.

Cai C(1), Itzel T(1), Gaitantzi H(1)(2), de la Torre C(3), Birgin E(2), Betge 
J(1), Gretz N(3), Teufel A(1), Rahbari NN(2), Ebert MP(1), Breitkopf-Heinlein 
K(1)(2).

Author information:
(1)Department of Medicine II, University Medical Center Mannheim, Medical 
Faculty Mannheim, Heidelberg University, Mannheim, Germany.
(2)Department of Surgery, University Medical Center Mannheim, Medical Faculty 
Mannheim, Heidelberg University, Mannheim, Germany.
(3)Medical Research Center, University Medical Center Mannheim, Medical Faculty 
Mannheim, Heidelberg University, Mannheim, Germany.

Colorectal cancer (CRC) is a high-incidence malignancy worldwide which still 
needs better therapy options. Therefore, the aim of the present study was to 
investigate the responses of normal or malignant human intestinal epithelium to 
bone morphogenetic protein (BMP)-9 and to find out whether the application of 
BMP-9 to patients with CRC or the enhancement of its synthesis in the liver 
could be useful strategies for new therapy approaches. In silico analyses of CRC 
patient cohorts (TCGA database) revealed that high expression of the BMP-target 
gene ID1, especially in combination with low expression of the BMP-inhibitor 
noggin, is significantly associated with better patient survival. Organoid lines 
were generated from human biopsies of colon cancer (T-Orgs) and corresponding 
non-malignant areas (N-Orgs) of three patients. The N-Orgs represented tumours 
belonging to three different consensus molecular subtypes (CMS) of CRC. Overall, 
BMP-9 stimulation of organoids promoted an enrichment of tumour-suppressive gene 
expression signatures, whereas the stimulation with noggin had the opposite 
effects. Furthermore, treatment of organoids with BMP-9 induced ID1 expression 
(independently of high noggin levels), while treatment with noggin reduced ID1. 
In summary, our data identify the ratio between ID1 and noggin as a new 
prognostic value for CRC patient outcome. We further show that by inducing ID1, 
BMP-9 enhances this ratio, even in the presence of noggin. Thus, BMP-9 is 
identified as a novel target for the development of improved anti-cancer 
therapies of patients with CRC.

© 2021 The Authors. Journal of Cellular and Molecular Medicine published by 
Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

DOI: 10.1111/jcmm.17084
PMCID: PMC8743662
PMID: 34841646 [Indexed for MEDLINE]

Conflict of interest statement: The authors confirm that there are no conflicts 
of interest.


223. Sci Rep. 2019 Nov 20;9(1):17178. doi: 10.1038/s41598-019-52841-y.

Prospective validation in epithelial tumors of a gene expression predictor of 
liver metastasis derived from uveal melanoma.

Tsantoulis P(1)(2)(3), Delorenzi M(4)(5)(6), Bièche I(7), Vacher S(7), Mariani 
P(8), Cassoux N(8), Houy A(7)(9), Stern MH(7)(9), Roman-Roman S(10), Dietrich 
PY(11)(12), Roth A(11)(12), Cacheux W(11)(7)(13).

Author information:
(1)Hôpitaux Universitaires de Genève, Service d'Oncologie, Geneva, Switzerland. 
petros.tsantoulis@hcuge.ch.
(2)University of Geneva, Geneva, Switzerland. petros.tsantoulis@hcuge.ch.
(3)SIB Swiss Institute of Bioinformatics, Bioinformatics Core Facility, 
Lausanne, Switzerland. petros.tsantoulis@hcuge.ch.
(4)SIB Swiss Institute of Bioinformatics, Bioinformatics Core Facility, 
Lausanne, Switzerland.
(5)University Lausanne, Department of Fundamental Oncology, Lausanne, 
Switzerland.
(6)Ludwig Institute for Cancer Research, Epalinges, Switzerland.
(7)Institut Curie, Département de génétique, Paris, France.
(8)Institut Curie, Département de chirurgie, Paris, France.
(9)Institut Curie, PSL Research University, INSERM U830, Paris, France.
(10)Institut Curie, PSL Research University, Translational Research Department, 
Paris, France.
(11)Hôpitaux Universitaires de Genève, Service d'Oncologie, Geneva, Switzerland.
(12)University of Geneva, Geneva, Switzerland.
(13)Hôpital Privé - Pays de Savoie, Oncology department, Annemasse, France.

Predicting the risk of liver metastasis can have important prognostic and 
therapeutic implications, given the availability of liver-directed therapy. 
Uveal melanoma has a striking predisposition for liver metastasis despite the 
absence of anatomical proximity. Understanding its biology may uncover factors 
promoting liver metastasis in other malignancies. We quantified gene expression 
by RNAseq in 76 uveal melanomas and combined with public data in a meta-analysis 
of 196 patients. The meta-analysis of uveal melanoma gene expression identified 
63 genes which remained prognostic after adjustment for chromosome 3 status. Two 
genes, PTP4A3 and JPH1, were selected by L1-penalized regression and combined in 
a prognostic score. The score predicted liver-specific relapse in a public 
pan-cancer dataset and in two public colorectal cancer datasets. The score 
varied between colorectal consensus molecular subtypes (CMS), as did the risk of 
liver relapse, which was lowest in CMS1. Additional prospective validation was 
done by real-time PCR in 463 breast cancer patients. The score was significantly 
correlated with liver relapse in hormone receptor positive tumors. In 
conclusion, the expression of PTP4A3 and JPH1 correlates with risk of liver 
metastasis in colorectal cancer and breast cancer. The underlying biological 
mechanism is an interesting area for further research.

DOI: 10.1038/s41598-019-52841-y
PMCID: PMC6868129
PMID: 31748560 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


224. Med Care. 2014 Mar;52(3):e15-20. doi: 10.1097/MLR.0b013e31824e342f.

Sensitivity of Medicare claims data for measuring use of standard multiagent 
chemotherapy regimens.

Lamont EB(1), Lan L.

Author information:
(1)*Departments of Medicine and Health Care Policy, Massachusetts General 
Hospital Cancer Center, Harvard Medical School, Boston, MA †Department of 
Biostatistics Duke University, Durham, NC.

PURPOSE: We sought to determine the accuracy with which Medicare billing data 
documents elderly Medicare cancer patients' receipt of common multiagent 
chemotherapy regimens.
METHODS: We merged gold-standard clinical trial data from 406 elderly cancer 
patients known to be treated on 1 of 6 Cancer and Leukemia Group B (CALGB) 
breast, colorectal, and lung cancer trials (trial numbers; 9344, 9730, 
9235,9732, 80203, 89803) with their Medicare claims data from Centers for 
Medicare and Medicaid Services (CMS). Comparing CMS chemotherapy codes to 
gold-standard CALGB treatment data, we estimated Medicare data's sensitivity at 
measuring the correct drugs and schedule for each of the multiagent chemotherapy 
regimens.
RESULTS: Overall 92% (375/406) of CALGB patients had contemporaneous CMS claims 
indicating receipt of chemotherapy. The overall sensitivity of CMS ambulatory 
claims for documenting treatment with the correct drugs and on the correct 
schedule (ie, all drugs had to be billed on the same day) for the 5 common 
multiagent chemotherapy regimens was 78% (275/354) for those potentially treated 
in the ambulatory setting. The sensitivity was similar for all treatment 
regimens: carboplatin and paclitaxel 83%, 5-fluorouracil and leucovorin 80%, 
fluorouracil, leucovorin, and irinotecan (FOLFIRI) 76%, doxorubicin and 
cyclophosphamide 75%, and cisplatin and etoposide 75%.
CONCLUSIONS: We correctly identified at least 3-quarters of elderly Medicare 
cancer patients treated on a clinical trial with standard first-line multiagent 
chemotherapy regimens in the ambulatory setting by applying coding algorithms to 
their CMS claims. The algorithms may be useful in identifying cohorts of elderly 
Medicare patients for observational studies of the comparative effectiveness of 
standard multiagent chemotherapy regimens.

DOI: 10.1097/MLR.0b013e31824e342f
PMCID: PMC3376655
PMID: 22410411 [Indexed for MEDLINE]


225. Asian Pac J Cancer Prev. 2015;16(12):4873-80. doi: 
10.7314/apjcp.2015.16.12.4873.

Gastrointestinal Stromal Tumors: A Clinicopathologic and Risk Stratification 
Study of 255 Cases from Pakistan and Review of Literature.

Ud Din N(1), Ahmad Z, Arshad H, Idrees R, Kayani N.

Author information:
(1)Department of Pathology and Microbiology, Section of Histopathology, Aga Khan 
University Hospital, Karachi, Pakistan E-mail : nasir.uddin@aku.edu.

PURPOSE: To describe the clinicopathological features of gastrointestinal 
stromal tumors (GIST) diagnosed in our section and to perform risk 
stratification of our cases by assigning them to specific risk categories and 
groups for disease progression based on proposals by Fletcher et al and 
Miettinen and Lasota.
MATERIALS AND RESULTS: We retrieved 255 cases of GIST diagnosed between 2003 and 
2014. Over 59% were male. The age range was 16 to 83 years with a mean of 51 
years. Over 70% occurred between 40 and 70 years of age. Average diameter of 
tumors was 10 cms. The stomach was the most common site accounting for about 
40%. EGISTs constituted about 16%. On histologic examination, spindle cell 
morphology was seen in almost of 85% cases. CD117 was the most useful 
immunohistochemical antibody, positive in 98%. Risk stratification was possible 
for 220 cases. Based on Fletcher's consensus proposal, 62.3 gastric, 81.8% 
duodenal, 68% small intestinal, 72% colorectal and 89% EGISTs were assigned to 
the high risk category; while based on Miettinen and Lasota's algorithm, about 
48% gastric, 100% duodenal, 76% small intestinal, 100% colorectal and 100% 
EGISTs in our study were associated with high risk for disease progression, 
tumor metastasis and tumor related death. Follow up was available in 95 
patients; 26 were dead and 69 alive at follow up. Most of the patients who died 
had high risk disease and on average death occurred just a few months to a 
maximum of one to two years after initial surgical resection.
CONCLUSIONS: Epidemiological and morphologic findings in our study were similar 
to international published data. The majority of cases in our study belonged to 
the high risk category.

DOI: 10.7314/apjcp.2015.16.12.4873
PMID: 26163607 [Indexed for MEDLINE]


226. J Exp Clin Cancer Res. 2022 Mar 29;41(1):113. doi: 10.1186/s13046-022-02309-1.

The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in 
consensus molecular subtype 1 colon cancer.

Mazzeschi M(#)(1), Sgarzi M(#)(1), Romaniello D(1), Gelfo V(1), Cavallo C(2), 
Ambrosi F(3), Morselli A(1), Miano C(4), Laprovitera N(1), Girone C(1), Ferracin 
M(1), Santi S(5)(6), Rihawi K(7), Ardizzoni A(1)(7), Fiorentino M(1), D'Uva 
G(1)(4), Győrffy B(8)(9), Palmer R(10), Lauriola M(11)(12).

Author information:
(1)Department of Experimental, Diagnostic and Specialty Medicine (DIMES), 
University of Bologna, Bologna, Italy.
(2)Laboratory of Preclinical Studies for Regenerative Medicine of the 
Musculoskeletal System (RAMSES), (IRCCS) Istituto Ortopedico Rizzoli, Bologna, 
Italy.
(3)Pathology Unit, Maggiore Hospital, AUSL Bologna, Bologna, Italy.
(4)National Laboratory of Molecular Biology and Stem Cell Engineering, National 
Institute of Biostructures and Biosystems (INBB), Bologna, Italy.
(5)Institute of Molecular Genetics, National Research Council of Italy, Bologna, 
Italy.
(6)IRCCS-Institute Orthopaedic Rizzoli, Bologna, Italy.
(7)Medical Oncology, IRCSS Azienda-Ospedaliero Universitaria di Bologna, Via 
Albertoni 15, 40138, Bologna, Italy.
(8)Semmelweis University Department of Bioinformatics and 2nd Department Of 
Pediatrics, Budapest, Hungary.
(9)TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, 
Hungary.
(10)Department of Medical Biochemistry and Cell Biology, Institute of 
Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
(11)Department of Experimental, Diagnostic and Specialty Medicine (DIMES), 
University of Bologna, Bologna, Italy. mattia.lauriola2@unibo.it.
(12)Centre for Applied Biomedical Research (CRBA), Bologna University Hospital 
Authority St. Orsola -Malpighi Polyclinic, Via Belmeloro 8, 40125, Bologna, 
Italy. mattia.lauriola2@unibo.it.
(#)Contributed equally

BACKGROUND: In the last years, several efforts have been made to classify 
colorectal cancer (CRC) into well-defined molecular subgroups, representing the 
intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes 
(CMSs).
METHODS: In this work, we performed a meta-analysis of CRC patients stratified 
into four CMSs. We identified a negative correlation between a high level of 
anaplastic lymphoma kinase (ALK) expression and relapse-free survival, 
exclusively in CMS1 subtype. Stemming from this observation, we tested cell 
lines, patient-derived organoids and mice with potent ALK inhibitors, already 
approved for clinical use.
RESULTS: ALK interception strongly inhibits cell proliferation already at 
nanomolar doses, specifically in CMS1 cell lines, while no effect was found in 
CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the 
dynamic formation of 3D tumor spheroids. Consistently, ALK appeares 
constitutively phosphorylated in CMS1, and it signals mainly through the AKT 
axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 
ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the 
activation of ALK pathway, responsible for the invasive phenotype. Consequently, 
disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, 
both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. 
In agreement with all these findings, the ALK signature encompassing 65 genes 
statistically associated with worse relapse-free survival in CMS1 subtype. 
Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated 
in both patient-derived organoids and in tumor xenografts in vivo.
CONCLUSIONS: Collectively, these findings suggest that ALK targeting may 
represent an attractive therapy for CRC, and CMS classification may provide a 
useful tool to identify patients who could benefit from this treatment. These 
findings offer rationale and pharmacological strategies for the treatment of 
CMS1 CRC.

© 2022. The Author(s).

DOI: 10.1186/s13046-022-02309-1
PMCID: PMC8962179
PMID: 35351152 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare they have no competing 
interest.


227. World J Surg Oncol. 2018 Oct 17;16(1):210. doi: 10.1186/s12957-018-1509-0.

Comparative study between colonic metallic stent and anal tube decompression for 
Japanese patients with left-sided malignant large bowel obstruction.

Kagami S(1), Funahashi K(2), Ushigome M(1), Koike J(1), Kaneko T(1), Koda T(1), 
Kurihara A(1), Nagashima Y(1), Yoshino Y(1), Goto M(1), Mikami T(3), Chino K(4).

Author information:
(1)Department of General and Gastroenterological Surgery, Toho University Omori 
Medical Center, 6-11-1 Omorinishi Otaku, Tokyo, 143-8541, Japan.
(2)Department of General and Gastroenterological Surgery, Toho University Omori 
Medical Center, 6-11-1 Omorinishi Otaku, Tokyo, 143-8541, Japan. 
kingkong@med.toho-u.ac.jp.
(3)Department of Pathology, Toho University School of Medicine, 5-21-16 
Omorinishi, Otaku, Tokyo, 143-8540, Japan.
(4)Department of Internal Medicine, United States Naval Hospital, 1-chome 
Tomari-cho, Yokosuka-shi, Kanagawa, 238-0001, Japan.

BACKGROUND: Surgical management of malignant bowel obstruction carries with high 
morbidity and mortality. Placement of a trans-anal decompression tube (TDT) has 
traditionally been used for malignant bowel obstruction as a bridge to surgery. 
Recently, colonic metallic stent (CMS) as a bridge to surgery for malignant 
bowel obstruction, particularly left-sided malignant large bowel obstruction 
(LMLBO) caused by colorectal cancer, has been reported to be both a safe and 
feasible option. The aim of this retrospective study is to evaluate the clinical 
effects of CMS for LMLBO as a bridge to surgery compared to TDT.
METHODS: Between January 2000 and December 2015, we retrospectively evaluated 
outcomes of 59 patients with LMLBO. We compared the outcomes of 26 patients with 
CMS for LMLBO between 2013 and 2015 (CMS group) with those of 33 patients 
managed with TDT between 2003 and 2011 (TDT group) by the historical study. 
LMLBO was defined as a large bowel obstruction due to a colorectal cancer that 
was diagnosed by computed tomography and required emergent decompression.
RESULTS: All patients in the CMS group were successfully decompressed (p = 0.03) 
and could initiate oral intake after the procedure (p <  0.01). Outcomes in the 
CMS group were superior to the TDT group in the following areas: duration of 
tube placement (p <  0.01), surgical approach (p <  0.01), operation time 
(p <  0.01), number of resected lymph nodes (p <  0.001), and rate of curative 
resection (p <  0.01). However, no significant differences were found in the 
overall postoperative complication rate (p = 0.151), surgical site infection 
rate (p = 0.685), hospital length of stay (p = 0.502), and the need for 
permanent ostomy (p = 0.745). The 3-year overall survival rate of patients in 
the CMS and TDT groups was 73.0% and 80.9%, respectively, and this was not 
significant (p = 0.423).
CONCLUSIONS: Treatment with CMS for patients with LMLBO as a bridge to surgery 
is safe and demonstrated higher rates of resumption of solid food intake and 
temporary discharge prior to elective surgery compared to TDT. Oncological 
outcomes during mid-term were equivalent.

DOI: 10.1186/s12957-018-1509-0
PMCID: PMC6193302
PMID: 30333034 [Indexed for MEDLINE]

Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The 
study was approved by the Ethics Committee of Toho University Omori Medical 
Center (No. M18003). The informed consent was waived because this is a 
retrospective study. CONSENT FOR PUBLICATION: Not applicable COMPETING 
INTERESTS: The authors declare that they have no competing interests. 
PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional 
claims in published maps and institutional affiliations.


228. J Clin Gastroenterol. 2014 Oct;48(9):745-51. doi: 10.1097/MCG.0000000000000188.

Computed tomography colonography: ready for prime time for colon cancer 
screening?

Parekh PJ(1), Shams R, Oldfield EC 4th, Nicholas JJ, Johnson DA.

Author information:
(1)*Division of Gastroenterology and Hepatology, Department of Internal 
Medicine, Tulane University, New Orleans, LA †Department of Internal Medicine, 
Eastern Virginia Medical School, Norfolk, VA ‡Eastern Virginia Medical School, 
Norfolk, VA §Department of Gastroenterology, Scripps Health, San Diego, CA 
∥Department of Internal Medicine, Gastroenterology Division, Eastern Virginia 
Medical School, Norfolk, VA.

In 2008, results from the landmark American College of Radiology Imaging Network 
(ACRIN) trial provided evidence supporting the use computed tomography 
colonography (CTC) as a comparable alternative to colonoscopy for colorectal 
cancer (CRC) screening. Subsequently, however, the United States Preventive Task 
Force decided against a recommendation in support of CTC for CRC screening. 
Following soon after, the Centers for Medicare and Medicaid Services (CMS) made 
noncoverage decision for the use of CTC in CRC screening. Since that decision, 
there have been a number of publications on CTC and CRC screening with a strong 
push from the radiology community to reassess CTC as a viable option. The 
purpose of this review was to address focused questions concerning the use of 
CTC in CRC screening, through an analysis of the available scientific evidence 
in an effort to provide recommendations for clinicians, patients, and payors who 
may evaluate the role of CTC for CRC screening.

DOI: 10.1097/MCG.0000000000000188
PMID: 25144899 [Indexed for MEDLINE]


229. BMC Genomics. 2017 May 30;18(1):421. doi: 10.1186/s12864-017-3798-z.

Genome-wide network-based pathway analysis of CSF t-tau/Aβ1-42 ratio in the ADNI 
cohort.

Cong W(1), Meng X(1)(2), Li J(1), Zhang Q(1)(3), Chen F(1), Liu W(1), Wang Y(1), 
Cheng S(1), Yao X(4)(5), Yan J(4)(5)(6), Kim S(4)(6), Saykin AJ(4)(6), Liang 
H(7), Shen L(8)(9); Alzheimer’s Disease Neuroimaging Initiative.

Author information:
(1)College of Automation, Harbin Engineering University, 145 Nantong Street, 
BLDG 61-5029, Harbin, 150001, China.
(2)Harbin Huade University, No.288 Xue Yuan Rd. Limin Development Zone, Harbin, 
150025, China.
(3)College of Information Engineering, Northeast Dianli University, 169 
Changchun Street, Jilin City, Jilin, 132012, China.
(4)Department of Radiology and Imaging Sciences, Indiana University School of 
Medicine, 355 W 16th St, Suite 4100, Indianapolis, IN, 46202, USA.
(5)School of Informatics and Computing, Indiana University, 719 Indiana Avenue, 
Indianapolis, IN, 46202, USA.
(6)Indiana University Network Science Institute, Bloomington, IN, 47405, USA.
(7)College of Automation, Harbin Engineering University, 145 Nantong Street, 
BLDG 61-5029, Harbin, 150001, China. lh@hrbeu.edu.cn.
(8)Department of Radiology and Imaging Sciences, Indiana University School of 
Medicine, 355 W 16th St, Suite 4100, Indianapolis, IN, 46202, USA. 
shenli@iu.edu.
(9)School of Informatics and Computing, Indiana University, 719 Indiana Avenue, 
Indianapolis, IN, 46202, USA. shenli@iu.edu.

BACKGROUND: The cerebrospinal fluid (CSF) levels of total tau (t-tau) and Aβ1-42 
are potential early diagnostic markers for probable Alzheimer's disease (AD). 
The influence of genetic variation on these CSF biomarkers has been investigated 
in candidate or genome-wide association studies (GWAS). However, the 
investigation of statistically modest associations in GWAS in the context of 
biological networks is still an under-explored topic in AD studies. The main 
objective of this study is to gain further biological insights via the 
integration of statistical gene associations in AD with physical protein 
interaction networks.
RESULTS: The CSF and genotyping data of 843 study subjects (199 CN, 85 SMC, 239 
EMCI, 207 LMCI, 113 AD) from the Alzheimer's Disease Neuroimaging Initiative 
(ADNI) were analyzed. PLINK was used to perform GWAS on the t-tau/Aβ1-42 ratio 
using quality controlled genotype data, including 563,980 single nucleotide 
polymorphisms (SNPs), with age, sex and diagnosis as covariates. Gene-level 
p-values were obtained by VEGAS2. Genes with p-value ≤ 0.05 were mapped on to a 
protein-protein interaction (PPI) network (9,617 nodes, 39,240 edges, from the 
HPRD Database). We integrated a consensus model strategy into the iPINBPA 
network analysis framework, and named it as CM-iPINBPA. Four consensus modules 
(CMs) were discovered by CM-iPINBPA, and were functionally annotated using the 
pathway analysis tool Enrichr. The intersection of four CMs forms a common 
subnetwork of 29 genes, including those related to tau phosphorylation (GSK3B, 
SUMO1, AKAP5, CALM1 and DLG4), amyloid beta production (CASP8, PIK3R1, PPA1, 
PARP1, CSNK2A1, NGFR, and RHOA), and AD (BCL3, CFLAR, SMAD1, and HIF1A).
CONCLUSIONS: This study coupled a consensus module (CM) strategy with the 
iPINBPA network analysis framework, and applied it to the GWAS of CSF 
t-tau/Aβ1-42 ratio in an AD study. The genome-wide network analysis yielded 4 
enriched CMs that share not only genes related to tau phosphorylation or amyloid 
beta production but also multiple genes enriching several KEGG pathways such as 
Alzheimer's disease, colorectal cancer, gliomas, renal cell carcinoma, 
Huntington's disease, and others. This study demonstrated that integration of 
gene-level associations with CMs could yield statistically significant findings 
to offer valuable biological insights (e.g., functional interaction among the 
protein products of these genes) and suggest high confidence candidates for 
subsequent analyses.

DOI: 10.1186/s12864-017-3798-z
PMCID: PMC5450240
PMID: 28558704 [Indexed for MEDLINE]


230. J Natl Compr Canc Netw. 2016 Mar;14(3):279-85. doi: 10.6004/jnccn.2016.0033.

Outcome Assessments and Cost Avoidance of an Oral Chemotherapy Management 
Clinic.

Wong SF(1), Bounthavong M(2), Nguyen CP(3), Chen T(4).

Author information:
(1)Chapman University School of Pharmacy, Orange, California
(2)University of Washington, Pharmaceutical Outcomes Research and Policy 
Program, Seattle, Washington
(3)University of California, Irvine Medical Center, Orange, California
(4)Veteran Affairs San Diego Healthcare System, San Diego, California

BACKGROUND: Increasing use of oral chemotherapy drugs increases the challenges 
for drug and patient management. An oral chemotherapy management clinic was 
developed to provide patients with oral chemotherapy management, concurrent 
medication (CM) education, and symptom management services. This evaluation aims 
to measure the need and effectiveness of this practice model due to scarce 
published data.
METHODS: This is a case series report of all patients referred to the oral 
chemotherapy management clinic. Data collected included patient demographics, 
depression scores, CMs, and types of intervention, including detection and 
management outcomes collected at baseline, 3-day, 7-day, and 3-month follow-ups. 
Persistence rate was monitored. Secondary analysis assessed potential cost 
avoidance.
RESULTS: A total of 86 evaluated patients (32 men and 54 women, mean age of 63.4 
years) did not show a high risk for medication nonadherence. The 3 most common 
cancer diagnoses were rectal, pancreatic, and breast, with capecitabine most 
prescribed. Patients had an average of 13.7 CMs. A total of 125 interventions 
(detection and management of adverse drug event detection, compliance, drug 
interactions, medication error, and symptom management) occurred in 201 visits, 
with more than 75% of interventions occurring within the first 14 days. A 
persistence rate was observed in 78% of 41 evaluable patients. The total 
estimated annual cost avoidance per 1.0 full time employee (FTE) was 
$125,761.93.
CONCLUSIONS: This evaluation demonstrated the need for additional support for 
patients receiving oral chemotherapy within standard of care medical service. A 
comprehensive oral chemotherapy management referral service can optimize patient 
care delivery via early interventions for adverse drug events, drug 
interactions, and medication errors up to 3 months after initiation of 
treatment.

Copyright © 2016 by the National Comprehensive Cancer Network.

DOI: 10.6004/jnccn.2016.0033
PMID: 26957614 [Indexed for MEDLINE]


231. Oncotarget. 2016 Jun 14;7(24):36632-36644. doi: 10.18632/oncotarget.9126.

Stratified analysis reveals chemokine-like factor (CKLF) as a potential 
prognostic marker in the MSI-immune consensus molecular subtype CMS1 of 
colorectal cancer.

Dunne PD(1), O'Reilly PG(1), Coleman HG(2), Gray RT(2), Longley DB(1), Johnston 
PG(1), Salto-Tellez M(1), Lawler M(1), McArt DG(1).

Author information:
(1)Centre for Cancer Research and Cell Biology, Faculty of Medicine, Health and 
Life Sciences, Queen's University Belfast, Belfast, UK.
(2)Centre for Public Health, Faculty of Medicine, Health and Life Sciences, 
Queen's University Belfast, Belfast, UK.

The Colorectal Cancer (CRC) Subtyping Consortium (CRCSC) recently published four 
consensus molecular subtypes (CMS's) representing the underlying biology in CRC. 
The Microsatellite Instable (MSI) immune group, CMS1, has a favorable prognosis 
in early stage disease, but paradoxically has the worst prognosis following 
relapse, suggesting the presence of factors enabling neoplastic cells to 
circumvent this immune response. To identify the genes influencing subsequent 
poor prognosis in CMS1, we analyzed this subtype, centered on risk of relapse. 
In a cohort of early stage colon cancer (n=460), we examined, in silico, changes 
in gene expression within the CMS1 subtype and demonstrated for the first time 
the favorable prognostic value of chemokine-like factor (CKLF) gene expression 
in the adjuvant disease setting [HR=0.18, CI=0.04-0.89]. In addition, using 
transcription profiles originating from cell sorted CRC tumors, we delineated 
the source of CKLF transcription within the colorectal tumor microenvironment to 
the leukocyte component of these tumors. Further to this, we confirmed that CKLF 
gene expression is confined to distinct immune subsets in whole blood samples 
and primary cell lines, highlighting CKLF as a potential immune cell-derived 
factor promoting tumor immune-surveillance of nascent neoplastic cells, 
particularly in CMS1 tumors. Building on the recently reported CRCSC data, we 
provide compelling evidence that leukocyte-infiltrate derived CKLF expression is 
a candidate biomarker of favorable prognosis, specifically in MSI-immune stage 
II/III disease.

DOI: 10.18632/oncotarget.9126
PMCID: PMC5095027
PMID: 27153559 [Indexed for MEDLINE]

Conflict of interest statement: PDD: None; POR: None; HGC: None; RTG: None; DBL: 
None; PGJ: Previous Founder and Shareholder of Almac Diagnostics; CV6 
Therapeutics: Expert Advisor and Shareholder; Chugai Pharmaceuticals: 
Consultant; MST: None; ML: None; DMA: None.


232. Cancer Epidemiol Biomarkers Prev. 2021 Sep;30(9):1726-1734. doi: 
10.1158/1055-9965.EPI-21-0078. Epub 2021 Jun 23.

Early Cost-effectiveness Analysis of Risk-Based Selection Strategies for 
Adjuvant Treatment in Stage II Colon Cancer: The Potential Value of Prognostic 
Molecular Markers.

Jongeneel G(1), Greuter MJE(2), Kunst N(2)(3)(4)(5), van Erning FN(6), Koopman 
M(7), Medema JP(8)(9), Vermeulen L(8)(9), Ijzermans JNM(10), Vink GR(6)(7), Punt 
CJA(11), Coupé VMH(2).

Author information:
(1)Department of Epidemiology and Data Science, Amsterdam UMC, VU University, 
Amsterdam, the Netherlands. g.jongeneel@amsterdamumc.nl.
(2)Department of Epidemiology and Data Science, Amsterdam UMC, VU University, 
Amsterdam, the Netherlands.
(3)Harvard Medical School & Harvard Pilgrim Health Care Institute, Boston, 
Massachusetts.
(4)Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, 
Yale University School of Medicine, New Haven, Connecticut.
(5)Public Health Modeling Unit, Yale University School of Public Health, New 
Haven, Connecticut.
(6)Department of Research and Development, Netherlands Comprehensive Cancer 
Organisation (IKNL), Utrecht, the Netherlands.
(7)University Medical Center Utrecht, Utrecht University, Utrecht, the 
Netherlands.
(8)Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Center for 
Experimental Molecular Medicine (CEMM), Amsterdam, the Netherlands.
(9)Oncode Institute, Amsterdam, the Netherlands.
(10)Department of General Surgery, Erasmus MC University Medical Center, 
Rotterdam, the Netherlands.
(11)Julius Center for Health Sciences and Primary Care, University Medical 
Center Utrecht, the Netherlands.

BACKGROUND: To explore the potential value of consensus molecular subtypes (CMS) 
in stage II colon cancer treatment selection, we carried out an early 
cost-effectiveness assessment of a CMS-based strategy for adjuvant chemotherapy.
METHODS: We used a Markov cohort model to evaluate three selection strategies: 
(i) the Dutch guideline strategy (MSS+pT4), (ii) the mutation-based strategy 
(MSS plus a BRAF and/or KRAS mutation or MSS plus pT4), and (iii) the CMS-based 
strategy (CMS4 or pT4). Outcomes were number of colon cancer deaths per 1,000 
patients, total discounted costs per patient (pp), and quality-adjusted 
life-years (QALY) pp. The analyses were conducted from a Dutch societal 
perspective. The robustness of model predictions was assessed in sensitivity 
analyses. To evaluate the value of future research, we performed a value of 
information (VOI) analysis.
RESULTS: The Dutch guideline strategy resulted in 8.10 QALYs pp and total costs 
of €23,660 pp. The CMS-based and mutation-based strategies were more effective 
and more costly, with 8.12 and 8.13 QALYs pp and €24,643 and €24,542 pp, 
respectively. Assuming a threshold of €50,000/QALY, the mutation-based strategy 
was considered as the optimal strategy in an incremental analysis. However, the 
VOI analysis showed substantial decision uncertainty driven by the molecular 
markers (expected value of partial perfect information: €18M).
CONCLUSIONS: On the basis of current evidence, our analyses suggest that the 
mutation-based selection strategy would be the best use of resources. However, 
the extensive decision uncertainty for the molecular markers does not allow 
selection of an optimal strategy at present.
IMPACT: Future research is needed to eliminate decision uncertainty driven by 
molecular markers.

©2021 American Association for Cancer Research.

DOI: 10.1158/1055-9965.EPI-21-0078
PMCID: PMC7611620
PMID: 34162659 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of interest: G Jongeneel, MJE Greuter, 
Kunst N, FN van Erning, JP Medema, L Vermeulen, JM Ijzermans, CJA Punt, VMH 
Coupé declared no potential conflicts of interests. Miriam Koopman declared a 
potential financial conflict of interest by having an advisory role for 
NordicFarma, Merck-Serono, Pierre Fabre, Servier and institutional 
scientificgrants from Bayer, Bristol Myers Squibb, Merck, Roche, Servier. 
Geraldine R. Vink declared potential financial conflicts of interests due to 
institutional grants for other research projects: Servier, Bayer, Sirtex, Merck, 
BMS, Lilly, Pierre Fabre, Personal Genome Diagnostics.


233. J Surg Oncol. 2019 Aug;120(2):280-286. doi: 10.1002/jso.25511. Epub 2019 May 27.

Cost of benign versus oncologic colon resection among fee-for-service Medicare 
enrollees.

Hughes BD(1), Hancock KJ(1), Shan Y(1), Thakker RA(2), Maharsi S(2), Tyler 
DS(1), Mehta HB(1), Senagore AJ(3).

Author information:
(1)Department of Surgery, University of Texas Medical Branch, Galveston, Texas.
(2)School of Medicine, University of Texas Medical Branch, Galveston, Texas.
(3)Department of Surgery, Western Michigan University Homer Stryker MD School of 
Medicine Kalamazoo, Michigan.

BACKGROUND AND OBJECTIVES: Reimbursement for colonic pathology by the Centers 
for Medicare and Medicaid Services (CMS) are grouped in the Medicare 
Severity-Diagnosis Related Groups (MS-DRG). With limited available data, we 
sought to compare the relative impact of malignant vs benign colonic pathology 
on reimbursement under the MS-DRG system.
METHODS: We used 5% national Medicare data from 2011 to 2014. Patients were 
classified as having benign disease or malignancy. Descriptive statistics and 
multivariate regression analysis were used to evaluate the surgical approach and 
health resource utilization.
RESULTS: Of 10 928 patients, most were Non-Hispanic White women. The majority 
underwent open colectomy in both cohorts (P < .001). Colectomy for benign 
disease was associated with higher total charges (P < .001) and a longer length 
of stay (P = .0002). Despite higher charges, payments were not significantly 
different between the cohorts (P = .434). Both inpatient mortality and discharge 
to a rehab facility were higher in the oncologic group (P < .001).
CONCLUSION: Payment methodology for colectomy under the CMS MS-DRG system does 
not appear to accurately reflect the episode cost of care. The data suggest that 
inpatient costs are not fully compensated. A transition to value-based payments 
with expanded episode duration will require a better understanding of unique 
costs before adoption.

© 2019 Wiley Periodicals, Inc.

DOI: 10.1002/jso.25511
PMCID: PMC6635007
PMID: 31134661 [Indexed for MEDLINE]

Conflict of interest statement: Disclosures: There are no conflicts of interest.


234. Virchows Arch. 2020 May;476(5):711-723. doi: 10.1007/s00428-019-02675-w. Epub 
2019 Nov 6.

Small-bowel carcinomas associated with celiac disease: transcriptomic profiling 
shows predominance of microsatellite instability-immune and mesenchymal 
subtypes.

Rizzo F(1)(2), Vanoli A(3), Sahnane N(4), Cerutti R(4), Trapani D(4), Rinaldi 
A(1), Sellitto A(1), Ciacci C(5), Volta U(6), Villanacci V(7), Calabrò A(8), 
Arpa G(3), Luinetti O(3), Paulli M(3), Solcia E(3), Di Sabatino A(9), Sessa 
F(4), Weisz A(1)(2), Furlan D(10).

Author information:
(1)Laboratory of Molecular Medicine and Genomics, Department of Medicine, 
Surgery and Dentistry, Scuola Medica Salernitana, Salerno, Italy.
(2)Medical Genomics Program, Department of Onco-Haematology SS. Giovanni di Dio 
e Ruggi d'Aragona University Hospital, University of Salerno, Salerno, Italy.
(3)Department of Molecular Medicine, University of Pavia and IRCCS San Matteo 
Hospital Foundation, Pavia, Italy.
(4)Unit of Pathology, Dept. of Medicine and Surgery and Research Center for the 
Study of Hereditary and Familial Tumors, University of Insubria, Via Rossi 9, 
21100, Varese, Italy.
(5)Gastrointestinal Unit, Department of Medicine, Surgery and Dentistry, Scuola 
Medica Salernitana, University of Salerno, Baronissi, Salerno, Italy.
(6)Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, 
University of Bologna, Bologna, Italy.
(7)Institute of Pathology, Spedali Civili, Brescia, Italy.
(8)Department of Experimental and Clinical Biomedical Sciences, Gastroenterology 
Unit, University of Florence, Florence, Italy.
(9)Department of Internal Medicine, University of Pavia and IRCCS San Matteo 
Hospital Foundation, Pavia, Italy.
(10)Unit of Pathology, Dept. of Medicine and Surgery and Research Center for the 
Study of Hereditary and Familial Tumors, University of Insubria, Via Rossi 9, 
21100, Varese, Italy. daniela.furlan@uninsubria.it.

Celiac disease (CD) is a risk factor for developing small-bowel carcinoma with a 
14-fold higher risk compared with general population. As small-bowel carcinomas 
associated with CD (CD-SBCs) are extremely rare, very few molecular data are 
available about their pathogenesis, and information about their transcriptomic 
profiling is lacking. We generated RNA-seq data on 13 CD-SBCs, taken from the 
largest well-characterized series published so far, collected by the Small Bowel 
Cancer Italian Consortium, and compared the tumor transcriptional signatures 
with the four Consensus Molecular Subtypes (CMS) of colorectal carcinoma by 
applying the "CMS classifier." CpG Island Methylator Phenotype (CIMP) was 
evaluated using methylation-sensitive multiple ligation-dependent probe 
amplification. Up to 12 of 13 cancers fell within the two main subtypes 
exhibiting high immune and inflammatory signatures, i.e., subtypes 1 and 4. The 
first and predominant subset was commonly microsatellite unstable, and exhibited 
CIMP and high CD3+ and CD8+ T cell infiltration. Moreover, it showed increased 
expression of genes associated with T helper 1 and natural killer cell 
infiltration, as well as upregulation of apoptosis, cell cycle progression, and 
proteasome pathways. By contrast, cancers falling in subtype 4 showed prominent 
transforming growth factor-β activation and were characterized by 
complement-associated inflammation, matrix remodeling, cancer-associated stroma 
production, and angiogenesis. Parallel histologic and histochemical analysis 
confirmed such tumor subtyping. In conclusion, two molecular subtypes have been 
consistently identified in our series of CD-SBCs, a microsatellite 
instability-immune and a mesenchymal subtype, the former likely associated with 
an indolent and the latter with a worse tumor behavior.

DOI: 10.1007/s00428-019-02675-w
PMID: 31696360 [Indexed for MEDLINE]


235. Oncology. 2020;98(8):534-541. doi: 10.1159/000506369. Epub 2020 Apr 1.

A Validation Study for Recurrence Risk Stratification of Stage II Colon Cancer 
Using the 55-Gene Classifier.

Shinto E(1), Oki E(2), Shimokawa M(3), Yamaguchi S(4), Ishiguro M(5), Morita 
M(6), Kusumoto T(7), Tomita N(8), Hashiguchi Y(9), Tanaka M(10), Ohnuma S(11), 
Tada S(12), Matsushima T(12), Hase K(13).

Author information:
(1)Department of Surgery, National Defense Medical College, Tokorozawa, Japan, 
shinto@ndmc.ac.jp.
(2)Department of Surgery and Science, Graduate School of Medical Sciences, 
Kyushu University, Fukuoka, Japan.
(3)Clinical Research Institute, National Hospital Organization Kyushu Cancer 
Center, Fukuoka, Japan.
(4)Department of Gastroenterological Surgery, Saitama Medical University 
International Medical Center, Hidaka, Japan.
(5)Department of Translational Oncology, Graduate School of Medical and Dental 
Science, Tokyo Medical and Dental University, Tokyo, Japan.
(6)Gastroenterological Surgery, National Hospital Organization Kyushu Cancer 
Center, Fukuoka, Japan.
(7)Department of Gastroenterological Surgery, Clinical Research Center, Cancer 
Research Division, National Hospital Organization Kyushu Medical Center, 
Fukuoka, Japan.
(8)Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
(9)Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.
(10)Coloproctology Center, Takano Hospital, Kumamoto, Japan.
(11)Department of Surgery, Tohoku University Hospital, Sendai, Japan.
(12)LS Business, Sysmex Corporation, Kobe, Japan.
(13)Department of Surgery, National Defense Medical College, Tokorozawa, Japan.

INTRODUCTION: DNA microarrays, such as the consensus molecular subtype (CMS) 
classification using >600 genes, are used to predict cancer patient prognosis. 
We recently constructed a simple 55-gene classifier (55GC) system to risk 
stratify colon cancer (CC).
OBJECTIVE: Here, we validate the 55GC specifically for stage II CC and compare 
it with CMS categories.
METHODS: Tissue sections from 232 stage II CC patients who underwent curative 
surgery without adjuvant chemotherapy between 2009 and 2012 were subjected to 
DNA microarray analysis.
RESULTS: Based on the 55GC, patients were classified into microsatellite 
instability-like (27%), chromosomal instability-like (41%), and stromal (32%) 
subtypes with 5-year relapse-free survival (RFS) rates of 88.5, 83.3, and 71.2%, 
respectively (stromal vs. others: p = 0.0049). Multivariate analysis by Cox's 
proportional hazard model revealed that the stromal subtype, pT4, and the number 
of lymph nodes examined (<12) were independent poor prognostic factors. The 
overall concordance rate between 55GC and CMS was 72%, and 5-year RFS rates of 
patients with CMS1, CMS2, CMS3, and CMS4 cancers were 100, 85.5, 92.3, and 
73.0%, respectively (p = 0.0113).
CONCLUSIONS: We conclude that the 55GC is a useful and reproducible grading 
system for stage II CC recurrence risk stratification.

© 2020 S. Karger AG, Basel.

DOI: 10.1159/000506369
PMID: 32235113 [Indexed for MEDLINE]


236. J Natl Cancer Inst. 2018 Jan 1;110(1). doi: 10.1093/jnci/djx136.

The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint 
Expression in the Prognosis of Colon Tumors.

Marisa L(1), Svrcek M(1), Collura A(1), Becht E(1), Cervera P(1), Wanherdrick 
K(1), Buhard O(1), Goloudina A(1), Jonchère V(1), Selves J(1), Milano G(1), 
Guenot D(1), Cohen R(1), Colas C(1), Laurent-Puig P(1), Olschwang S(1), Lefèvre 
JH(1), Parc Y(1), Boige V(1), Lepage C(1), André T(1), Fléjou JF(1), Dérangère 
V(1), Ghiringhelli F(1), de Reynies A(1), Duval A(1).

Author information:
(1)Programme "Cartes d'Identité des Tumeurs," Ligue Nationale Contre le Cancer, 
Paris, France; INSERM, UMRS 938 - Centre de Recherche Saint-Antoine, Equipe 
"Instabilité des Microsatellites et Cancers," Equipe labellisée par la Ligue 
Nationale contre le Cancer, Paris, France; Sorbonne Université, UPMC Univ Paris 
06, Paris, France; AP-HP, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie 
Pathologiques, Paris, France; Centre de Recherche en Cancérologie de Toulouse, 
UMR 1037 INSERM - Université Toulouse III, Department of Pathology, CHU, 
Toulouse, France; Laboratoire d'Oncopharmacologie, EA 3836, Centre Antoine 
Lacassagne, Nice, France; INSERM, U682, Développement et Physiopathologie de 
l'Intestin et du Pancréas, Strasbourg, France; AP-HP, Hôpital Saint-Antoine, 
Service d'Oncologie Médicale, Paris, France; AP-HP, Laboratoire d'oncogénétique 
et d'Angiogénétique, GH Pitié-Salpétrière, Paris, France; INSERM, Unité Mixte de 
Recherche, Paris Sorbonne Cité, Université Paris Descartes, Paris, France; Aix 
Marseille Univ, INSERM, GMGF, Marseille, France and RGDS, HP Clairval, 
Marseille, France; AP-HP, Service de Chirurgie Générale et Digestive, Hôpital 
Saint-Antoine, Paris, France; Department of Oncologic Medicine, Gustave-Roussy, 
Villejuif, France; Université Paris Descartes, Paris Sorbonne Cité INSERM 
UMR-S775, Paris, France; INSERM, Burgundy Cancer Registry, U866, Burgundy 
University, Dijon University Hospital, BP 87900?21079 Dijon, France; Department 
of Medical Oncology, Centre Georges-François Leclerc, Dijon, France; INSERM, 
UMR866, Burgundy University; Platform of transfer in oncology, Burgundy 
University, Centre Georges-François Leclerc, Dijon, France.

BACKGROUND: Immune checkpoint (ICK) expression might represent a surrogate 
measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more 
accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL 
enumeration as measured by the Immunoscore.
METHODS: The expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and 
metagenes, including Immunoscore-like metagenes, were evaluated in three 
independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 
non-MSI). Their associations with patient survival were analyzed by Cox models, 
taking into account the microsatellite instability (MSI) status and affiliation 
with various Consensus Molecular Subgroups (CMS). PD-L1 and CD8 expression were 
examined on a subset of tumors with immunohistochemistry. All statistical tests 
were two-sided.
RESULTS: The expression of Immunoscore-like metagenes was statistically 
significantly associated with improved outcome in non-MSI tumors displaying low 
levels of both CTLs and immune checkpoints (ICKs; CMS2 and CMS3; hazard ratio 
[HR] = 0.63, 95% confidence interval [CI] = 0.43 to 0.92, P = .02; and 
HR = 0.55, 95% CI = 0.34 to 0.90, P = .02, respectively), but clearly had no 
prognostic relevance in CRCs displaying higher levels of CTLs and ICKs (CMS1 and 
CMS4; HR = 0.46, 95% CI = 0.10 to 2.10, P = .32; and HR = 1.13, 95% CI = 0.79 to 
1.63, P = .50, respectively), including MSI tumors. ICK metagene expression was 
statistically significantly associated with worse prognosis independent of tumor 
staging in MSI tumors (HR = 3.46, 95% CI = 1.41 to 8.49, P = .007). ICK 
expression had a negative impact on the proliferation of infiltrating CD8 T 
cells in MSI neoplasms (median = 0.56 in ICK low vs median = 0.34 in ICK high, P 
= .004).
CONCLUSIONS: ICK expression cancels the prognostic relevance of CTLs in highly 
immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.

© The Author 2017. Published by Oxford University Press. All rights reserved. 
For Permissions, please email: journals.permissions@oup.com

DOI: 10.1093/jnci/djx136
PMID: 28922790 [Indexed for MEDLINE]


237. Oncotarget. 2019 Jul 23;10(45):4630-4639. doi: 10.18632/oncotarget.27050. 
eCollection 2019 Jul 23.

Fibroblast-derived Gremlin1 localises to epithelial cells at the base of the 
intestinal crypt.

Dutton LR(1)(2), Hoare OP(3)(2), McCorry AMB(3)(2), Redmond KL(3), Adam 
NE(1)(4), Canamara S(1)(5), Bingham V(3), Mullan PB(3), Lawler M(3), Dunne 
PD(3)(6), Brazil DP(1)(6).

Author information:
(1)Wellcome-Wolfson Institute for Experimental Medicine, Queen's University 
Belfast, Belfast, Northern Ireland, UK.
(2)These authors contributed equally to this work.
(3)Centre for Cancer Research and Cell Biology, Queen's University Belfast, 
Belfast, Northern Ireland, UK.
(4)Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai 
Healthcare City, United Arab Emirates.
(5)Indonesia International Institute for Life-Sciences, University of East 
Jakarta, Jakarta Timur, Indonesia.
(6)Co-senior authors.

Gremlin1 (GREM1) is a secreted glycoprotein member of the differential 
screening-selected gene in aberrant neuroblastoma (DAN) family of bone 
morphogenetic protein (BMP) antagonists, which binds to BMPs preventing their 
receptor engagement. Previous studies have identified that stage II colorectal 
cancer (CRC) patients with high levels of GREM1 gene expression in their tumour 
tissue have a poorer prognosis. Using a series of in silico and in situ 
methodologies, we demonstrate that GREM1 gene expression is significantly higher 
(p < 0.0001) in CRC consensus molecular subtype 4 (CMS4), compared to the other 
CMS subtypes and correlates (p < 0.0001) with levels of cancer-associated 
fibroblasts (CAFs) within the CRC tumour microenvironment (TME). Our optimised 
immunohistochemistry protocol identified endogenous GREM1 protein expression in 
both the muscularis mucosa and adjacent colonic crypt bases in mouse intestine, 
in contrast to RNA expression which was shown to localise specifically to the 
muscularis mucosa, as determined by in situ hybridisation. Importantly, we 
demonstrate that cells with high levels of GREM1 expression display low levels 
of phospho-Smad1/5, consistent with reduced BMP signalling. Taken together, 
these data highlight a novel paracrine signalling circuit, which involves uptake 
of mature GREM1 protein by colonic crypt cells following secretion from 
neighbouring fibroblasts in the TME.

DOI: 10.18632/oncotarget.27050
PMCID: PMC6659803
PMID: 31384391

Conflict of interest statement: CONFLICTS OF INTEREST None.


238. Perspect Health Inf Manag. 2022 Jan 1;19(1):1o. eCollection 2022 Winter.

Observing Provider Utilization of Electronic Health Records to Improve Clinical 
Quality Metrics.

Brooks K, Polverento M, Houdeshell-Putt L, Sarzynski E, Ford S.

INTRODUCTION: This study compared changes of healthcare quality in a Michigan 
Medicaid population before and after physician adoption of electronic health 
records (EHRs) via the Meaningful Use (MU) program for selected Healthcare 
Effectiveness Data and Information Set (HEDIS) quality of care measures.
METHODS: Healthcare measures included well-child visits, cancer screening, and 
chronic illness quality measures. Utilization data were obtained from Medicaid 
paid claims and encounter data with providers (N=291) receiving their first MU 
incentive in 2014 and at least one HEDIS-defined outpatient visit with a 
Michigan Medicaid enrollee. Paired t-tests with a repeated measures design were 
utilized to analyze the data.
RESULTS: Improvements in quality of infant well-child visits (mean difference = 
10.2) and colorectal cancer screening (mean difference = 8.0 percent) were 
observed. We found no change or slight decreases for the other selected 
measures.
CONCLUSION: These outcomes inform the performance and ability of EHRs to improve 
quality of healthcare standards particularly as technology continues to evolve 
under the Centers for Medicare & Medicaid Services (CMS) Interoperability and 
Patient Access final rule.

Copyright © 2022 by the American Health Information Management Association.

PMCID: PMC9013221
PMID: 35440927 [Indexed for MEDLINE]


239. Vascul Pharmacol. 2017 Feb;89:19-30. doi: 10.1016/j.vph.2016.10.004. Epub 2016 
Oct 4.

Colon cancer-derived myofibroblasts increase endothelial cell migration by 
glucocorticoid-sensitive secretion of a pro-migratory factor.

Drebert Z(1), MacAskill M(2), Doughty-Shenton D(3), De Bosscher K(4), Bracke 
M(1), Hadoke PWF(5), Beck IM(1).

Author information:
(1)Laboratory of Experimental Cancer Research, Department of Radiation Oncology 
& Experimental Cancer Research, Ghent University, Ghent, Belgium; Cancer 
Research Institute Ghent (CRIG), Ghent, Belgium.
(2)University/BHF Centre for Cardiovascular Science, The Queen's Medical 
Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
(3)Edinburgh Phenotypic Assay Centre, The Queen's Medical Research Institute, 
University of Edinburgh, Edinburgh, United Kingdom.
(4)Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Receptor Research 
Laboratories, Nuclear Receptor Lab (NRL), VIB Department of Medical Protein 
Research, Ghent University, Ghent, Belgium.
(5)University/BHF Centre for Cardiovascular Science, The Queen's Medical 
Research Institute, University of Edinburgh, Edinburgh, United Kingdom. 
Electronic address: Patrick.hadoke@ed.ac.uk.

Angiogenesis is important in cancer progression and can be influenced by 
tumor-associated myofibroblasts. We addressed the hypothesis that 
glucocorticoids indirectly affect angiogenesis by altering the release of 
pro-angiogenic factors from colon cancer-derived myofibroblasts. Our study shows 
that glucocorticoids reduced prostanoids, urokinase-type plasminogen activator 
(uPA) and angiopoietin-like protein-2 (ANGPTL2) levels, but increased angiogenin 
(ANG) in supernatant from human CT5.3hTERT colon cancer-derived myofibroblasts. 
Conditioned medium from solvent- (CMS) and dexamethasone (Dex)-treated (CMD) 
myofibroblasts increased human umbilical vein endothelial cell (HUVEC) 
proliferation, but did not affect expression of pro-angiogenic factors or 
tube-like structure formation (by HUVECs or human aortic ECs). In a HUVEC 
scratch assay CMS-induced acceleration of wound healing was blunted by CMD 
treatment. Moreover, CMS-induced neovessel growth in mouse aortic rings ex vivo 
was also blunted using CMD. The latter effect could be ascribed to both 
Dex-driven reduction of secreted factors and potential residual Dex present in 
CMD (indicated using a dexamethasone-spiked CMS control). A similar control in 
the scratch assay, however, revealed that altered levels of factors in the CMD, 
and not potential residual Dex, were responsible for decreased wound closure. In 
conclusion, our results suggest that glucocorticoids indirectly alter 
endothelial cell function during tumor development in vivo.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.vph.2016.10.004
PMCID: PMC5328197
PMID: 27717848 [Indexed for MEDLINE]


240. Genes Chromosomes Cancer. 2007 Dec;46(12):1080-9. doi: 10.1002/gcc.20493.

The putative tumor suppressor AIM2 is frequently affected by different genetic 
alterations in microsatellite unstable colon cancers.

Woerner SM(1), Kloor M, Schwitalle Y, Youmans H, Doeberitz Mv, Gebert J, 
Dihlmann S.

Author information:
(1)Department of Applied Tumor Biology, Institute of Pathology, University 
Hospital Heidelberg, Im Neuenheimer Feld 220/221, D-69120 Heidelberg, Germany.

Mismatch repair (MMR) deficiency is a major mechanism of colorectal 
tumorigenesis that is observed in 10-15% of sporadic colorectal cancers and 
those associated with the hereditary nonpolyposis colorectal cancer (HNPCC) 
syndrome. MMR deficiency leads to the accumulation of mutations mainly at short 
repetitive sequences termed microsatellites, constituting the high level 
microsatellite instability (MSI-H) phenotype. In recent years, several genes 
have been described that harbor microsatellites in their coding region (coding 
microsatellites, cMS) and are frequently affected by mutations in MMR-deficient 
cancers. However, evidence for a functional role of most of the known 
cMS-containing genes is missing, and further analyses are needed for a better 
understanding of MSI tumorigenesis. Here, we examined in detail alterations of 
the absent in melanoma 2 (AIM2) gene that shows a high frequency of cMS 
frameshift mutations in MSI-H colorectal, gastric, and endometrial tumors. AIM2 
belongs to the HIN-200 family of interferon (IFN)-inducible proteins, its role 
in colon carcinogenesis, however, is unknown. Sequencing of the entire coding 
region of AIM2 revealed a high frequency of frameshift and missense mutations in 
primary MSI-H colon cancers (9/20) and cell lines (9/15). Biallelic AIM2 
alterations were detected in 8 MSI-H colon tumors and cell lines. In addition, 
AIM2 promoter hypermethylation conferred insensitivity to IFN-gamma-induced AIM2 
expression of three MSI-H colon cancer cell lines. These results demonstrate 
that inactivation of AIM2 by genetic and epigenetic mechanisms is frequent in 
MMR-deficient colorectal cancers, thus suggesting that AIM2 is a mutational 
target relevant for the progression of MSI-H colorectal cancers.

(c) 2007 Wiley-Liss, Inc.

DOI: 10.1002/gcc.20493
PMID: 17726700 [Indexed for MEDLINE]


241. Clin Cancer Res. 2022 Mar 7:clincanres.0041.2022. doi: 
10.1158/1078-0432.CCR-22-0041. Online ahead of print.

Transcriptomic profiling of MSI-H/dMMR gastrointestinal tumors to identify 
determinants of responsiveness to anti-PD-1 therapy.

Chida K(1), Kawazoe A(2), Suzuki T(3), Kawazu M(4), Ueno T(5), Takenouchi K(6), 
Nakamura Y(7), Kuboki Y(2), Kotani D(2), Kojima T(2), Bando H(7), Mishima S(7), 
Kuwata T(2), Sakamoto N(8), Watanabe J(9), Mano H(10), Ikeda M(11), Shitara 
K(2), Endo I(12), Nakatsura T(6), Yoshino T(13).

Author information:
(1)National Cancer Center Hospital East, Chiba, Japan.
(2)National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
(3)Exploratory Oncology Research & Clinical Trial Center, National Cancer 
Center, Japan.
(4)National Cancer Centre, Chuo-ku, Tokyo, Japan.
(5)National Cancer Center Research Institute, Tokyo, Tokyo, Japan.
(6)National Cancer Centre, Kashiwa, Japan.
(7)National Cancer Center Hospital East, Kashiwa, Japan.
(8)Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, 
Japan.
(9)Yokohama City University Medical Center, Yokohama, Kanagawa, Japan.
(10)National Cancer Centre, Chuoku, Tokyo, Japan.
(11)National Cancer Center Hospital East, Kashiwa Chiba, Japan.
(12)Department of Gastroenterological Surgery, Yokohama City University Graduate 
School of Medicine, Yokohama, Japan., Japan.
(13)National Cancer Center East, Kashiwa, Chiba, Japan.

PURPOSE: Transcriptomic profiling was performed for microsatellite 
instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) 
tumors to determine the predictors of response to PD-1 blockade.
EXPERIMENTAL DESIGN: Thirty-six patients with MSI-H/dMMR GI tumors, including 
gastric cancer, colorectal cancer (CRC), cholangiocarcinoma, small intestine 
cancer, and pancreatic cancer, being treated with PD-1 blockade were analyzed. 
We conducted the transcriptomic analysis of GI tumors using RNA sequencing data, 
including the consensus molecular subtypes (CMS) of CRC.
RESULTS: Gene set enrichment analysis (GSEA) demonstrated that non-responders 
had upregulations of epithelial mesenchymal transition, angiogenesis, hypoxia, 
mTORC1, TNF-α, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related 
signaling pathways. Meanwhile, the IFN-γ pathway was enriched in responders. 
Based on the leading-edge analysis of GSEA, VEGF-A was significantly correlated 
with enriched pathways in non-responders. Patients with high VEGF-A expression, 
compared to those with low expression, had significantly shorter 
progression-free survival (PFS) (median 4.8 months vs. not reached [NR], P = 
0.032) and overall survival (median 11.1 months vs. NR, P = 0.045). Among 13 
patients with CRC evaluable for CMS classification, the objective response rate 
was 100%, 0%, 0%, and 16.7% in CMS1, CMS2, CMS3 and CMS4, respectively. Patients 
with CMS1 had significantly longer PFS (NR vs. 4.8 months, P = 0.017) than those 
with CMS2, CMS3, or CMS4.
CONCLUSIONS: Several transcriptomic features, including CMS classification and 
related genes, were associated with response to PD-1 blockade in MSI-H/dMMR GI 
tumors. These findings can help develop predictive biomarkers or combination 
immunotherapies.

DOI: 10.1158/1078-0432.CCR-22-0041
PMID: 35254400


242. Oncogene. 2019 Aug;38(33):6109-6122. doi: 10.1038/s41388-019-0868-5. Epub 2019 
Jul 15.

Gene expression profiles of CMS2-epithelial/canonical colorectal cancers are 
largely driven by DNA copy number gains.

Berg KCG(1)(2)(3), Sveen A(1)(2)(3), Høland M(1)(2)(3), Alagaratnam S(1)(2), 
Berg M(1)(4), Danielsen SA(1)(2), Nesbakken A(2)(3)(5), Søreide K(4)(6)(7), 
Lothe RA(8)(9)(10).

Author information:
(1)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway.
(2)K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, P.O. 
Box 4953, Nydalen, NO-0424, Oslo, Norway.
(3)Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 
P.O. Box 4950, Nydalen, NO-0424, Oslo, Norway.
(4)Gastrointestinal Translational Research Unit, Lab for Molecular Biology, 
Stavanger University Hospital, P.O. Box 8100, NO-4011, Stavanger, Norway.
(5)Department of Gastrointestinal Surgery, Oslo University Hospital, P.O. Box 
4950, Nydalen, NO-0424, Oslo, Norway.
(6)Department of Gastrointestinal Surgery, Stavanger University Hospital, P.O. 
Box 8100, NO-4011, Stavanger, Norway.
(7)Department of Clinical Medicine, University of Bergen, P.O. Box 7804, 
NO-5020, Bergen, Norway.
(8)Department of Molecular Oncology, Institute for Cancer Research, Oslo 
University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway. 
rlothe@rr-research.no.
(9)K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, P.O. 
Box 4953, Nydalen, NO-0424, Oslo, Norway. rlothe@rr-research.no.
(10)Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 
P.O. Box 4950, Nydalen, NO-0424, Oslo, Norway. rlothe@rr-research.no.

About 80% of colorectal cancers (CRCs) have chromosomal instability, which is an 
integral part of aggressive malignancy development, but the importance of 
specific copy number aberrations (CNAs) in modulating gene expression, 
particularly within the framework of clinically relevant molecular subtypes, 
remains mostly elusive. We performed DNA copy number profiling of 257 stage I-IV 
primary CRCs and integrative gene expression analysis in 151 microsatellite 
stable (MSS) tumors, focusing on high-level amplifications and the effect of 
CNAs on the characteristics of the gene expression-based consensus molecular 
subtypes (CMS). The results were validated in 323 MSS tumors from TCGA. Novel 
recurrent high-level amplifications (≥15 additional copies) with a major impact 
on gene expression were found for TOX3 (16q) at 1.5% frequency, as well as for 
CCND2 (12p) and ANXA11 (10q) at 1% frequency, in addition to the well-known 
targets ERBB2 (17q) and MYC (8q). Focal amplifications with ≥15 or ≥5 additional 
copies of at least one of these regions were associated with a poor overall 
survival among patients with stage I-III MSS CRCs (multivariable hazard 
ratio ≥3.2, p ≤ 0.01). All high-level amplifications were focal and had a more 
consistent relationship with gene expression than lower amplitude and/or 
broad-range amplifications, suggesting specific targeting during carcinogenesis. 
Genome-wide, copy number driven gene expression was enriched for pathways 
characteristic of the CMS2-epithelial/canonical subtype, including DNA repair 
and cell cycle progression. Furthermore, 50% of upregulated genes in 
CMS2-epithelial/canonical MSS CRCs were driven by CNAs, an enrichment compared 
with the other CMS groups, and associated with the stronger correspondence 
between CNAs and gene expression in malignant epithelial cells than in the cells 
of the tumor microenvironment (fibroblasts, endothelial cells, leukocytes). In 
conclusion, we identify novel recurrent amplifications with impact on gene 
expression in CRC and provide the first evidence that CMS2 may have a stronger 
copy-number related genetic basis than subtypes more heavily influenced by gene 
expression signals from the tumor microenvironment.

DOI: 10.1038/s41388-019-0868-5
PMCID: PMC6756070
PMID: 31308487 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that they have no conflict 
of interest.


243. BMC Bioinformatics. 2022 Mar 31;23(1):114. doi: 10.1186/s12859-022-04641-x.

classifieR a flexible interactive cloud-application for functional annotation of 
cancer transcriptomes.

Quinn GP(1), Sessler T(1), Ahmaderaghi B(2), Lambe S(1), VanSteenhouse H(3), 
Lawler M(1), Wappett M(1), Seligmann B(4), Longley DB(1), McDade SS(5).

Author information:
(1)Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 97 
Lisburn Road, Belfast, BT9 7AE, Northern Ireland, UK.
(2)Electronics, Electrical Engineering and Computer Science, Queen's University 
Belfast, Belfast, UK.
(3)BioClavis, Glasgow, UK.
(4)BioSpyder Technologies, Carlsbad, CA, USA.
(5)Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 97 
Lisburn Road, Belfast, BT9 7AE, Northern Ireland, UK. s.mcdade@qub.ac.uk.

BACKGROUND: Transcriptionally informed predictions are increasingly important 
for sub-typing cancer patients, understanding underlying biology and to inform 
novel treatment strategies. For instance, colorectal cancers (CRCs) can be 
classified into four CRC consensus molecular subgroups (CMS) or five intrinsic 
(CRIS) sub-types that have prognostic and predictive value. Breast cancer (BRCA) 
has five PAM50 molecular subgroups with similar value, and the OncotypeDX test 
provides transcriptomic based clinically actionable treatment-risk 
stratification. However, assigning samples to these subtypes and other 
transcriptionally inferred predictions is time consuming and requires 
significant bioinformatics experience. There is no "universal" method of using 
data from diverse assay/sequencing platforms to provide subgroup classification 
using the established classifier sets of genes (CMS, CRIS, PAM50, OncotypeDX), 
nor one which in provides additional useful functional annotations such as 
cellular composition, single-sample Gene Set Enrichment Analysis, or prediction 
of transcription factor activity.
RESULTS: To address this bottleneck, we developed classifieR, an easy-to-use 
R-Shiny based web application that supports flexible rapid single sample 
annotation of transcriptional profiles derived from cancer patient samples form 
diverse platforms. We demonstrate the utility of the " classifieR" framework to 
applications focused on the analysis of transcriptional profiles from colorectal 
(classifieRc) and breast (classifieRb). Samples are annotated with disease 
relevant transcriptional subgroups (CMS/CRIS sub-types in classifieRc and 
PAM50/inferred OncotypeDX in classifieRb), estimation of cellular composition 
using MCP-counter and xCell, single-sample Gene Set Enrichment Analysis (ssGSEA) 
and transcription factor activity predictions with Discriminant Regulon 
Expression Analysis (DoRothEA).
CONCLUSIONS: classifieR provides a framework which enables labs without access 
to a dedicated bioinformation can get information on the molecular makeup of 
their samples, providing an insight into patient prognosis, druggability and 
also as a tool for analysis and discovery. Applications are hosted online at 
https://generatr.qub.ac.uk/app/classifieRc and 
https://generatr.qub.ac.uk/app/classifieRb after signing up for an account on 
https://generatr.qub.ac.uk .

© 2022. The Author(s).

DOI: 10.1186/s12859-022-04641-x
PMCID: PMC8974006
PMID: 35361119 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that they have no competing 
interests. BS is employed by BioSpyder Technologies and HVS is employed by 
BioClavis, however, the work contained within this manuscript was not in any way 
contributed to or influenced by these roles nor is there any potential financial 
gain.


244. Ann Rheum Dis. 2007 Oct;66(10):1296-304. doi: 10.1136/ard.2006.068650. Epub 2007 
Mar 7.

Non-steroidal anti-inflammatory drugs and myocardial infarctions: comparative 
systematic review of evidence from observational studies and randomised 
controlled trials.

Scott PA(1), Kingsley GH, Smith CM, Choy EH, Scott DL.

Author information:
(1)Department of Cardiology, Queen Alexandra Hospital, Portsmouth, UK.

Comment in
    Nat Clin Pract Rheumatol. 2008 Apr;4(4):182-3.

OBJECTIVE: The comparative risk of myocardial infarction (MI) with 
cyclo-oxygenase-2-specific drugs and traditional non-steroidal anti-inflammatory 
drugs (NSAIDs) was determined.
METHODS: The results of studies of a suitable size in colonic adenoma and 
arthritis-that had been published in English and from which crude data about MIs 
could be extracted-were evaluated. Medline, Embase and Cinahl (2000-2006) 
databases, as well as published bibliographies, were used as data sources. 
Systematic reviews examined MI risks in case-control and cohort studies, as well 
as in randomised controlled trials (RCTs).
RESULTS: 14 case-control studies (74 673 MI patients, 368 968 controls) showed 
no significant association of NSAIDs with MI in a random-effects model (OR 1.17; 
95% CI 0.99 to 1.37) and a small risk of MI in a fixed-effects model (OR 1.32; 
95% CI 1.29 to 1.35). Sensitivity analyses showed higher risks of MI in large 
European studies involving matched controls. Six cohort studies (387 983 patient 
years, 1 120 812 control years) showed no significant risk of MI with NSAIDs (RR 
1.03; 95% CI 1.00 to 1.07); the risk was higher with rofecoxib (RR 1.25; 95% CI 
1.17 to 1.34) but not with any other NSAIDs. Four RCTs of NSAIDs in colonic 
adenoma (6000 patients) showed an increased risk of MI (RR 2.68; 95% CI 1.43 to 
5.01). Fourteen RCTs in arthritis (45 425 patients) showed more MIs with 
cyclo-oxygenase-2-specific drugs (Peto OR 1.6; 95% CI 1.1 to 2.4), but fewer 
serious upper gastrointestinal events (Peto OR 0.40; 95% CI 0.31 to 0.53).
CONCLUSION: The overall risk of MI with NSAIDs and cyclo-oxygenase-2-specific 
drugs was small; rofecoxib showed the highest risk. There was an increased MI 
risk with cyclo-oxygenase-2-specific drugs compared with NSAIDs, but less 
serious upper gastrointestinal toxicity.

DOI: 10.1136/ard.2006.068650
PMCID: PMC1994282
PMID: 17344246 [Indexed for MEDLINE]

Conflict of interest statement: Competing interests: PAS, GHK and CMS have 
received no direct payments from companies involved in the evaluation or 
marketing of non‐steroidal anti‐inflammatory drugs in the last 5 years, 
including support to attend meetings, fees for consulting, and funding for 
research or educational support. EHC and DLS have received clinical trial 
grants, unrestricted educational grants and personal sponsorship for attending 
meetings from many companies involved in clinical trials and marketing of 
current anti‐rheumatic drugs, including all those involved in 
cyclo‐oxygenase‐2‐specific drugs. DLS has received fees for speaking at 
meetings, membership of national and international advisory boards, and giving 
professional advice from many pharmaceutical companies in the last 5 years 
including Amgen, Merck Sharp and Dhome, Novartis, Pfizer, Sumitomo 
Pharmaceuticals and Wyeth. He is medical adviser to Arthritis Care and Medical 
Vice‐Chair of the Arthritis and Musculoskeletal Alliance, which have both 
received unrestricted grants from pharmaceutical companies. No pharmaceutical 
company or adviser or representative has been involved directly or indirectly in 
the inception, preparation or writing of this manuscript; its contents have not 
been disclosed to any pharmaceutical company before submission.


245. Nat Protoc. 2019 Jul;14(7):1970-1990. doi: 10.1038/s41596-019-0167-1. Epub 2019 
Jun 5.

Systems-level analysis of isotopic labeling in untargeted metabolomic data by 
X(13)CMS.

Llufrio EM(1), Cho K(1)(2), Patti GJ(3)(4).

Author information:
(1)Department of Chemistry, Washington University in St. Louis, St. Louis, MO, 
USA.
(2)Department of Medicine, Washington University in St. Louis, St. Louis, MO, 
USA.
(3)Department of Chemistry, Washington University in St. Louis, St. Louis, MO, 
USA. gjpattij@wustl.edu.
(4)Department of Medicine, Washington University in St. Louis, St. Louis, MO, 
USA. gjpattij@wustl.edu.

Identification of previously unreported metabolites (so-called 'unknowns') in 
untargeted metabolomic data has become an increasingly active area of research. 
Considerably less attention, however, has been dedicated to identifying unknown 
metabolic pathways. Yet, for each unknown metabolite structure, there is 
potentially a yet-to-be-discovered chemical transformation. Elucidating these 
biochemical connections is essential to advancing our knowledge of cellular 
metabolism and can be achieved by tracking an isotopically labeled precursor to 
an unexpected product. In addition to their role in mapping metabolic fates, 
isotopic labels also provide critical insight into pathway dynamics (i.e., 
metabolic fluxes) that cannot be obtained from conventional label-free 
metabolomic analyses. When labeling is compared quantitatively between 
conditions, for example, isotopic tracers can enable relative pathway activities 
to be inferred. To discover unexpected chemical transformations or unanticipated 
differences in metabolic pathway activities, we have developed X13CMS, a 
platform for analyzing liquid chromatography/mass spectrometry (LC/MS) data at 
the systems level. After providing cells, animals, or patients with an 
isotopically enriched metabolite (e.g., 13C, 15N, or 2H), X13CMS identifies 
compounds that have incorporated the isotopic tracer and reports the extent of 
labeling for each. The analysis can be performed with a single condition, or 
isotopic fates can be compared between multiple conditions. The choice of which 
metabolite to enrich and which isotopic label to use is highly context 
dependent, but 13C-glucose and 13C-glutamine are often applied because they feed 
a large number of metabolic pathways. X13CMS is freely available.

DOI: 10.1038/s41596-019-0167-1
PMCID: PMC7323898
PMID: 31168088 [Indexed for MEDLINE]

Conflict of interest statement: Competing Financial Interests G.J.P. is a 
scientific advisory board member for Cambridge Isotope Laboratories and a 
recipient of the 2017 Agilent Early Career Professor Award. The remaining 
authors declare no competing interests.


246. Oncogene. 2005 Apr 7;24(15):2525-35. doi: 10.1038/sj.onc.1208456.

Microsatellite instability of selective target genes in HNPCC-associated colon 
adenomas.

Woerner SM(1), Kloor M, Mueller A, Rueschoff J, Friedrichs N, Buettner R, 
Buzello M, Kienle P, Knaebel HP, Kunstmann E, Pagenstecher C, Schackert HK, 
Möslein G, Vogelsang H, von Knebel Doeberitz M, Gebert JF; German HNPCC 
Consortium.

Author information:
(1)Institute of Molecular Pathology, University of Heidelberg, Germany.

Microsatellite instability (MSI) occurs in most hereditary nonpolyposis 
colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result 
of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites 
(cMS) in specific target genes causes frameshift mutations and functional 
inactivation of affected proteins, thereby providing a selective growth 
advantage to MMR deficient cells. At present, little is known about Selective 
Target Gene frameshift mutations in preneoplastic lesions. In this study, we 
examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of 
dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to 
our previous model, represent Selective Target genes of MSI. About 30% (8/26) of 
these genes showed a high mutation frequency (> or =50%) in colorectal adenomas, 
similar to the frequencies reported for colorectal carcinomas. Mutations in one 
gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to 
published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023). Biallelic 
inactivation was observed in nine genes, thus emphasizing the functional impact 
of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of 
frameshift mutations already at early stages of MSI colorectal tumorigenesis 
that increased with grade of dysplasia and transition to carcinoma. These 
include known Target Genes like BAX and TGFBR2, as well as three novel 
candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of 
potential relevance for the initiation and progression of MSI tumorigenesis, 
thus representing promising candidates for novel diagnostic and therapeutic 
approaches directed towards MMR-deficient tumors.

DOI: 10.1038/sj.onc.1208456
PMID: 15735733 [Indexed for MEDLINE]


247. JAMA Oncol. 2016 Sep 1;2(9):1162-9. doi: 10.1001/jamaoncol.2016.2314.

Clinical Outcome From Oxaliplatin Treatment in Stage II/III Colon Cancer 
According to Intrinsic Subtypes: Secondary Analysis of NSABP C-07/NRG Oncology 
Randomized Clinical Trial.

Song N(1), Pogue-Geile KL(1), Gavin PG(1), Yothers G(2), Kim SR(1), Johnson 
NL(1), Lipchik C(1), Allegra CJ(3), Petrelli NJ(4), O'Connell MJ(1), Wolmark 
N(5), Paik S(6).

Author information:
(1)National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, 
Pittsburgh, Pennsylvania.
(2)NRG Oncology, Pittsburgh, Pennsylvania3University of Pittsburgh, Pittsburgh, 
Pennsylvania.
(3)National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, 
Pittsburgh, Pennsylvania4Department of Medicine, University of Florida Health, 
Gainesville.
(4)National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, 
Pittsburgh, Pennsylvania5Helen F. Graham Cancer Center and Research Institute at 
Christiana Care, Newark, Delaware.
(5)National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, 
Pittsburgh, Pennsylvania6Allegheny Cancer Center at Allegheny General Hospital, 
Pittsburgh, Pennsylvania.
(6)National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology, 
Pittsburgh, Pennsylvania7Division of Medical Oncology, Severance Biomedical 
Science Institute, Yonsei University College of Medicine, Seoul, South Korea.

IMPORTANCE: Oxaliplatin added to fluorouracil plus leucovorin therapy for 
patients with colon cancer has been shown to provide significant but modest 
absolute benefit for disease-free survival. However, acute and chronic 
neurotoxic effects from this regimen underscore the need for markers that 
predict oxaliplatin benefit.
OBJECTIVE: To test our hypothesis that molecular subtypes of colon cancer would 
be associated with differential prognosis and benefit from oxaliplatin added to 
fluorouracil plus leucovorin therapy.
DESIGN, SETTING, AND PARTICIPANTS: Participants in the NSABP C-07 trial were 
divided into discovery (n = 848) and validation (n = 881) cohorts based on the 
order of tissue block submission. A reestimated centroid using 72 genes was used 
to determine Colorectal Cancer Assigner subtypes and their association with 
oxaliplatin benefit in the discovery cohort. The validation cohort was examined 
with a locked-down algorithm for subtype classification and statistical analysis 
plan. Post hoc analysis included examination of the entire cohort with 
Colorectal Cancer Assigner, Colorectal Cancer Subtype (CCS), and Consensus 
Molecular Subtype (CMS) methods.
INTERVENTIONS: Fluorouracil plus leucovorin with or without oxaliplatin.
MAIN OUTCOMES AND MEASURES: Percent recurrence-free survival.
RESULTS: Among 1729 patients, 744 (43%) were female and mean (SD) age was 58 
(11) years. Although C-07 participants with stage III disease with an enterocyte 
subtype showed a statistically significant benefit from oxaliplatin in the 
discovery cohort (hazard ratio, 0.22 [95% CI, 0.09-0.56]; P = .001 [N = 65]), no 
statistically significant benefit was observed in the validation cohort (hazard 
ratio, 0.53 [95% CI, 0.22-1.24]; P = .14 [N = 70]). The stemlike subtype was 
associated with poor prognosis and lack of benefit from oxaliplatin treatment 
(HR, 0.99 [95% CI, 0.73-1.34]; P = .96 [N = 367]). Examination of the different 
subtyping methods shows that all 3 methods robustly identified patients with 
poor prognosis (stemlike, CCS-3, and CMS-4) in both stage II and III.
CONCLUSIONS AND RELEVANCE: Patients with stemlike tumors may be appropriate for 
clinical trials testing experimental therapies because stemlike tumors were 
robustly identified and associated with a poor prognosis regardless of stage or 
chemotherapy regimen. The clinical utility of using subtyping for the 
identification of patients for treatment with oxaliplatin requires validation in 
independent clinical trial cohorts.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00004931.

DOI: 10.1001/jamaoncol.2016.2314
PMCID: PMC5065181
PMID: 27270348 [Indexed for MEDLINE]

Conflict of interest statement: Disclosures: Dr Yothers has acted in a 
consulting/advisory role for Pharmacyclics. No other disclosures are reported.


248. Oncotarget. 2017 Jun 13;8(24):39367-39381. doi: 10.18632/oncotarget.17023.

Prognosis of stage III colorectal carcinomas with FOLFOX adjuvant chemotherapy 
can be predicted by molecular subtype.

Kwon Y(1), Park M(1), Jang M(1), Yun S(1), Kim WK(1), Kim S(2), Paik S(2), Lee 
HJ(3), Hong S(3), Kim TI(3), Min B(4), Kim H(1).

Author information:
(1)Department of Pathology and BK21 for Medical Science, Yonsei University 
College of Medicine, Seoul, Korea.
(2)Severance Biomedical Science Institute and BK21 for Medical Science, Yonsei 
University College of Medicine, Seoul, Korea.
(3)Department of Internal Medicine, Yonsei University College of Medicine, 
Seoul, Korea.
(4)Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

Individualizing adjuvant chemotherapy is important in patients with advanced 
colorectal cancers (CRCs), and the ability to identify molecular subtypes 
predictive of good prognosis for stage III CRCs after adjuvant chemotherapy 
could be highly beneficial. We performed microarray-based gene expression 
analysis on 101 fresh-frozen primary samples from patients with stage III CRCs 
treated with FOLFOX adjuvant chemotherapy and 35 matched non-neoplastic mucosal 
tissues. CRC samples were classified into four molecular subtypes using 
nonnegative matrix factorization, and for comparison, we also grouped CRC 
samples using the proposed consensus molecular subtypes (CMSs). Of the 101 
cases, 80 were classified into a CMS group, which shows a 79% correlation 
between the CMS classification and our four molecular subtypes. We found that 
two of our subtypes showed significantly higher disease-free survival and 
overall survival than the others. Group 2, in particular, which showed no 
disease recurrence or death, was characterized by high microsatellite 
instability (MSI-H, 6/21), abundant mucin production (12/21), and right-sided 
location (12/21); this group strongly correlated with CMS1 (microsatellite 
instability immune type). We further identified the molecular characteristics of 
each group and selected 10 potential biomarker genes from each. When these were 
compared to the previously reported molecular classifier genes, we found that 31 
out of 40 selected genes were matched with those previously reported. Our 
findings indicate that molecular classification can reveal specific molecular 
subtypes correlating with clinicopathologic features of CRCs and can have 
predictive value for the prognosis for stage III CRCs with FOLFOX adjuvant 
chemotherapy.

DOI: 10.18632/oncotarget.17023
PMCID: PMC5503619
PMID: 28455965 [Indexed for MEDLINE]

Conflict of interest statement: CONFLICTS OF INTEREST The authors declare no 
conflict of interest.


249. J Agric Food Chem. 2018 Jul 18;66(28):7358-7366. doi: 10.1021/acs.jafc.8b01604. 
Epub 2018 Jul 6.

Bioaccessibility during In Vitro Digestion and Antiproliferative Effect of 
Bioactive Compounds from Andean Berry ( Vaccinium meridionale Swartz) Juice.

Agudelo CD(1), Luzardo-Ocampo I(2), Campos-Vega R(2), Loarca-Piña G(2), 
Maldonado-Celis ME(3).

Author information:
(1)Instituto de Biología, Facultad de Ciencias Exactas y Naturales , Universidad 
de Antioquia , Calle 67 #53-108 , Medellín AA 1226 , Colombia.
(2)Programa de Posgrado del Centro de la República (PROPAC), Research and 
Graduate Studies in Food Science, School of Chemistry , Universidad Autónoma de 
Querétaro , Santiago de Querétaro 76010 , México.
(3)Escuela de Nutrición y Dietética , Universidad de Antioquia , Ciudadela de 
Robledo Carrera 75 # 65-87 , Medellín AA 1226 , Colombia.

Berry consumption is associated with colorectal-cancer chemoprevention, but 
digestive conditions can affect this property. The bioaccessibility and apparent 
permeability coefficients of bioactive compounds from Andean Berry Juice (ABJ) 
after in vitro gastrointestinal digestion and colonic fermentation were 
analyzed. The antiproliferative effect of the fermented nondigestible fraction 
was evaluated against SW480 colon-adenocarcinoma cells. Gallic acid displayed 
the highest bioaccessibility in the mouth, stomach, small intestine, and colon. 
However, chlorogenic acid exhibited the highest apparent permeability 
coefficients (up to 1.98 × 10-4 cm/s). The colonic-fermentation fraction showed 
an increase of ≥50% antiproliferative activity against SW480 cells (19.32%, 
v/v), equivalent to those of gallic acid (13.04 μg/g), chlorogenic acid (7.07 
μg/g), caffeic acid (0.40 μg/g), ellagic acid (7.32 μg/g), rutin (6.50 μg/g), 
raffinose (0.14 mg/g), stachyose (0.70 mg/g), and xylose (9.41 mg/g). Bioactive 
compounds from ABJ are bioaccessible through the gastrointestinal tract and 
colon fermentation, resulting in antiproliferative activity.

DOI: 10.1021/acs.jafc.8b01604
PMID: 29913068 [Indexed for MEDLINE]


250. J Agric Food Chem. 2020 Aug 26;68(34):9235-9244. doi: 10.1021/acs.jafc.0c04690. 
Epub 2020 Aug 14.

Dietary Polyphenols Inhibit the Cytochrome P450 Monooxygenase Branch of the 
Arachidonic Acid Cascade with Remarkable Structure-Dependent Selectivity and 
Potency.

Kampschulte N(1), Alasmer A(1), Empl MT(2), Krohn M(1), Steinberg P(2), Schebb 
NH(1)(2).

Author information:
(1)Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, 
University of Wuppertal, Gaussstr. 20, 42119 Wuppertal, Germany.
(2)Institute for Food Toxicology, University of Veterinary Medicine Hannover, 
Bischofsholer Damm 15, 30173 Hannover, Germany.

The products of the cytochrome P450 monooxygenase (CYP)-catalyzed oxidation of 
arachidonic acid (AA), that is, epoxy- and hydroxy-fatty acids, play a crucial 
role in the homeostasis of several physiological processes. In a liver 
microsome-based multienzyme assay using AA as natural substrate, we investigated 
how polyphenols inhibit different oxylipin-forming CYP in parallel but 
independently from each other. The ω-hydroxylating CYP4F2 and CYP4A11 were 
investigated, as well as the epoxidizing CYP2C-subfamily and CYP3A4 along with 
the (ω-n)-hydroxylating CYP1A1 and CYP2E1. The oxylipin formation was inhibited 
by several polyphenols with a remarkable selectivity and a potency comparable to 
known CYP inhibitors. The flavone apigenin inhibited the epoxidation, 
ω-hydroxylation, and (ω-n)-hydroxylation of AA with IC50 values of 4.4-9.8, 
2.9-10, and 10-25 μM, respectively. Other flavones such as wogonin selectively 
inhibited CYP1A1-catalyzed (ω-n)-hydroxylation with an IC50 value of 0.10-0.22 
μM, while the isoflavone genistein was a selective ω-hydroxylase inhibitor 
(IC50: 5.5-46 μM). Of note, the flavanone naringenin and the anthocyanidin 
perlargonidin did not inhibit CYPs of the AA cascade. Moderate permeability of 
apigenin as tested in the Caco-2 model of intestinal absorption (Papp: 4.5 ± 1 × 
10-6 cm/s) and confirmation of the inhibition of 20-HETE formation by apigenin 
in the colorectal cancer-derived cell line HCT 116 (IC50: 1.5-8.8 μM) underline 
the possible in vivo relevance of these effects. Further research is needed to 
better understand how polyphenols impact human health by this newly described 
molecular mode of action.

DOI: 10.1021/acs.jafc.0c04690
PMID: 32786866 [Indexed for MEDLINE]


251. Sci Rep. 2022 Jan 14;12(1):760. doi: 10.1038/s41598-022-04822-x.

Non-invasive laparoscopic detection of small tumors of the digestive tract using 
inductive sensors of proximity.

Calborean A(1), Macavei S(2), Mocan M(3), Ciuce C(3), Bintintan A(3), Cordos 
A(3), Pestean C(4), Chira R(3), Zarbo L(2), Barbu-Tudoran L(2), Dindelegan G(3), 
Nickel F(5), Mocan B(6), Surlin V(7), Bintintan V(3).

Author information:
(1)National Institute for Research and Development of Isotopic and Molecular 
Technologies, Donath Street, No 67-103, Cluj-Napoca, Romania. 
adrian.calborean@gmail.com.
(2)National Institute for Research and Development of Isotopic and Molecular 
Technologies, Donath Street, No 67-103, Cluj-Napoca, Romania.
(3)Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, V. Babeş 
Street No. 8, 400012, Cluj-Napoca, Romania.
(4)University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca, 
Calea Manastur Street No. 3-5, Cluj-Napoca, Romania.
(5)Clinic for General, Visceral and Transplantation Surgery, University of 
Heidelberg, INF 110, Heidelberg, Germany.
(6)Technical University Cluj-Napoca, Memorandumului, Street No.28, Cluj-Napoca, 
Romania.
(7)University of Medicine and Pharmacy Craiova, Petru Rares Street No. 2, 
700115, Craiova, Romania.

The precise location of gastric and colorectal tumors is of paramount importance 
for the oncological surgeon as it dictates the limits of resection and the 
extent of lymphadenectomy. However, this task proves sometimes to be very 
challenging, especially in the laparoscopic setting when the tumors are small, 
have a soft texture, and do not invade the serosa. In this view, our research 
team has developed a new instrument adapted to minimally-invasive surgery, and 
manipulated solely by the operating surgeon which has the potential to locate 
precisely tumors of the digestive tract. It consists of an inductive proximity 
sensor and an electronic block encapsulated into an autoclavable stainless-steel 
cage that works in tandem with an endoscopic hemostatic clip whose structure was 
modified to increase detectability. By scanning the serosal side of the colon or 
stomach, the instrument is capable to accurately pinpoint the location of the 
clip placed previously during diagnostic endoscopy on the normal bowel mucosa, 
adjacent to the tumor. In the current in-vivo experiments performed on large 
animals, the modified clips were transported without difficulties to the point 
of interest and attached to the mucosa of the bowel. Using a laparoscopic 
approach, the detection rate of this system reached 65% when the sensor scanned 
the bowel at a speed of 0.3 cm/s, and applying slight pressure on the serosa. 
This value increased to 95% when the sensor was guided directly on the point of 
clip attachment. The detection rate dropped sharply when the scanning speed 
exceeded 1 cm/s and when the sensor-clip distance exceeded the cut-off value of 
3 mm. In conclusion, the proposed detection system demonstrated its potential to 
offer a swift and convenient solution for the digestive laparoscopic surgeons, 
however its detection range still needs to be improved to render it useful for 
the clinical setting.

© 2022. The Author(s).

DOI: 10.1038/s41598-022-04822-x
PMCID: PMC8760327
PMID: 35031673 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.


252. Gastrointest Endosc. 2008 Mar;67(3):489-96. doi: 10.1016/j.gie.2007.08.041. Epub 
2008 Jan 7.

Patterns of endoscopy in the United States: analysis of data from the Centers 
for Medicare and Medicaid Services and the National Endoscopic Database.

Sonnenberg A(1), Amorosi SL, Lacey MJ, Lieberman DA.

Author information:
(1)Portland VA Medical Center, Portland 97239, Oregon, USA.

BACKGROUND: Patterns of GI endoscopy are influenced by the underlying 
epidemiology of GI disease, as well as by policy and practice guidelines.
OBJECTIVE: To compare practice patterns of GI endoscopy between two large 
national databases of the United States.
DESIGN: Descriptive database analysis.
SETTING: A 5% sample of the entire U.S. Medicare population (Centers for 
Medicare and Medicaid Services, CMS data files) and endoscopic data repository 
of U.S. gastroenterology practices (Clinical Outcomes Research Initiative, CORI 
database) from 1999 to 2003.
PATIENTS: The study population included 1,121,215 Medicare and 635,573 CORI 
patients undergoing various types of GI endoscopy.
INTERVENTIONS: EGD, colonoscopy, and flexible sigmoidoscopy.
MAIN OUTCOME MEASUREMENTS: Patient demographics, endoscopic diagnoses, time 
trends of diagnoses.
RESULTS: A colonoscopy was the most common endoscopic procedure performed (CMS 
53%, CORI 58%), followed by an EGD (37%, 32%), and a flexible sigmoidoscopy 
(10%, 10%). In the CMS data, women accounted for 59% of the EGDs, 57% of the 
colonoscopies, and 56% of the flexible sigmoidoscopies, and in the CORI data, 
the corresponding numbers were 57%, 55%, and 54%, respectively. Compared with 
their distribution in the U.S. census population, nonwhite patients in both 
databases underwent relatively more EGDs and fewer colonoscopies. The most 
common upper-GI diagnosis was GERD, followed by GI bleeding, gastric ulcer, and 
duodenal ulcer. The most common lower-GI diagnosis was colorectal polyp. Over 
the period of 1999 to 2003, the rates of colorectal cancer diagnosed with 
colonoscopy declined.
LIMITATIONS: Only a limited amount of information about individual patients was 
retrievable from the electronic databases.
CONCLUSIONS: A colonoscopy is now the most common endoscopic procedure in the 
United States. Women undergo both upper and lower endoscopic procedures more 
often than men. Nonwhite patients are underrepresented in the use of colonoscopy 
relative to the prevalence of nonwhite persons in the U.S. population. Increased 
use of a colonoscopy for colon screening and surveillance has been associated 
with a decreased rate of cancer diagnosis.

DOI: 10.1016/j.gie.2007.08.041
PMID: 18179793 [Indexed for MEDLINE]


253. Hum Genet. 2007 Jan;120(5):701-11. doi: 10.1007/s00439-006-0254-6. Epub 2006 Sep 
26.

High-resolution mapping of DNA methylation in human genome using oligonucleotide 
tiling array.

Hayashi H(1), Nagae G, Tsutsumi S, Kaneshiro K, Kozaki T, Kaneda A, Sugisaki H, 
Aburatani H.

Author information:
(1)Genome Science Division, Research Center for Advanced Science and Technology, 
The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, Japan.

DNA methylation is an epigenetic mark crucial in regulation of gene expression. 
Aberrant DNA methylation causes silencing of tumor suppressor genes and promotes 
chromosomal instability in human cancers. Most of previous studies for DNA 
methylation have focused on limited genomic regions, such as selected genes or 
promoter CpG islands (CGIs) containing recognition sites of 
methylation-sensitive restriction enzymes. Here, we describe a method for 
high-resolution analysis of DNA methylation using oligonucleotide tiling arrays. 
The input material is methylated DNA immunoprecipitated with anti-methylcytosine 
antibodies. We examined the ENCODE region ( approximately 1% of human genome) in 
three human colorectal cancer cell lines and identified over 700 candidate 
methylated sites (CMS), where 24 of 25 CMS selected randomly were subsequently 
verified by bisulfite sequencing. CMS were enriched in the 5' regulatory regions 
and the 3' regions of genes. We also compared DNA methylation patterns with 
histone H3 and H4 acetylation patterns in the HOXA cluster region. Our analysis 
revealed no acetylated histones in the hypermethylated region, demonstrating 
reciprocal relationship between DNA methylation and histone H3 and H4 
acetylation. Our method recognizes DNA methylation with little bias by genomic 
location and, therefore, is useful for comprehensive high-resolution analysis of 
DNA methylation providing new findings in the epigenomics.

DOI: 10.1007/s00439-006-0254-6
PMID: 17024368 [Indexed for MEDLINE]


254. Zhong Xi Yi Jie He Xue Bao. 2010 Sep;8(9):863-9. doi: 10.3736/jcim20100910.

[Absorption and transportation characteristics of scutellarin and scutellarein 
across Caco-2 monolayer model].

[Article in Chinese]

You HS(1), Zhang HF, Dong YL, Chen SY, Wang MY, Dong WH, Xing JF.

Author information:
(1)Department of Pharmacy, the First Affiliated Hospital of Medical College, 
Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.

OBJECTIVE: To investigate the absorption and transepithelial transport 
characteristics of scutellarin and scutellarein in the human colonic 
adenocarcinoma cell (Caco-2) monolayer model. The influence factors on these two 
compounds' absorption were investigated, such as buffer solution, duration of 
culture, and inhibitors of multidrug resistance-associated protein 2 (MRP(2)), 
breast cancer drug resistance protein (BCRP) and P-glycoprotein (P-gp).
METHODS: By using Caco-2 monolayer as an intestinal epithelial cell model, the 
transport process was studied from apical (AP) side to basolateral (BL) side or 
from BL to AP. The two compounds were determined by high-performance liquid 
chromatography coupled with diode-array-detector detection. Transport parameters 
and apparent permeability coeffients (P(app)) were calculated.
RESULTS: The P(app) values of scutellarin and scutellarein were different in two 
buffer solutions, respectively. In phosphate buffered saline, scutellarin had no 
absorption from AP to BL, while its P(app) value was 0.74×10(-6) to 1.58×10(-6) 
cm/s from BL to AP. The P(app) values of scutellarein were 4.33×10(-6) to 
6.79×10(-6) cm/s and 1.32×10(-6) to 2.56×10(-6) cm/s from AP to BL and from BL 
to AP, respectively. The P(app) value gradually decreased with time. The 
absorption of scutellarein was better than that of scutellarin. The scutellarin 
absorption was improved by verapamil, MK-571 and reserpine. The scutellarein 
absorption was improved by verapamil whereas its excretion was improved by 
MK-571.
CONCLUSION: Absorption of scutellarin is difficult in Caco-2 monolayer cells, 
which contributes to its low bioavailability. Scutellarein absorption is better 
than scutellarin absorption. Scutellarein transepithelial transport is passive 
diffusion. The inhibitor of P-gp can improve scutellarin and scutellarein 
transportation. The inhibitors of MRP(2) and BCRP can promote transportation of 
scutellarin. The inhibitor of MRP(2) can promote efflux of scutellarein. The 
multidrug resistance-associated protein may be the second reason for low 
bioavailability of scutellarin.

DOI: 10.3736/jcim20100910
PMID: 20836977 [Indexed for MEDLINE]


255. J Gen Intern Med. 2013 Sep;28(9):1208-14. doi: 10.1007/s11606-013-2414-4.

Predictors of CT colonography utilization among asymptomatic medicare 
beneficiaries.

Zafar HM(1), Yang J, Harhay M, Lev-Toaff A, Armstrong K.

Author information:
(1)Department of Radiology, Hospital of the University of Pennsylvania, 
Philadelphia, PA 19104, USA. Hanna.zafar@uphs.upenn.edu

Comment in
    J Gen Intern Med. 2013 Sep;28(9):1224.

BACKGROUND: Although the Centers for Medicare and Medicaid Services (CMS) denied 
coverage for screening computed tomography colonography (CTC) in March 2009, 
little is understood about whether CTC was targeted to the appropriate patient 
population prior to this decision.
OBJECTIVE: Evaluate patient characteristics and known relative clinical 
indications for screening CTC among patients who received CTC compared to 
optical colonoscopy (OC).
DESIGN/PARTICIPANTS: Cross-sectional study of all 10,538 asymptomatic Medicare 
beneficiaries who underwent CTC between January 2007 and December 2008, compared 
to a cohort of 160,113 asymptomatic beneficiaries who underwent OC, matched on 
county of residence and year of examination.
MAIN MEASURES: Patient characteristics and known relative appropriate and 
inappropriate clinical indications for screening CTC.
KEY RESULTS: CTC utilization was higher among women, patients > 65 years of age, 
white patients, and those with household income > 75 % (p = 0.001). Patients 
with relatively appropriate clinical indications for screening CTC were more 
likely to undergo CTC than OC including presumed incomplete OC (OR 80.7, 95 % CI 
76.01-85.63); sedation risk (OR 1.11, 95 % CI 1.05-1.17); and chronic 
anticoagulation risk (OR 1.46, 95 % CI 1.38-1.54), after adjusting for patient 
characteristics and known clinical indications. Conversely, patients undergoing 
high-risk screening, an inappropriate indication, were less likely to receive 
CTC (OR 0.4, 95 % CI 0.37-0.42). Overall, 83 % of asymptomatic patients referred 
to CTC had at least one clinical indication relatively appropriate for CTC 
(8,772/10,538).
CONCLUSION: During the 2 years preceding CMS denial for screening, CTC was 
targeted to asymptomatic patients with relatively appropriate clinical 
indications for CTC/not receiving OC. However, CTC utilization was lower among 
certain demographic groups, including minority patients. These findings raise 
the possibility that future coverage of screening CTC might exacerbate 
disparities in colorectal cancer screening while increasing overall screening 
rates.

DOI: 10.1007/s11606-013-2414-4
PMCID: PMC3744296
PMID: 23539282 [Indexed for MEDLINE]


256. Mol Cell Oncol. 2022 Jan 27;9(1):2024051. doi: 10.1080/23723556.2021.2024051. 
eCollection 2022.

Rewired lipid metabolism as an actionable vulnerability of aggressive colorectal 
carcinoma.

Capece D(1)(2), Franzoso G(1).

Author information:
(1)Department of Immunology and Inflammation, Imperial College London, London, 
UK.
(2)Department of Biotechnological and Applied Clinical Sciences (DISCAB), 
University of L'Aquila, L'Aquila, Italy.

Cancer cells reprogram lipid metabolism to fuel cell division, adaptation to 
stress, and metastatic dissemination. NF-κB transcription factors control this 
mechanism in aggressive Consensus Molecular Subtype (CMS)4 of colorectal 
carcinoma (CRC) via triacylglycerol (TAG) lipase, carboxylesterase 1 (CES1), 
thereby linking obesity-associated inflammation with metabolic adaptation and 
cytoprotection from lipid-induced toxicity. Our findings identify a potential 
therapeutic route to treat patients with metastasis-prone CRC and provide an 
example for targeting core tumor subtype-based vulnerabilities in cancers beyond 
CRC.

© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.

DOI: 10.1080/23723556.2021.2024051
PMCID: PMC8890390
PMID: 35252551

Conflict of interest statement: No potential conflict of interest was reported 
by the author(s).


257. J Am Coll Radiol. 2009 Nov;6(11):756-772.e4. doi: 10.1016/j.jacr.2009.09.007.

ACR Colon Cancer Committee white paper: status of CT colonography 2009.

McFarland EG(1), Fletcher JG, Pickhardt P, Dachman A, Yee J, McCollough CH, 
Macari M, Knechtges P, Zalis M, Barish M, Kim DH, Keysor KJ, Johnson CD; 
American College of Radiology.

Author information:
(1)Center for Diagnostic Imaging, St Louis, Missouri, USA.

PURPOSE: To review the current status and rationale of the updated ACR practice 
guidelines for CT colonography (CTC).
METHODS: Clinical validation trials in both the United States and Europe are 
reviewed. Key technical aspects of the CTC examination are emphasized, including 
low-dose protocols, proper insufflation, and bowel preparation. Important issues 
of implementation are discussed, including training and certification, 
definition of the target lesion, reporting of colonic and extracolonic findings, 
quality metrics, reimbursement, and cost-effectiveness.
RESULTS: Successful validation trials in screening cohorts both in the United 
States with ACRIN and in Germany demonstrated sensitivity > or = 90% for 
patients with polyps >10 mm. Proper technique is critical, including low-dose 
techniques in screening cohorts, with an upper limit of the CT dose index by 
volume of 12.5 mGy per examination. Training new readers includes the 
requirement of interactive workstation training with 2-D and 3-D image display 
techniques. The target lesion is defined as a polyp > or = 6 mm, consistent with 
the American Cancer Society joint guidelines. Five quality metrics have been 
defined for CTC, with pilot data entered. Although the CMS national noncoverage 
decision in May 2009 was a disappointment, multiple third-party payers are 
reimbursing for screening CTC. Cost-effective modeling has shown CTC to be a 
dominant strategy, including in a Medicare cohort.
CONCLUSION: Supported by third-party payer reimbursement for screening, CTC will 
continue to further transition into community practice and can provide an 
important adjunctive examination for colorectal screening.

DOI: 10.1016/j.jacr.2009.09.007
PMID: 19878883 [Indexed for MEDLINE]


258. Prev Chronic Dis. 2013 Apr 25;10:E61. doi: 10.5888/pcd10.120137.

Prevalence of multiple chronic conditions among Medicare beneficiaries, United 
States, 2010.

Lochner KA(1), Cox CS.

Author information:
(1)Office of the Regional Administrator, Centers for Medicare and Medicaid 
Services, 61 Forsyth St SW, Ste 4T20, Atlanta, GA 30303-8909, USA. 
Kimberly.Lochner@cms.hhs.gov

INTRODUCTION: The increase in chronic health conditions among Medicare 
beneficiaries has implications for the Medicare system. The objective of this 
study was to use the US Department of Health and Human Services Strategic 
Framework on multiple chronic conditions as a basis to examine the prevalence of 
multiple chronic conditions among Medicare beneficiaries.
ANALYSIS: We analyzed Centers for Medicare and Medicaid Services administrative 
claims data for Medicare beneficiaries enrolled in the fee-for-service program 
in 2010. We included approximately 31 million Medicare beneficiaries and 
examined 15 chronic conditions. A beneficiary was considered to have a chronic 
condition if a Medicare claim indicated that the beneficiary received a service 
or treatment for the condition. We defined the prevalence of multiple chronic 
conditions as having 2 or more chronic conditions.
RESULTS: Overall, 68.4% of Medicare beneficiaries had 2 or more chronic 
conditions and 36.4% had 4 or more chronic conditions. The prevalence of 
multiple chronic conditions increased with age and was more prevalent among 
women than men across all age groups. Non-Hispanic black and Hispanic women had 
the highest prevalence of 4 or more chronic conditions, whereas Asian or Pacific 
Islander men and women, in general, had the lowest.
SUMMARY: The prevalence of multiple chronic conditions among the Medicare 
fee-for-service population varies across demographic groups. Multiple chronic 
conditions appear to be more prevalent among women, particularly non-Hispanic 
black and Hispanic women, and among beneficiaries eligible for both Medicare and 
Medicaid benefits. Our findings can help public health researchers target 
prevention and management strategies to improve care and reduce costs for people 
with multiple chronic conditions.

DOI: 10.5888/pcd10.120137
PMCID: PMC3652723
PMID: 23618541 [Indexed for MEDLINE]


259. Cancer Immun. 2004 Nov 25;4:14.

Immunogenic peptides generated by frameshift mutations in DNA mismatch 
repair-deficient cancer cells.

Schwitalle Y(1), Linnebacher M, Ripberger E, Gebert J, von Knebel Doeberitz M.

Author information:
(1)Institute of Molecular Pathology, University of Heidelberg, D-69120 
Heidelberg, Germany.

About 15% of all human colorectal, gastric, and endometrial tumors, and the 
majority of tumors in patients suffering from hereditary nonpolyposis colorectal 
cancer syndrome, are caused by loss of DNA mismatch repair functions. In the 
affected cancer cells, this results in insertion or deletion mutations at short, 
repetitive DNA sequences referred to as microsatellites. Such mutations in 
coding microsatellites (cMS) cause translational frameshifts that may destroy 
gene function. These frameshift mutations could also cause the translation of 
immunogenic neopeptides at the carboxy terminus. Several such mutations have 
been identified recently. However, since none of the frameshift-induced 
neopeptides identified so far is generated in all cancer cells with 
microsatellite instability (MSI), we aim to define a broad but comprehensive set 
of frameshift peptides (FSPs) that might be combined in a multivalent vaccine 
for MSI+ cancers. Here, we characterize the immunogenic properties of five 
additional HLA-A0201-restricted frameshift-induced neopeptides derived from 
mutations in three cMS-containing genes (Caspase-5, TAF-1b, and HT001) that are 
frequently hit in MSI+ cancer cells. One Caspase-5-derived FSP, (67)-FLIIWQNTM 
(FSP26), was identified as a novel HLA-A0201-restricted CTL epitope. 
FSP26-specific CTLs efficiently lysed colon carcinoma cells expressing HLA-A0201 
and the underlying (-1) mutation. This mutation in an A(10) cMS is observed in 
up to 66% of MSI+ colorectal cancers. Thus, this newly identified CTL epitope 
may be another essential component of a multivalent vaccine against cancers with 
MSI.

PMID: 15563124 [Indexed for MEDLINE]


260. Gastrointest Endosc Clin N Am. 2010 Oct;20(4):735-50. doi: 
10.1016/j.giec.2010.07.014.

Defining an episode of care for colonoscopy: work of the High Value Health Care 
Project characterizing episodes and costs of care.

Brennan NJ(1), Lee TA, Wilk AS, Lyttle CS, Weiss KB.

Author information:
(1)Engelberg Center for Health Care Reform, The Brookings Institution, 1775 
Massachusetts Avenue, NW, Washington, DC 20036, USA. niall.brennan@cms.hhs.gov

Working with a group of key stakeholders, the authors developed an episode-based 
resource use measure focused on the use of colonoscopy. This measure is intended 
to identify differences in health care resource use in a short time frame 
surrounding the colonoscopy. The ultimate intent in the development of this 
measure was to pair it with a measure of quality so that both the cost and 
quality of care can be evaluated together. In initial testing, the authors found 
the use of general anesthesia with colonoscopy to be associated with higher 
episode costs. Eventually, when paired with quality measures, it is hoped this 
measure will provide actionable information for health care payers and providers 
to more efficiently provide colonoscopy services without compromising quality.

Published by Elsevier Inc.

DOI: 10.1016/j.giec.2010.07.014
PMID: 20889075 [Indexed for MEDLINE]


261. J Coll Physicians Surg Pak. 2004 Sep;14(9):566-9.

Hand-assisted laparoscopic surgery for colorectal malignancies.

Memon MA(1), Fitzgibbons RJ.

Author information:
(1)Department of Surgery, Nottingham City Hospital, Nottingham, England, UK. 
mmemon@yahoo.com

OBJECTIVE: To report our initial experience with hand-assisted laparoscopic 
surgery (HALS) for colorectal malignancies using a specially-designed 
laparoscopic hand cannula.
PATIENTS AND METHODS: Nine caucasians patients with colorectal malignancies 
underwent HALS which included 02 right hemicolectomies, 01 transverse colectomy, 
03 sigmoid colectomies, 01 anterior resection and 02 low anterior resections.
RESULTS: There were 4 males and 5 females. The mean length of incision for 
placement of the cannula was 7 cms (range 7-8 cms). The mean operating time was 
180 minutes. Postoperatively on an average patients were ambulatory by day 2 
(range 1-4) and taking oral fluids by day 3 (range 1-4). There were no 
conversions to laparotomy. Furthermore there was no operative mortality and no 
complication directly related to the use of the device.
CONCLUSION: HALS appears to be a useful adjuvant for laparoscopic colectomy due 
to advantages provided by tactile sensation. A curative resection for malignancy 
can be performed without compromising oncological principles.

PMID: 15353146 [Indexed for MEDLINE]


262. J Med Chem. 2016 Feb 11;59(3):1078-101. doi: 10.1021/acs.jmedchem.5b01685. Epub 
2016 Jan 21.

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule 
Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.

Mallinger A(1), Schiemann K(2), Rink C(1), Stieber F(2), Calderini M(2), 
Crumpler S(1), Stubbs M(1), Adeniji-Popoola O(1), Poeschke O(2), Busch M(2), 
Czodrowski P(2), Musil D(2), Schwarz D(2), Ortiz-Ruiz MJ(1), Schneider R(2), 
Thai C(1), Valenti M(1), de Haven Brandon A(1), Burke R(1), Workman P(1), Dale 
T(3), Wienke D(2), Clarke PA(1), Esdar C(2), Raynaud FI(1), Eccles SA(1), 
Rohdich F(2), Blagg J(1).

Author information:
(1)Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer 
Research, London, SW7 3RP, U.K.
(2)Merck KGaA , Darmstadt, 64293, Germany.
(3)School of Bioscience, Cardiff University , Cardiff, CF10 3AX, U.K.

The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated 
in human disease, particularly in colorectal cancer where it has been reported 
as a putative oncogene. Here we report the discovery of 109 (CCT251921), a 
potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent 
affinity for CDK19. We describe a structure-based design approach leading to the 
discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the 
application of physicochemical property analyses to successfully reduce in vivo 
metabolic clearance, minimize transporter-mediated biliary elimination while 
maintaining acceptable aqueous solubility. Compound 109 affords the optimal 
compromise of in vitro biochemical, pharmacokinetic, and physicochemical 
properties and is suitable for progression to animal models of cancer.

DOI: 10.1021/acs.jmedchem.5b01685
PMCID: PMC5362750
PMID: 26796641 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare the following competing 
financial interest(s): A.M., C.R., S.C., M.S., O.A-P., M.-J.O.-R., C.T., M.V., 
A.d.H.B., R.B., P.W., T.D., P.A.C., F.I.R., S.A.E., and J.B. are current or 
former employees of The Institute of Cancer Research, which has a commercial 
interest in the development of WNT pathway inhibitors. K.S., F.S., M.C., O.P., 
M.B., P.C., D.M., D.S., R.S., D.W., C.E. and F.R. are current employees of 
Merck.


263. J Gastroenterol. 2022 Apr 21. doi: 10.1007/s00535-022-01875-7. Online ahead of 
print.

Comprehensive genetic characterization of rectal cancer in a large cohort of 
Japanese patients: differences according to tumor location.

Hino H(1), Shiomi A(2), Hatakeyama K(3), Kagawa H(2), Manabe S(2), Yamaoka Y(2), 
Nagashima T(4)(5), Ohshima K(3), Urakami K(4), Akiyama Y(6), Yamaguchi K(7).

Author information:
(1)Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, 1007 
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan. 
h.hino@scchr.jp.
(2)Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, 1007 
Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
(3)Medical Genetics Division, Shizuoka Cancer Center Research Institute, 
Sunto-gun, Shizuoka, 411-8777, Japan.
(4)Cancer Diagnostics Research Division, Shizuoka Cancer Center Research 
Institute, Sunto-gun, Shizuoka, 411-8777, Japan.
(5)SRL Inc., Shinjuku-ku, Tokyo, 163-0409, Japan.
(6)Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, 
Shizuoka, 411-8777, Japan.
(7)Shizuoka Cancer Center, Sunto-gun, Shizuoka, 411-8777, Japan.

BACKGROUND: In clinical practice, rectal cancer (RC) is classified according to 
tumor location. However, RC's genetic characteristics according to tumor 
location remain unclear. Therefore, we aimed to compare RC's genetic 
characteristics according to tumor location.
METHODS: In 611 patients with surgically resected RC, we performed genetic 
analyses and compared the results between low and other RCs. Low RC was defined 
according to the European Society for Medical Oncology (ESMO) guidelines and 
Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma (JCCRC).
RESULTS: KRAS mutation accumulation was significantly higher in low RC under the 
ESMO classification. Gene expression levels significantly differed between the 
groups for CTNNB1, KRAS, and ERBB2, under the ESMO classification and for TP53, 
KRAS, and ERBB2 under the JCCRC. Under the JCCRC, low RC had a significantly 
higher prevalence of fusion genes, such as EIF3E-RSPO2, PTPRK-RSPO3, and 
VTI1A-TCF7L2. Consensus molecular subtype (CMS) distribution was significantly 
different between the groups under both classifications. In particular, low RC 
had lower and higher frequencies of CMS2 and CMS4, respectively. CMS2 and CMS4 
frequencies in low RC were 14.8% and 41.5% under the ESMO classification and 
14.5% and 41.6% under the JCCRC, respectively. Multivariate Cox regression 
analysis demonstrated that pT3-4, pN1-2, and CMS4 were associated with poor 
relapse-free survival.
CONCLUSIONS: Low RC exhibited distinct genetic characteristics from other RCs. 
In particular, CMS4 was more frequent in low RC and was a risk factor for poor 
prognosis. These findings potentially avail further information regarding tumor 
biology and could lead to improvements in RC treatment.

© 2022. Japanese Society of Gastroenterology.

DOI: 10.1007/s00535-022-01875-7
PMID: 35449312


264. Cell Syst. 2022 Feb 16;13(2):109-130.e6. doi: 10.1016/j.cels.2021.09.012. Epub 
2021 Oct 14.

Tissue schematics map the specialization of immune tissue motifs and their 
appropriation by tumors.

Bhate SS(1), Barlow GL(2), Schürch CM(3), Nolan GP(4).

Author information:
(1)Department of Microbiology and Immunology, Stanford University School of 
Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology, 
Stanford University School of Medicine, Stanford University, Stanford, CA 94305, 
USA; Department of Bioengineering, Stanford University Schools of Medicine and 
Engineering, Stanford University, Stanford, CA 94305, USA.
(2)Department of Microbiology and Immunology, Stanford University School of 
Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology, 
Stanford University School of Medicine, Stanford University, Stanford, CA 94305, 
USA; Program in Immunology, Stanford University School of Medicine, Stanford 
University, Stanford, CA 94305, USA.
(3)Department of Microbiology and Immunology, Stanford University School of 
Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology, 
Stanford University School of Medicine, Stanford University, Stanford, CA 94305, 
USA; Department of Pathology and Neuropathology, University Hospital and 
Comprehensive Cancer Center Tübingen, Tübingen, Germany.
(4)Department of Microbiology and Immunology, Stanford University School of 
Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology, 
Stanford University School of Medicine, Stanford University, Stanford, CA 94305, 
USA. Electronic address: gnolan@stanford.edu.

Comment in
    Nat Methods. 2021 Dec;18(12):1450.
    Cell Syst. 2022 Feb 16;13(2):107-108.

A schematic of a biological system, i.e., a representation of its pieces, how 
they are combined, and what they do, would facilitate understanding its 
essential organization and alteration in pathogenesis or evolution. We present a 
computational approach for constructing tissue schematics (TSs) from 
high-parameter imaging data and a biological model for interpreting them. TSs 
map the spatial assembly of cellular neighborhoods into tissue motifs, whose 
modular composition, we propose, enables the generation of complex outputs. We 
developed our approach in human lymphoid tissue (HLT), identifying the 
follicular outer zone as a potential relay between neighboring zones and a core 
lymphoid assembly with modifications characteristic of each HLT type. Applying 
the TS approach to the tumor microenvironment in human colorectal cancer 
identified a higher-order motif, whose mutated assembly was negatively 
associated with patient survival. TSs may therefore elucidate how immune 
architectures can be specialized and become vulnerable to reprogramming by 
tumors.

Copyright © 2021. Published by Elsevier Inc.

DOI: 10.1016/j.cels.2021.09.012
PMID: 34653369 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of interests G.P.N. has equity in 
and is a scientific advisory board member of Akoya Biosciences, which provides 
the experimental technology used to collect the data utilized in this study. 
C.M.S. is a scientific advisor to Enable Medicine. The other authors declare no 
competing interests.


265. JCO Precis Oncol. 2022 Mar;6:e2100245. doi: 10.1200/PO.21.00245.

Landscape of KRAS(G12C), Associated Genomic Alterations, and Interrelation With 
Immuno-Oncology Biomarkers in KRAS-Mutated Cancers.

Salem ME(1), El-Refai SM(2), Sha W(1), Puccini A(3), Grothey A(4), George TJ(5), 
Hwang JJ(1), O'Neil B(2), Barrett AS(2), Kadakia KC(1), Musselwhite LW(1), 
Raghavan D(1), Van Cutsem E(6), Tabernero J(7), Tie J(8)(9).

Author information:
(1)Levine Cancer Institute, Atrium Health, Charlotte, NC.
(2)Tempus Labs Inc, Chicago, IL.
(3)University of Genoa, Ospedale Policlinico San Martino IRCCS, Genoa, Italy.
(4)West Cancer Center, Germantown, TN.
(5)University of Florida, Gainesville, FL.
(6)University Hospitals Gasthuisberg, Leuven & KULeuven, Leuven, Belgium.
(7)Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, 
UVic-UCC, Barcelona, Spain.
(8)Peter MacCallum Cancer Centre, Melbourne, Australia.
(9)Walter + Eliza Hall Institute of Medical Research, Melbourne, Australia.

PURPOSE: Promising single-agent activity from sotorasib and adagrasib in 
KRASG12C-mutant tumors has provided clinical evidence of effective KRAS 
signaling inhibition. However, comprehensive analysis of KRAS-variant 
prevalence, genomic alterations, and the relationship between KRAS and 
immuno-oncology biomarkers is lacking.
MATERIALS AND METHODS: Retrospective analysis of deidentified records from 
79,004 patients with various cancers who underwent next-generation sequencing 
was performed. Fisher's exact test evaluated the association between cancer 
subtypes and KRAS variants. Logistic regression assessed KRASG12C comutations 
with other oncogenes and the association between KRAS variants and 
immuno-oncology biomarkers.
RESULTS: Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, 
with 1,632 (11.9%) harboring KRASG12C and 12,126 (88.1%) harboring other KRAS 
variants (KRASnon-G12C). Compared with KRASnon-G12C across all tumor subtypes, 
KRASG12C was more prevalent in females (56% v 51%, false discovery rate-adjusted 
P value [FDR-P] = .0006), current or prior smokers (85% v 56%, FDR-P < .0001), 
and patients age > 60 years (73% v 63%, FDR-P ≤ .0001). The most frequent KRAS 
variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D 
(6.5%), and G12R (6.2%). KRASG12C was most prevalent in patients with 
non-small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of 
unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. 
Compared with KRASnon-G12C-mutated, KRASG12C-mutated tumors were significantly 
associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio 
[OR] = 2.38; FDR-P < .0001). KRASG12C-mutated tumors exhibited a distinct 
comutation profile from KRASnon-G12C-mutated tumors, including higher 
comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR-P < .01) and KEAP1 (15.38% 
v 4.61%, OR = 3.76; FDR-P < .01).
CONCLUSION: This study presents the first large-scale, pan-cancer genomic 
characterization of KRASG12C. The KRASG12C mutation was more prevalent in 
females and older patients and appeared to be associated with smoking status. 
KRASG12C tumors exhibited a distinct comutation profile and were associated with 
tumor mutational burden-high status.

DOI: 10.1200/PO.21.00245
PMCID: PMC8966967
PMID: 35319967 [Indexed for MEDLINE]

Conflict of interest statement: Mohamed E. SalemConsulting or Advisory Role: 
Taiho Pharmaceutical, Exelixis, Bristol Myers Squibb, Exelixis, QED 
Therapeutics, Novartis, PfizerSpeakers' Bureau: Taiho Pharmaceutical, Daiichi 
Sankyo/Astra Zeneca, BMS, Merck Sherif M. El-RefaiEmployment: TempusStock and 
Other Ownership Interests: Tempus Axel GrotheyHonoraria: Elsevier, Aptitude 
Health, IMEDEXConsulting or Advisory Role: Genentech/Roche, Bayer (Inst), 
Bristol Myers Squibb (Inst), Lilly (Inst), Boston Biomedical (Inst), Amgen 
(Inst), Array BioPharma (Inst), Daiichi Sankyo (Inst), OBI PharmaResearch 
Funding: Genentech/Roche (Inst), Bayer (Inst), Pfizer (Inst), Eisai (Inst), 
Lilly (Inst), Boston Biomedical (Inst), Daiichi Sankyo (Inst), Array BioPharma 
(Inst)Travel, Accommodations, Expenses: Genentech/Roche, Bayer Thomas J. 
GeorgeConsulting or Advisory Role: Tempus, PfizerResearch Funding: Bristol Myers 
Squibb (Inst), Merck (Inst), AstraZeneca/MedImmune (Inst), Lilly (Inst), Bayer 
(Inst), Incyte (Inst), Ipsen (Inst), Seattle Genetics (Inst), Genentech (Inst), 
Astellas Pharma (Inst), BioMed Valley Discoveries (Inst), GlaxoSmithKline 
(Inst),Open Payments Link: https://openpaymentsdata.cms.gov/physician/321938 
Jimmy J. HwangConsulting or Advisory Role: Bristol Myers Squibb, Boehringer 
Ingelheim, Caris Centers of Excellence, Pfizer, QED Therapeutics, Deciphera, 
IncyteSpeakers' Bureau: Bristol Myers Squibb, Deciphera, IncyteResearch Funding: 
Caris Centers of Excellence (Inst), Boehringer Ingelheim (Inst). Bert 
O'NeilEmployment: Lilly, TempusHonoraria: AstraZeneca Alexander S. 
BarrettEmployment: TempusStock and Other Ownership Interests: Tempus Derek 
RaghavanConsulting or Advisory Role: Gerson Lehrman Group, Caris Life Sciences 
(Inst). Eric Van CutsemConsulting or Advisory Role: Bayer, Lilly, Roche, 
SERVIER, Bristol Myers Squibb, Celgene, Merck Sharp & Dohme, Merck KGaA, 
Novartis, AstraZeneca, Halozyme, Array BioPharma, Biocartis, GlaxoSmithKline, 
Daiichi Sankyo, Pierre Fabre, Sirtex Medical, Taiho Pharmaceutical, Incyte, 
Astellas PharmaResearch Funding: amgen (Inst), Bayer (Inst), Boehringer 
Ingelheim (Inst), Lilly (Inst), Novartis (Inst), Roche (Inst), Celgene (Inst), 
Ipsen (Inst), Merck (Inst), Merck KGaA (Inst), SERVIER (Inst), Bristol Myers 
Squibb (Inst). Josep TaberneroConsulting or Advisory Role: Bayer, Boehringer 
Ingelheim, Lilly, MSD, Merck Serono, Novartis, Sanofi, Taiho Pharmaceutical, 
Peptomyc, Chugai Pharma, Pfizer, Seattle Genetics, Array BioPharma, AstraZeneca, 
Genentech, Menarini, Servier, HalioDx, F. Hoffmann LaRoche, Mirati Therapeutics, 
Pierre Fabre, Tessa Therapeutics, TheraMyc, Daiichi Sankyo, Samsung Bioepis, 
IQvia, Ikena Oncology, Merus, Neophore, Orion Biotechnology, Hutchison 
MediPharma, Avvinity, Scandion Oncology, Ona Therapeutics, Sotio Biotech, 
Inspirna IncOther Relationship: Imedex, Medscape, MJH Life Sciences, Peerview, 
Physicans' Education Resource Jeanne TieHonoraria: SERVIER, InivataConsulting or 
Advisory Role: AstraZeneca/MedImmune, Bristol Myers Squibb, Pierre Fabre, MSD 
Oncology, Inivata, Haystack OncologyNo other potential conflicts of interest 
were reported.


266. J Clin Oncol. 2022 Feb 25:JCO2102342. doi: 10.1200/JCO.21.02342. Online ahead of 
print.

Impact of the Oncology Care Model on Use of Supportive Care Medications During 
Cancer Treatment.

Brooks GA(1), Landrum MB(2), Kapadia NS(1), Liu PH(2), Wolf R(2), Riedel LE(2), 
Hsu VD(3), Jhatakia Parekh S(4), Simon C(4), Hassol A(5), Keating NL(2)(6).

Author information:
(1)Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of 
Medicine, Lebanon, NH.
(2)Department of Health Care Policy, Harvard Medical School, Boston, MA.
(3)General Dynamics Information Technology, Falls Church, VA.
(4)The Lewin Group, Falls Church, VA.
(5)Abt Associates, Cambridge, MA.
(6)Division of General Internal Medicine, Brigham and Women's Hospital, Boston, 
MA.

PURPOSE: The Oncology Care Model (OCM) is an episode-based alternative payment 
model for cancer care that seeks to reduce Medicare spending while maintaining 
care quality. We evaluated the impact of OCM on appropriate use of supportive 
care medications during cancer treatment.
METHODS: We evaluated chemotherapy episodes assigned to OCM (n = 201) and 
comparison practices (n = 534) using Medicare claims (2013-2019). We assessed 
denosumab use for beneficiaries with bone metastases from breast, lung, or 
prostate cancer; prophylactic WBC growth factor use for beneficiaries receiving 
chemotherapy for breast, lung, or colorectal cancer; and prophylactic use of 
neurokinin-1 (NK1) antagonists and long-acting serotonin antagonists for 
beneficiaries receiving chemotherapy for any cancer type. Analyses used a 
difference-in-difference approach.
RESULTS: After its launch in 2016, OCM led to a relative reduction in the use of 
denosumab for beneficiaries with bone metastases receiving bone-modifying 
medications (eg, 5.0 percentage point relative reduction in breast cancer 
episodes [90% CI, -7.1 to -2.8]). There was no OCM impact on use of prophylactic 
WBC growth factors during chemotherapy with high or low risk for febrile 
neutropenia. Among beneficiaries receiving chemotherapy with intermediate 
febrile neutropenia risk, OCM led to a 7.6 percentage point reduction in the use 
of prophylactic WBC growth factors during breast cancer episodes (90% CI, -12.6 
to -2.7); there was no OCM impact in lung or colorectal cancer episodes. Among 
beneficiaries receiving chemotherapy with high or moderate emetic risk, OCM led 
to reductions in the prophylactic use of NK1 antagonists and long-acting 
serotonin antagonists (eg, 6.0 percentage point reduction in the use of NK1 
antagonists during high emetic risk chemotherapy [90% CI, -9.0 to -3.1]).
CONCLUSION: OCM led to the reduced use of some high-cost supportive care 
medications, suggesting more value-conscious care.

DOI: 10.1200/JCO.21.02342
PMID: 35213212

Conflict of interest statement: Gabriel A. BrooksConsulting or Advisory Role: 
CareCentrix, UnitedHealthcare, IpsenResearch Funding: Boston Biomedical (Inst), 
Roche/Genentech (Inst)Open Payments Link: 
https://openpaymentsdata.cms.gov/physician/197685 Van Doren HsuStock and Other 
Ownership Interests: GlaxoSmithKline, Johnson & Johnson, Abbott Laboratories 
Shalini Jhatakia ParekhEmployment: United Health GroupStock and Other Ownership 
Interests: United Health Group Carol SimonEmployment: United Health GroupStock 
and Other Ownership Interests: United Health GroupPatents, Royalties, Other 
Intellectual Property: Patent pending on the software tool for identifying 
social determinants and local factors that predict health outcomesNo other 
potential conflicts of interest were reported.


267. PLoS One. 2010 Dec 31;5(12):e16012. doi: 10.1371/journal.pone.0016012.

Nonsense mediated decay resistant mutations are a source of expressed mutant 
proteins in colon cancer cell lines with microsatellite instability.

Williams DS(1), Bird MJ, Jorissen RN, Yu YL, Walker F, Zhang HH, Nice EC, 
Burgess AW.

Author information:
(1)Epithelial Biochemistry Laboratory, Ludwig Institute for Cancer Research, 
Melbourne Branch, Parkville, Victoria, Australia. David.Williams@austin.org.au

Erratum in
    PLoS One. 2011;6(1). doi: 
10.1371/annotation/53805ecf-7d10-4d99-9cec-f27f5e0d4166. Walker, Franscesa 
[corrected to Walker, Francesca].

BACKGROUND: Frameshift mutations in microsatellite instability high (MSI-High) 
colorectal cancers are a potential source of targetable neo-antigens. Many 
nonsense transcripts are subject to rapid degradation due to nonsense-mediated 
decay (NMD), but nonsense transcripts with a cMS in the last exon or near the 
last exon-exon junction have intrinsic resistance to nonsense-mediated decay 
(NMD). NMD-resistant transcripts are therefore a likely source of expressed 
mutant proteins in MSI-High tumours.
METHODS: Using antibodies to the conserved N-termini of predicted mutant 
proteins, we analysed MSI-High colorectal cancer cell lines for examples of 
naturally expressed mutant proteins arising from frameshift mutations in coding 
microsatellites (cMS) by immunoprecipitation and Western Blot experiments. 
Detected mutant protein bands from NMD-resistant transcripts were further 
validated by gene-specific short-interfering RNA (siRNA) knockdown. A 
genome-wide search was performed to identify cMS-containing genes likely to 
generate NMD-resistant transcripts that could encode for antigenic expressed 
mutant proteins in MSI-High colon cancers. These genes were screened for cMS 
mutations in the MSI-High colon cancer cell lines.
RESULTS: Mutant protein bands of expected molecular weight were detected in 
mutated MSI-High cell lines for NMD-resistant transcripts (CREBBP, EP300, TTK), 
but not NMD-sensitive transcripts (BAX, CASP5, MSH3). Expression of the mutant 
CREBBP and EP300 proteins was confirmed by siRNA knockdown. Five cMS-bearing 
genes identified from the genome-wide search and without existing mutation data 
(SFRS12IP1, MED8, ASXL1, FBXL3 and RGS12) were found to be mutated in at least 5 
of 11 (45%) of the MSI-High cell lines tested.
CONCLUSION: NMD-resistant transcripts can give rise to expressed mutant proteins 
in MSI-High colon cancer cells. If commonly expressed in primary MSI-High colon 
cancers, MSI-derived mutant proteins could be useful as cancer specific 
immunological targets in a vaccine targeting MSI-High colonic tumours.

DOI: 10.1371/journal.pone.0016012
PMCID: PMC3013145
PMID: 21209843 [Indexed for MEDLINE]

Conflict of interest statement: Competing Interests: The authors have declared 
that no competing interests exist.


268. J Clin Oncol. 2022 Apr 28:JCO2200032. doi: 10.1200/JCO.22.00032. Online ahead of 
print.

Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total 
Neoadjuvant Therapy.

Garcia-Aguilar J(1), Patil S(2), Gollub MJ(3), Kim JK(1), Yuval JB(1), Thompson 
HM(1), Verheij FS(1), Omer DM(1), Lee M(1), Dunne RF(4), Marcet J(5), Cataldo 
P(6), Polite B(7), Herzig DO(8), Liska D(9), Oommen S(10), Friel CM(11), Ternent 
C(12), Coveler AL(13), Hunt S(14), Gregory A(15), Varma MG(16), Bello BL(17), 
Carmichael JC(18), Krauss J(19), Gleisner A(20), Paty PB(1), Weiser MR(1), Nash 
GM(1), Pappou E(1), Guillem JG(21), Temple L(22), Wei IH(1), Widmar M(1), Lin 
S(2), Segal NH(23), Cercek A(23), Yaeger R(23), Smith JJ(1), Goodman KA(24), Wu 
AJ(25), Saltz LB(23).

Author information:
(1)Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer 
Center, New York, NY.
(2)Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer 
Center, New York, NY.
(3)Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, 
NY.
(4)Department of Medicine, Wilmot Cancer Institute, University of Rochester 
Medical Center, Rochester, NY.
(5)Division of Colon and Rectal Surgery, Department of Surgery, University of 
South Florida, Tampa, FL.
(6)Division of General Surgery, Department of Surgery, University of Vermont, 
Burlington, VT.
(7)Department of Medicine, Comprehensive Cancer Center, University of Chicago, 
Chicago, IL.
(8)Division of Gastrointestinal and General Surgery, Oregon Health and Science 
University, Portland, OR.
(9)Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH.
(10)Division of Gastrointestinal Oncology, John Muir Cancer Institute, John Muir 
Health, Walnut Creek, CA.
(11)Division of General Surgery, Department of Surgery, University of Virginia, 
Charlottesville, VA.
(12)Department of Surgery, Colorectal Service at Bergan Mercy Medical Center, 
Omaha, NE.
(13)Department of Medicine, Fred Hutch Cancer Center, University of Washington, 
Seattle, WA.
(14)Department of Surgery, Washington University School of Medicine, St Louis, 
MO.
(15)Department of Surgery, St Joseph Hospital Orange County, Orange, CA.
(16)Section of Colon and Rectal Surgery, Department of Surgery, University of 
California, San Francisco, San Francisco, CA.
(17)Division of Colorectal Surgery, Department of Surgery, Medstar Washington 
Hospital Center, Washington, DC.
(18)Division of Colon and Rectal Surgery, Department of Surgery, University of 
California, Irvine, Irvine, CA.
(19)Department of Medicine, Rogel Cancer Center at the University of Michigan, 
Ann Arbor, MI.
(20)Division of Surgical Oncology, Department of Surgery, University of 
Colorado, Denver, CO.
(21)Division of Gastrointestinal Surgery, Department of Surgery, University of 
North Carolina, Chapel Hill, NC.
(22)Division of Colorectal Surgery, Department of Surgery, University of 
Rochester Medical Center, Rochester, NY.
(23)Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, 
NY.
(24)Department of Radiation Oncology, Tisch Cancer Institute, Icahn School of 
Medicine at Mount Sinai, New York, NY.
(25)Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 
New York, NY.

PURPOSE: Prospective data on the efficacy of a watch-and-wait strategy to 
achieve organ preservation in patients with locally advanced rectal cancer 
treated with total neoadjuvant therapy are limited.
METHODS: In this prospective, randomized phase II trial, we assessed the 
outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with 
induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or 
chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either 
total mesorectal excision (TME) or watch-and-wait on the basis of tumor 
response. Patients in both groups received 4 months of infusional 
fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 
5,600 cGy of radiation combined with either continuous infusion fluorouracil or 
capecitabine during radiotherapy. The trial was designed as two stand-alone 
studies with disease-free survival (DFS) as the primary end point for both 
groups, with a comparison to a null hypothesis on the basis of historical data. 
The secondary end point was TME-free survival.
RESULTS: Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) 
for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in 
line with the 3-year DFS rate (75%) observed historically. Three-year TME-free 
survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 
62) in the CRT-CNCT group. No differences were found between groups in local 
recurrence-free survival, distant metastasis-free survival, or overall survival. 
Patients who underwent TME after restaging and patients who underwent TME after 
regrowth had similar DFS rates.
CONCLUSION: Organ preservation is achievable in half of the patients with rectal 
cancer treated with total neoadjuvant therapy, without an apparent detriment in 
survival, compared with historical controls treated with chemoradiotherapy, TME, 
and postoperative chemotherapy.

DOI: 10.1200/JCO.22.00032
PMID: 35483010

Conflict of interest statement: Julio Garcia-AguilarStock and Other Ownership 
Interests: Intuitive SurgicalConsulting or Advisory Role: Medtronic, Intuitive 
Surgical, Johnson & Johnson Sujata PatilConsulting or Advisory Role: ByHeart 
Marc J. GollubStock and Other Ownership Interests: Pfizer Meghan LeeEmployment: 
ICON Clinical Research Richard F. DunneConsulting or Advisory Role: Exelixis, 
Helsinn Therapeutics Jorge MarcetConsulting or Advisory Role: Baxter, Stryker, 
Medtronic Blase PoliteHonoraria: Physicans' Education Resource, Simon-Kucher and 
Partners, American Journal of Managed Care, HMP, GenzymeConsulting or Advisory 
Role: Cancer Expert NowSpeakers' Bureau: NateraTravel, Accommodations, Expenses: 
Tapestry Pharmaceuticals, Institute for Clinical and Economic ReviewOpen 
Payments Link: https://openpaymentsdata.cms.gov/physician/1196539 David 
LiskaConsulting or Advisory Role: Olympus Medical Systems Charles 
TernentHonoraria: Intuitive SurgicalConsulting or Advisory Role: Virtual 
Incisions IncTravel, Accommodations, Expenses: Intuitive Surgical Andrew L. 
CovelerConsulting or Advisory Role: Halozyme, Seattle Genetics, Merrimack, 
AbbVieResearch Funding: XBiotech (Inst), Newlink Genetics (Inst), Taiho 
Pharmaceutical (Inst), Immunomedics (Inst), Onconova Therapeutics (Inst), Lilly 
(Inst), Gilead Sciences (Inst), Genentech (Inst), Seattle Genetics (Inst), 
AbGenomics International (Inst), Halozyme (Inst), Novocure (Inst), MedImmune 
(Inst), Amgen (Inst), Actuate Therapeutics (Inst), Surface Oncology 
(Inst)Travel, Accommodations, Expenses: Halozyme, AbbVie Joseph C. 
CarmichaelConsulting or Advisory Role: Johnson & JohnsonSpeakers' Bureau: 
Johnson & Johnson John KraussResearch Funding: Ignyta (Inst), Boston Biomedical 
(Inst), Boehringer Ingelheim (Inst), AbbVie (Inst), ACCRU (Inst), NSABP 
Foundation (Inst), Amgen (Inst), Isofol Medical (Inst), NSABP Foundation (Inst), 
Novartis (Inst), Hutchison MediPharma (Inst), Cardiff Oncology, 
AstraZeneca/MedImmune (Inst), Tempest Therapeutics (Inst), Tempest Therapeutics 
(Inst), Pfizer (Inst), Alliance for Clinical Trials in Oncology (Inst), Daiichi 
Sankyo/Arqule (Inst), Bristol Myers Squibb/Medarex (Inst) Martin R. 
WeiserConsulting or Advisory Role: PreciscaResearch Funding: Clinical 
GenomicsPatents, Royalties, Other Intellectual Property: UpToDate Section Editor 
Garrett M. NashOpen Payments Link: 
https://openpaymentsdata.cms.gov/physician/851428 Emmanouil PappouTravel, 
Accommodations, Expenses: Intuitive Surgical José G. GuillemEmployment: 
Intuitive SurgicalHonoraria: Intuitive Surgical, Myriad GeneticsSpeakers' 
Bureau: Intuitive Surgical Maria WidmarEmployment: BridgeBio (I)Stock and Other 
Ownership Interests: BridgeBio Neil H. SegalConsulting or Advisory Role: 
Roche/Genentech, GlaxoSmithKline, ABL Bio, Boehringer Ingelheim, Novartis, 
Revitope, AstraZenecaResearch Funding: Bristol Myers Squibb, Pfizer, 
Roche/Genentech, Merck, Immunocore, AstraZeneca, Regeneron (Inst), PureTech 
(Inst) Andrea CercekConsulting or Advisory Role: Bayer, GlaxoSmithKline, Incyte, 
Merck, Janssen, Seattle GeneticsResearch Funding: Seattle Genetics, Rgenix 
(Inst), GlaxoSmithKline Rona YaegerConsulting or Advisory Role: Array BioPharma, 
Natera, Mirati TherapeuticsResearch Funding: Array BioPharma (Inst), Boehringer 
Ingelheim (Inst), Pfizer (Inst), Mirati Therapeutics (Inst) J. Joshua 
SmithConsulting or Advisory Role: Guardant Health Karyn A. GoodmanConsulting or 
Advisory Role: RenovoRx, Roche/Genentech, Novartis, Philips Healthcare Abraham 
J. WuStock and Other Ownership Interests: SimphotekConsulting or Advisory Role: 
AstraZeneca, MORE Health, NanoViResearch Funding: CivaTech OncologyTravel, 
Accommodations, Expenses: CivaTech OncologyOpen Payments Link: 
https://openpaymentsdata.cms.gov/physician/368691 Leonard B. SaltzConsulting or 
Advisory Role: GenorResearch Funding: Taiho PharmaceuticalNo other potential 
conflicts of interest were reported.


269. BMC Bioinformatics. 2022 Jan 18;23(1):46. doi: 10.1186/s12859-022-04570-9.

CellSeg: a robust, pre-trained nucleus segmentation and pixel quantification 
software for highly multiplexed fluorescence images.

Lee MY(#)(1)(2)(3), Bedia JS(#)(4), Bhate SS(1)(2)(5), Barlow GL(1)(2), Phillips 
D(1)(2)(6), Fantl WJ(4)(7)(8), Nolan GP(2)(7), Schürch CM(9)(10)(11).

Author information:
(1)Department of Microbiology and Immunology, Stanford University School of 
Medicine, Stanford, CA, 94305, USA.
(2)Department of Pathology, Stanford University School of Medicine, Stanford, 
CA, 94305, USA.
(3)Department of Computer Science, Stanford, CA, 94305, USA.
(4)Department of Urology, Stanford University School of Medicine, Stanford, CA, 
94305, USA.
(5)Department of Bioengineering, Stanford University School of Medicine, 
Stanford, CA, 94305, USA.
(6)Department of Dermatology, Stanford University School of Medicine, Stanford, 
CA, 94305, USA.
(7)Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
CA, 94305, USA.
(8)Department of Obstetrics and Gynecology, Stanford University School of 
Medicine, Stanford, CA, 94305, USA.
(9)Department of Microbiology and Immunology, Stanford University School of 
Medicine, Stanford, CA, 94305, USA. christian.schuerch@med.uni-tuebingen.de.
(10)Department of Pathology, Stanford University School of Medicine, Stanford, 
CA, 94305, USA. christian.schuerch@med.uni-tuebingen.de.
(11)Department of Pathology and Neuropathology, University Hospital and 
Comprehensive Cancer Center Tübingen, Tübingen, Germany. 
christian.schuerch@med.uni-tuebingen.de.
(#)Contributed equally

BACKGROUND: Algorithmic cellular segmentation is an essential step for the 
quantitative analysis of highly multiplexed tissue images. Current segmentation 
pipelines often require manual dataset annotation and additional training, 
significant parameter tuning, or a sophisticated understanding of programming to 
adapt the software to the researcher's need. Here, we present CellSeg, an 
open-source, pre-trained nucleus segmentation and signal quantification software 
based on the Mask region-convolutional neural network (R-CNN) architecture. 
CellSeg is accessible to users with a wide range of programming skills.
RESULTS: CellSeg performs at the level of top segmentation algorithms in the 
2018 Kaggle Data Challenge both qualitatively and quantitatively and generalizes 
well to a diverse set of multiplexed imaged cancer tissues compared to 
established state-of-the-art segmentation algorithms. Automated segmentation 
post-processing steps in the CellSeg pipeline improve the resolution of immune 
cell populations for downstream single-cell analysis. Finally, an application of 
CellSeg to a highly multiplexed colorectal cancer dataset acquired on the 
CO-Detection by indEXing (CODEX) platform demonstrates that CellSeg can be 
integrated into a multiplexed tissue imaging pipeline and lead to accurate 
identification of validated cell populations.
CONCLUSION: CellSeg is a robust cell segmentation software for analyzing highly 
multiplexed tissue images, accessible to biology researchers of any programming 
skill level.

© 2022. The Author(s).

DOI: 10.1186/s12859-022-04570-9
PMCID: PMC8767664
PMID: 35042474 [Indexed for MEDLINE]

Conflict of interest statement: M.Y.L. is a co-founder of and has equity in 
Biodock, Inc. G.P.N. is a co-founder and stockholder of Akoya Biosciences, Inc., 
and inventor on patent US9909167. C.M.S. is a scientific advisor to, has stock 
options in, and has received research funding from Enable Medicine, Inc. The 
other authors declare that no competing financial interests exist.


270. Med Dosim. 2014 Autumn;39(3):272-5. doi: 10.1016/j.meddos.2014.05.001. Epub 2014 
Jun 7.

Dosimetric comparison of IMRT rectal and anal canal plans generated using an 
anterior dose avoidance structure.

Leicher B(1), Day E(2), Colonias A(3), Gayou O(3).

Author information:
(1)Department of Radiation Oncology, Allegheny General Hospital, Pittsburgh, PA. 
Electronic address: bleicher@wpahs.org.
(2)Department of Radiation Oncology, Allegheny General Hospital, Pittsburgh, PA.
(3)Department of Radiation Oncology, Allegheny General Hospital, Pittsburgh, PA; 
Drexel University College of Medicine, Allegheny Campus, Philadelphia, PA.

To describe a dosimetric method using an anterior dose avoidance structure 
(ADAS) during the treatment planning process for intensity-modulated radiation 
therapy (IMRT) for patients with anal canal and rectal carcinomas. A total of 20 
patients were planned on the Elekta/CMS XiO treatment planning system, version 
4.5.1 (Maryland Heights MO) with a superposition algorithm. For each patient, 2 
plans were created: one employing an ADAS (ADAS plan) and the other replanned 
without an ADAS (non-ADAS plan). The ADAS was defined to occupy the volume 
between the inguinal nodes and primary target providing a single organ at risk 
that is completely outside of the target volume. Each plan used the same beam 
parameters and was analyzed by comparing target coverage, overall plan dose 
conformity using a conformity number (CN) equation, bowel dose-volume 
histograms, and the number of segments, daily treatment duration, and global 
maximum dose. The ADAS and non-ADAS plans were equivalent in target coverage, 
mean global maximum dose, and sparing of small bowel in low-dose regions (5, 10, 
15, and 20 Gy). The mean difference between the CN value for the non-ADAS plans 
and ADAS plans was 0.04 ± 0.03 (p < 0.001). The mean difference in the number of 
segments was 15.7 ± 12.7 (p < 0.001) in favor of ADAS plans. The ADAS plan 
delivery time was shorter by 2.0 ± 1.5 minutes (p < 0.001) than the non-ADAS 
one. The ADAS has proven to be a powerful tool when planning rectal and anal 
canal IMRT cases with critical structures partially contained inside the target 
volume.

Copyright © 2014 American Association of Medical Dosimetrists. Published by 
Elsevier Inc. All rights reserved.

DOI: 10.1016/j.meddos.2014.05.001
PMID: 24913467 [Indexed for MEDLINE]


271. J Biophotonics. 2014 Nov;7(11-12):938-47. doi: 10.1002/jbio.201300141. Epub 2014 
Jan 24.

Evaluation of ultrasound and glucose synergy effect on the optical clearing and 
light penetration for human colon tissue using SD-OCT.

Zhao Q(1), Wei H, He Y, Ren Q, Zhou C.

Author information:
(1)School of Biomedical Engineering, Shanghai Jiao Tong University, No. 800 
Dongchuan Road, Shanghai 200240, China.

Topical application optical clearing agents (OCAs) can effectively enhance the 
tissue optical clearing on the human colon tissue, which has been demonstrated 
in our previous studies. Nevertheless, the strong light scattering still limits 
the diffusion rate of OCAs and penetration depth of light into the tissue. In 
this study, in order to further increase the diffusion of the OCA of glucose 
into tissue, we employ a method to improve the glucose permeability and light 
penetration with ultrasound (sonophoretic delivery, SP) and glucose (G) synergy 
on human normal and cancerous colon tissues in vitro, which was measured and 
quantified with spectral-domain optical coherence tomography (SD-OCT) 
technology. To evaluate the effect of ultrasound mediation, the percentages of 
OCT signal enhancement (PSE) and 1/e light-penetration depth were calculated for 
G alone and ultrasound-G treatments. The PSE was calculated at approximately 313 
μm from the sample tissue surface. For normal and cancerous colon tissues the 
PSE were about 91.1 ± 10.6% and 65.3% ± 12.3% with 30% G/SP, but for the 30% G 
alone treatment it was about 78.6 ± 11.2% and 54.5% ± 9.3%, respectively. The 
max value of 1/e light-penetration depth for normal colon tissue was 0.47 ± 0.02 
mm with 30% G alone and 0.60 ± 0.05 mm (p < 0.05)with 30% G/SP synergy. However, 
for the cancerous colon tissue the max value was 0.45 ± 0.01 mm and 0.57 ± 0.03 
mm (p < 0.05), respectively. The obtained permeability coefficients showed a 
significant enhancement with ultrasound mediation. The mean permeability 
coefficients of 30% G/SP in normal and cancerous colon tissues were (6.3 ± 0.16) 
× 10(-6) cm/s and (12.1 ± 0.34) × 10(-6) cm/s (p < 0.05), respectively. These 
preliminary experiments showed that ultrasound can effectively enhance the 
tissue optical clearing and glucose diffusion rate as well as increase the 
light-penetration depth into biotissues.

Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI: 10.1002/jbio.201300141
PMID: 24458608 [Indexed for MEDLINE]


272. In Vivo. 2008 Nov-Dec;22(6):699-705.

Effects of neonatal administration of diethylstilbestrol on aberrant crypt foci 
induced by 7,12-dimethylbenz[alpha] anthracene in rats.

Kawashima H(1), Kawaguchi H, Umekita Y, Souda M, Gejima K, Komokata T, Sakata R, 
Yoshida H.

Author information:
(1)Department of Tumor Pathology, Field of Oncology, Kagoshima University 
Graduate School of Medical and Dental Sciences, Kagoshima, Japan. 
kawa@m3.kufm.kagoshima-u.ac.jp

Gastrointestinal carcinoma is affected environmental factors, however, it 
remains to be determined whether neonatal administration of an estrogenic 
endocrine disruptor, such as diethylstilbestrol (DES), affects gastrointestinal 
carcinogenesis. The effects of neonatally administered DES on gastrointestinal 
tumorigenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) were investigated 
in male and female rats. Male and female rats in group I were daily administered 
oil alone from 0-14 days after birth. Male and female rats in groups II and III 
were daily administered DES at 1 and 10 microg/rat, respectively. The 
administration periods of DES in subgroups a (IIa and IIIa), b (IIb and IIIb) 
and c (IIc and IIIc) were from 0-14, 0-5 and 6-14 days after birth, 
respectively. At 28, 42 and 56 days after birth, all male rats were given 10 mg 
of DMBA. At 50 days after birth, all female rats were given 10 mg of DMBA. In 
the digestive tracts of male rats, forestomach masses (FMs) in all groups 
(13-58%), small intestine masses in group IIIa (17%), and colon masses (CMs) in 
groups IIIa (8%) and IIIb (33%) were observed, although there were no 
significant changes in the incidence and number. In the digestive tracts of 
female rats, FMs in groups I (10%), IIa (13%), IIb (33%), IIc (25%) and IIIc 
(33%), CMs in groups IIa (6%) and IIIa (6%) were seen, although there were no 
significant changes in the incidence. Aberrant crypt foci (ACF) in the colon and 
rectum were seen in all male and female rats. The neonatal administration of DES 
in male rats increased the number of ACF while that in female rats did not. 
These results suggest that neonatal administration of DES may affect male 
colorectal carcinogenesis.

PMID: 19180994 [Indexed for MEDLINE]


273. Cancer Imaging. 2009 Oct 2;9 Spec No A(Special issue A):S59-62. doi: 
10.1102/1470-7330.2009.9025.

CT colonography screening: ready for prime time?

Heiken JP(1).

Author information:
(1)Department of Radiology, Mallinckrodt Institute of Radiology, Washington 
University School of Medicine, 510 South Kingshighway Boulevard, St Louis, MO 
63110, USA. heikenj@mir.wustl.edu

Every year more than one million new patients are diagnosed with colon cancer 
worldwide. Although multiple prospective randomized trials and observational 
studies have demonstrated that mortality from colon cancer can be reduced with 
screening and removal of adenomatous polyps, compliance with screening 
guidelines remains low. Recent CT colonography (CTC) trials have shown that CTC 
is capable of demonstrating adenomatous polyps > or =10 mm (and in most cases > 
or = 6 mm) with sensitivities comparable to those for optical colonoscopy. Based 
on these results, at least two expert panels have recommended CTC as an option 
for colorectal cancer screening. Despite these endorsements, the Centers for 
Medicare and Medicaid Services (CMS) in the United States recently decided to 
deny coverage of CTC for colorectal cancer screening. This article addresses the 
reservations raised by CMS and provides a perspective on whether CTC is ready 
for routine use as a colorectal cancer screening test.

DOI: 10.1102/1470-7330.2009.9025
PMCID: PMC2797457
PMID: 19965295 [Indexed for MEDLINE]


274. Tech Coloproctol. 2012 Oct;16(5):385-8. doi: 10.1007/s10151-012-0830-9. Epub 
2012 Apr 12.

Avoiding extraction site herniation after laparoscopic right colectomy.

Williams GL(1), Beaton C, Codd R, Stephenson BM.

Author information:
(1)Department of General and Colorectal Surgery, Royal Gwent Hospital, Cardiff 
Road, Newport, South Wales, NP20 2UB, UK. gethin.williams@gwent.wales.nhs.uk

Transverse abdominal wall incisions are favoured as part of enhanced recovery 
programmes. We explored the use of rectus-preserving extraction site incisions 
in laparoscopic right colectomy. The approach involved minimal anterior 
abdominal wall disruption with preservation of the rectus abdominis muscle: the 
rectus abdominis muscle extraction site (RAMES). In 15 patients, a RAMES was 
used electively in right colectomy for malignancy. The median wound length was 
6 cms. There was no clinical or radiological evidence of incisional herniation 
in the 15 patients at 12-month and in the 12 survivors at 24-month follow-up. An 
anatomical dissection at specimen extraction site reduces early incisional 
herniation rates and should be of benefit in the longer term.

DOI: 10.1007/s10151-012-0830-9
PMID: 22527925 [Indexed for MEDLINE]


275. Eur J Drug Metab Pharmacokinet. 2016 Feb;41(1):33-43. doi: 
10.1007/s13318-014-0234-5. Epub 2014 Oct 29.

Evaluation of physicochemical properties and intestinal permeability of six 
dietary polyphenols in human intestinal colon adenocarcinoma Caco-2 cells.

Rastogi H(1), Jana S(2).

Author information:
(1)Suresh Gyan Vihar University, Mahal, Jagatpura, Jaipur, 302025, India.
(2)Laila Nutraceuticals Research and Development Centre, Kanuru, Vijayawada, 
520007, India. jana.snehasis@rediffmail.com.

Phenolic compounds are common ingredients in many dietary supplements and 
functional foods. However, data concerning physicochemical properties and 
permeability of polyphenols on the intestinal epithelial cells are scarce. The 
aims of this study were to determine the experimental partition coefficient (Log 
P), and parallel artificial membrane permeability assay (PAMPA), to characterize 
the bi-directional transport of six phenolic compounds viz. caffeic acid, 
chrysin, gallic acid, quercetin, resveratrol and rutin in Caco-2 cells. The 
experimental Log P values of six polyphenols were correlated (R (2) = 0.92) well 
with the calculated Log P values. The apparent permeability (P app) range of all 
polyphenols in PAMPA for the apical (AP) to basolateral (BL) was 1.18 ± 0.05 × 
10(-6) to 5.90 ± 0.16 × 10(-6) cm/s. The apparent Caco-2 permeability (P app) 
range for the AP-BL was 0.96 ± 0.03 × 10(-6) to 3.80 ± 0.45 × 10(-6) cm/s. The 
efflux ratio of P app (BL → AP) to P app (AP → BL) for all phenolics was <2, 
suggesting greater permeability in the absorptive direction. Six compounds 
exhibited strong correlations between Log P and PAMPA/Caco-2 cell monolayer 
permeation data. Dietary six polyphenols were poorly absorbed through PAMPA and 
Caco-2 cells, and their transepithelial transports were mainly by passive 
diffusion.

DOI: 10.1007/s13318-014-0234-5
PMID: 25351179 [Indexed for MEDLINE]


276. Tumour Biol. 1998;19(5):374-83. doi: 10.1159/000030030.

Microsensor-aided measurements of cellular signalling and metabolism on tumor 
cells. The cell monitoring system (cms(R)).

Wolf B(1), Brischwein M, Baumann W, Ehret R, Henning T, Lehmann M, Schwinde A.

Author information:
(1)AG Medical Physics and Electron Microscopy, Institute of Immunobiology, 
University of Freiburg, Germany. bwolf@ruf.uni-freiburg.de

Microsensors provide instruments particularly suited for the rapid, noninvasive 
and on-line analysis of cell and tissue cultures. The microsensor system 
presented in this paper is a modular arrangement of various planar and nonplanar 
sensor elements for the measurement of physiological parameters of cell 
cultures. An optic access to the cultures (e.g. for light microscopy and 
spectrophotometric techniques) is also provided for a parallel and comparative 
data acquisition. The system was originally designed for biomedical research in 
chemotherapy (predicative chemotherapy assays) and pharmacology but it turned 
out to be also an effective tool for toxicological and environmental research.

DOI: 10.1159/000030030
PMID: 9701728 [Indexed for MEDLINE]


277. Mol Pharm. 2008 Sep-Oct;5(5):863-75. doi: 10.1021/mp800050q. Epub 2008 Jul 24.

Effects of monoglycerides on P-glycoprotein: modulation of the activity and 
expression in Caco-2 cell monolayers.

Barta CA(1), Sachs-Barrable K, Feng F, Wasan KM.

Author information:
(1)Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical 
Sciences, The University of British Columbia, Vancouver, British Columbia, 
Canada. cbarta@chem.ubc.ca

Comment in
    AAPS J. 2016 Jul;18(4):830-43.

The purpose of this study was to analyze the effects of two common monoglyceride 
components of lipid excipients, 1-monoolein and 1-monostearin, on the activity 
and expression of P-glycoprotein (P-gp) in Caco-2 cells. Non-cytotoxic 
concentrations of 1-monoolein and 1-monostearin were determined by assessing 
membrane permeability and mitochondrial activity in Caco-2 cells, a human colon 
adenocarcinoma cell line. Concentrations of 500 and 100 microM were used to 
evaluate P-gp activity through Rh123 accumulation and bifunctional transport 
studies. The P-gp protein expression levels were quantified through the use of 
immunoblots. The changes in cell membrane fluidity and nuclear membrane 
integrity upon the addition of monoglycerides were analyzed by fluorescence 
anisotropy using DPH and TMA-DPH as the fluorescent labels and by using 
increasing salt concentrations to release the nuclear contents, respectively. 
The absorptive flux (apical to basolateral) in the bifunctional transport 
studies was not found to be statistically significant for the non-cytotoxic 
concentrations of 1-monoolein and 1-monostearin. However, treatments of 500 and 
100 microM of 1-monoolein or 1-monostearin displayed statistically lowered 
efflux (basolaterial to apical, P < 0.05) compared to the controls (7.9 +/- 0.8, 
12.9 +/- 2.6 x 10 (6) cm/s for 1-monoolein or 11.1 +/- 2.0, 11.4 +/- 2.3 x 10 
(6) cm/s for 1-monostearin, respectively, compared to the untreated control, 
21.1 +/- 2.9 x 10 (6) cm/s, n = 5). Rh123 accumulation was also found to be 
enhanced upon 24 h incubation with both concentrations of the monoglycerides; 
however, only concentrations of 500 muM of the monoglycerides were shown to 
significantly reduce the P-gp protein expression. The results from this study 
suggest that these two monoglycerides, common components in various lipid 
excipients, are inhibitors of P-gp.

DOI: 10.1021/mp800050q
PMID: 18651749 [Indexed for MEDLINE]


278. AAPS PharmSciTech. 2017 Apr;18(3):867-874. doi: 10.1208/s12249-016-0578-z. Epub 
2016 Jun 30.

Evaluating the Potential for Delivery of Irinotecan via the Buccal Route: 
Physicochemical Characterization and In Vitro Permeation Assessment Across 
Porcine Buccal Mucosa.

Shah V(1)(2)(3), Bellantone RA(4), Taft DR(4).

Author information:
(1)Division of Pharmaceutical Sciences, Long Island University, Brooklyn, New 
York, 11201, USA. shahv@oregonstate.edu.
(2)Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State 
University/OHSU, Portland, Oregon, 97201, USA. shahv@oregonstate.edu.
(3)College of Pharmacy, Oregon State University/OHSU, Collaborative Life Science 
Building, 2730 SW Moody Ave, Portland, Oregon, 97201, USA. 
shahv@oregonstate.edu.
(4)Division of Pharmaceutical Sciences, Long Island University, Brooklyn, New 
York, 11201, USA.

Irinotecan (CPT-11) is used to treat advanced colorectal cancer as an 
intravenous therapy. Depending on pH, CPT-11 exists in either a lactone (active) 
or carboxylate (inactive) form, or both. In this investigation, the feasibility 
for systemic delivery of CPT-11 through the buccal route was evaluated. 
Permeation of CPT-11 across porcine buccal mucosa was studied in vitro using 
side-by-side flow through diffusion cells at 37°C. Experiments were performed 
over a pH range from 4 to 9, and the permeability of both the lactone and 
carboxylate forms of CPT-11 was measured. CPT-11 steady state flux was 
determined over a range of donor concentrations at pH 4 (0.5, 1, 5, 10, 15, 
20 mg/ml) and pH 6.8 (0.5, 5, 10 mg/ml). Steady state flux increased linearly 
with increasing donor concentration of CPT-11 at pH 4 (r 2 = 0.9935) and at 
pH 6.8 (r 2 = 0.9886). CPT-11 permeability was independent of pH, although the 
distribution coefficient increased with increasing pH. Estimates of permeability 
for the lactone and carboxylate forms were 4.16 × 10-5 cm/s and 2.6 × 10-5 cm/s, 
respectively. These calculated permeability values were in agreement with the in 
vitro experimental data. Overall, CPT-11 was found to permeate through porcine 
buccal mucosa via passive diffusion. CPT-11 permeability was independent of pH, 
suggesting that the compound was transported mainly via a paracellular route. 
Overall, the results of this research suggest that the buccal route is a 
potential extravascular mode of delivery for CPT-11.

DOI: 10.1208/s12249-016-0578-z
PMID: 27363416 [Indexed for MEDLINE]


279. Cancer Res. 1994 Jul 1;54(13):3352-6.

Microvascular permeability and interstitial penetration of sterically stabilized 
(stealth) liposomes in a human tumor xenograft.

Yuan F(1), Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jain RK.

Author information:
(1)Department of Radiation Oncology, Massachusetts General Hospital and Harvard 
Medical School, Boston 02114.

Microvascular permeability and interstitial penetration of sterically stabilized 
liposomes in both normal s.c. tissue and human colon adenocarcinoma LS174T 
xenograft were quantified by using the dorsal skin-fold chamber implanted in 
severe combined immunodeficient mice and intravital fluorescence microscopy. 
Significant extravascular accumulation was the dominant feature of liposome 
distribution in tumors, whereas only minimal intramural accumulation in 
postcapillary and collecting venules was observed in normal s.c. tissue. The 
extravasated liposomes in tumors distributed heterogeneously and formed 
perivascular clusters that did not move significantly and could be observed for 
up to 1 week. The effective permeability of tumor vessels to liposomes (2.0 +/- 
1.6 x 10(-8) cm/s; n = 23) was six times smaller than that to bovine serum 
albumin (1.2 +/- 0.5 x 10(-7) cm/s; n = 6). These results provide new insights 
into the mechanisms of transendothelial pathways of liposomes and improvements 
in liposome-mediated drug delivery.

PMID: 8012948 [Indexed for MEDLINE]


280. J BUON. 2010 Apr-Jun;15(2):378-81.

Ultrasonographic examination of the liver circulation in patients with liver 
metastasis from colorectal cancer.

Bogdanov M(1), Perisic M, Jurisic V, Stojacic-Djenic S, Kerkez MM.

Author information:
(1)School of Medicine, University of Kragujevac, Department of Pathophysiology, 
Kragujevac, Serbia.

PURPOSE: Conventional imaging modalities are presently recommended for the 
detection of liver metastases. However, the presence of liver micrometastases is 
a major diagnostic problem. It has been known that micrometastases could be 
associated with changes in the liver blood flow.
METHODS: We examined several parameters by color Doppler ultrasound to estimate 
hepatic artery flow in 30 patients without and 17 patients with liver metastases 
from colon cancer.
RESULTS: Mean values of hepatic artery diameter (4.25 + or - 0.81 mm in patients 
with liver metastases were not statistically different from those in patients 
without metastases (3.98 + or - 0.81). Patients with liver metastasis had 
significantly higher (p=0.007) mean values of systolic speed (61.33 + or - 30.01 
cm/s) in comparison to patients without metastasis (41.38 + or - 16 cm/s).
CONCLUSION: Based on these results we suggest that color Doppler examination can 
be an additional quick noninvasive method in the detection of circulatory 
changes in the estimation of liver metastases.

PMID: 20658739 [Indexed for MEDLINE]


281. J Biomed Opt. 2012 Oct;17(10):105004. doi: 10.1117/1.JBO.17.10.105004.

Ex vivo determination of glucose permeability and optical attenuation 
coefficient in normal and adenomatous human colon tissues using spectral domain 
optical coherence tomography.

Zhao Q(1), Zhou C, Wei H, He Y, Chai X, Ren Q.

Author information:
(1)School of Biomedical Engineering, Shanghai Jiao Tong University, No. 800 
Dongchuan Road, Shanghai 200240, China.

Recent reports have suggested that spectral domain optical coherence tomography 
(SD-OCT) is a useful tool for quantifying the permeability of hyperosmotic 
agents in various tissues. We report our preliminary results on quantification 
of glucose diffusion and assessment of the optical attenuation change due to the 
diffusion of glucose in normal and adenomatous human colon tissues in vitro by 
using a SD-OCT and then calculated the permeability coefficients (PC) and 
optical attenuation coefficients (AC). The PC of a 30% aqueous solution of 
glucose was 3.37±0.23×10⁻⁶ cm/s in normal tissue and 5.65±0.16×10⁻⁶ cm/s in 
cancerous colon tissue. Optical AC in a normal colon ranged from 3.48±0.37 to 
2.68±0.82  mm⁻¹ and was significantly lower than those seen in the cancerous 
tissue (8.48±0.95 to 3.16±0.69  mm⁻¹, p<0.05). The results suggest that 
quantitative measurements of using PC and AC from OCT images could be a 
potentially powerful method for colon cancer detection.

DOI: 10.1117/1.JBO.17.10.105004
PMID: 23223998 [Indexed for MEDLINE]


282. Orv Hetil. 1991 Feb 24;132(8):403-8.

[Sphincter-saving procedure of abdomino-peritoneal amputation? Surgical 
management of cancer of the lower two third of the rectum].

[Article in Hungarian]

Csiky M(1), Gál S, Fekete G, Noskó K.

Author information:
(1)Nógrád Megyei Madzsar József Kórház-Rendelöintézet, Salgótarján.

The authors report their results in surgical treatments of carcinoma localized 
in the low two thirds of the rectum done between 1980 and 1988. The number of 
patients was 150. Resectability: 119/150 = 79.33 per cent. Lethality: 4/119 = 
3.3 per cent. Seventy three of the patients (61 per cent) had sphincter saving 
procedures and 46 of them (38.7 per cent) had abdominoperineal excision. Out of 
the 64 low anterior resection 2 patients (L: 2/64 = 3.1 per cent) and out of the 
46 abdominoperineal excision also 2 patients (L: 2/46 = 4.5 per cent) were lost. 
In the sphincter saving group the distal clearance margin was decreased to below 
3 cms at 29 patients without having local recurrence.
CONCLUSION: in many cases of the carcinoma localized in the middle third of the 
rectum (at 82 per cent of our own patients) the sphincter can be saved without 
having more local recurrences. Decreasing the distal clearance margin to 2.5 cms 
does not increase the possibility of local recurrence if we do it cranially the 
same way as at Miles operation and remove the mesorectum caudally and laterally.

PMID: 2003027 [Indexed for MEDLINE]


283. Drug Metab Dispos. 2008 Jun;36(6):1153-65. doi: 10.1124/dmd.107.019182. Epub 
2008 Mar 20.

Predictive physiologically based pharmacokinetic model for antibody-directed 
enzyme prodrug therapy.

Fang L(1), Sun D.

Author information:
(1)Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 
500 W 12th Ave, Columbus, OH 43210, USA.

Antibody-directed enzyme prodrug therapy (ADEPT) using anti-TAG-72 antibody and 
geldanamycin (GA) prodrug were validated in vitro. To understand the complexity 
and to explore optimal therapeutic regimens for ADEPT in vivo, a physiologically 
based pharmacokinetic model (PBPK) is applied to analyze each anatomical 
component/organ. The baseline model predicts that active drug tumor/plasma 
exposure (AUC) ratio is 2-fold, although antibody-enzyme conjugates (AbE) are 
distributed into tumors up to 9-fold higher than in plasma. However, the active 
drug tumor/plasma AUC ratio can be increased up to 100-fold when AbE are 
depleted from plasma. Similarly, the active drug tumor/plasma AUC ratio can be 
increased from 2- to 6-fold when the intrinsic clearance of AbE is accelerated 
by 10-fold. Several sensitive parameters are identified: 1) increasing flow 
inside tumor (J(iso,tumor)) significantly increases active drug tumor/plasma AUC 
ratio; 2) increasing permeability of prodrug (from range 1.4 x 10(-6) to 1.4 x 
10(-4) cm/s) increases active drug tumor/plasma AUC ratio significantly, whereas 
active drug permeability enhancement (from range 5 x 10(-4) to 5 x 10(-2) cm/s) 
has minimal effect; 3) decreasing E(max) and increasing EC(50) for converting 
prodrug to active drug increase tumor/plasma AUC ratio for active drug. The PBPK 
model predicts that the optimal dosing interval between AbE and prodrug 
administration is 5 days, the optimal AbE dose is 0.1 B(max), and the optimal 
dose for GA prodrug is 60 mg/kg. The current PBPK model successfully identifies 
sensitive parameters and predicts an optimal dosing regimen for ADEPT.

DOI: 10.1124/dmd.107.019182
PMID: 18356268 [Indexed for MEDLINE]


284. Int J Colorectal Dis. 1994;9(4):207-10. doi: 10.1007/BF00292252.

Alteration of maximum anal resting pressure by digital rectal examination prior 
to manometry: analysis of agreement between repeat measurements.

Herbst F(1), Teleky B.

Author information:
(1)Department of General Surgery, University of Vienna, Austria.

To study whether digital examination preceding anal manometry causes significant 
alteration of maximum resting pressure reading and to quantify the 
discrepancies, 78 individuals (64 incontinent, 14 controls) were investigated. 
Recordings of maximum resting pressure were taken before and after digital 
rectal examination. There was a mean discrepancy of only -1.8 cms H2O between 
the readings and excellent correlation, but analysis of agreement revealed a 
bias that tended to be greater with smaller measurements and unacceptable 
variability between test results. Furthermore, the bias was not related to age, 
gender, the grade of incontinence, maximum voluntary contraction, functional 
anal canal length and threshold volume. Digital rectal examination prior to 
manometry causes unpredictable results especially in patients with lower maximum 
resting pressures and should strictly be avoided.

DOI: 10.1007/BF00292252
PMID: 7876726 [Indexed for MEDLINE]


285. Gen Physiol Biophys. 2009 Sep;28(3):309-15.

Transepithelial transport of ambroxol hydrochloride across human intestinal 
Caco-2 cell monolayers.

Stetinová V(1), Smetanová L, Kholová D, Svoboda Z, Kvetina J.

Author information:
(1)Institute of Experimental Biopharmaceutics, Joint Research Centre of the 
Academy of Sciences of the Czech Republic and PRO.MED.CS Praha a.s., Heyrovského 
1207, 500 03 Hradec Králové, Czech Republic. stetinova@uebf.cas.cz

This study aimed i) to characterize the transepithelial transport of the 
mucolytic agent ambroxol hydrochloride across the intestinal barrier, ii) to 
classify the ambroxol according to Biopharmaceutics Classification System (BCS) 
and iii) to predict ambroxol absorption in humans. Transport of ambroxol (100, 
300 and 1000 micromol/l) was studied in a human colon carcinoma cell line Caco-2 
in apical to basolateral and basolateral to apical direction, under iso-pH 7.4 
and pH-gradient (6 vs. 7.4) conditions. The relative contribution of the 
paracellular route was estimated using Ca2+-free transport medium. Ambroxol 
samples from receiver compartments were analysed by HPLC with UV detection (242 
nm). Results showed that ambroxol transport is linear with time, pH-dependent 
and direction-independent, displays non-saturable (first-order) kinetics. Thus, 
the transport seems to be transcellular mediated by passive diffusion. Estimated 
high solubility and high permeability (P(app) = 45 x 10(-6) cm/s) of ambroxol 
rank it among well absorbed compounds and class I of BCS. It can be expected 
that the oral dose fraction of ambroxol absorbed in human intestine is high.

PMID: 20037197 [Indexed for MEDLINE]


286. Colorectal Dis. 2011 Mar;13(3):e42-5. doi: 10.1111/j.1463-1318.2010.02476.x.

Novel use of an air-filled breast prosthesis to allow radiotherapy to recurrent 
colonic cancer.

O'Duffy F(1), Toomey DP, Fleming F, McNamara DA.

Author information:
(1)Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland. 
fergaloduffy@hotmail.com

AIM: The authors present the novel and successful use of an air-filled breast 
prosthesis for extra pelvic exclusion of small bowel to facilitate adjuvant 
radiotherapy following resection of recurrent adenocarcinoma of the ascending 
bowel. The therapeutic use of radiotherapy in colon cancer can cause acute or 
chronic radiation enteropathy. Mobile small bowel can be sequestered in 'dead 
space' or by adhesions exposing it to adjuvant radiotherapy. A variety of pelvic 
partitioning methods have been described to exclude bowel from radiation fields 
using both native and prosthetic materials.
METHOD: In this case a 68 year old presented with ascending colon adenocarcinoma 
invading the peritoneum and underwent en bloc peritoneal resection. Thirty-seven 
months later surveillance CT identified a local recurrence. Subsequent resection 
resulted in a large iliacus muscle defect which would sequester small bowel 
loops thus exposing the patient to radiation enteropathy. The lateral position 
of the defect precluded the use of traditional pelvic partitioning methods which 
would be unlikely to remain in place long enough to allow radiotherapy. A 
lightweight air-filled breast prosthesis (Allergan 133 FV 750 cms) secured in 
place with an omentoplasty was used to fill the defect.
RESULTS: Following well tolerated radiotherapy the prosthesis was deflated under 
ultrasound guidance and removed via a 7-cm transverse incision above the right 
iliac crest. The patient is disease free 18 months later with no evidence of 
treatment related morbidity.
CONCLUSION: The use of a malleable air-filled prosthesis for pelvic partitioning 
allows specific tailoring of the prosthesis size and shape for individual 
patient defects. It is also lightweight enough to be secured in place using an 
omentoplasty to prevent movement related prosthesis migration. In the absence of 
adequate omentum a mesh sling may be considered to allow fixation. In this case 
the anatomy of the prosthesis position allowed for its removal without the need 
for repeat laparotomy. Pre-operative deflation of the air-filled prosthesis 
under ultrasound guidance also reduces the size of the incision required for 
removal. This technique may be valuable to prevent collateral small bowel 
irradiation following resection of renal or retroperitoneal malignancy.

© 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology 
of Great Britain and Ireland.

DOI: 10.1111/j.1463-1318.2010.02476.x
PMID: 21320268 [Indexed for MEDLINE]


287. Medicine (Baltimore). 2016 Jul;95(30):e4386. doi: 10.1097/MD.0000000000004386.

Blood flow speed of the gastric conduit assessed by indocyanine green 
fluorescence: New predictive evaluation of anastomotic leakage after 
esophagectomy.

Koyanagi K(1), Ozawa S, Oguma J, Kazuno A, Yamazaki Y, Ninomiya Y, Ochiai H, 
Tachimori Y.

Author information:
(1)Division of Esophageal Surgery Division of Colorectal Surgery, Department of 
Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo Department of 
Gastroenterological Surgery, Tokai University School of Medicine, Isehara, 
Japan.

Anastomotic leakage is considered as an independent risk factor for 
postoperative mortality after esophagectomy, and an insufficient blood flow in 
the reconstructed conduit may be a risk factor of anastomotic leakage. We 
investigated the clinical significance of blood flow visualization by 
indocyanine green (ICG) fluorescence in the gastric conduit as a means of 
predicting the leakage of esophagogastric anastomosis after esophagectomy.Forty 
patients who underwent an esophagectomy with gastric conduit reconstruction were 
prospectively investigated. ICG fluorescence imaging of the gastric conduit was 
detected by a near-infrared camera system during esophagectomy and correlated 
with clinical parameters or surgical outcomes.In 25 patients, the flow speed of 
ICG fluorescence in the gastric conduit wall was simultaneous with that of the 
greater curvature vessels (simultaneous group), whereas in 15 patients this was 
slower than that of the greater curvature vessels (delayed group). The reduced 
speed of ICG fluorescence stream in the gastric conduit wall was associated with 
intraoperative blood loss (P = 0.008). Although anastomotic leakage was not 
found in the simultaneous group, it occurred in 7 patients of the delayed group 
(P < 0.001). A flow speed of ICG fluorescence in the gastric conduit wall of 
1.76 cm/s or less was determined by a receiver operating characteristic (ROC) 
curve, identified as a significant independent predictor of anastomotic leakage 
after esophagectomy (P = 0.004).This preliminary study demonstrates that 
intraoperative evaluation of blood flow speed by ICG fluorescence in the gastric 
conduit wall is a useful means to predict the risk of anastomotic leakage after 
esophagectomy.

DOI: 10.1097/MD.0000000000004386
PMCID: PMC5265869
PMID: 27472732 [Indexed for MEDLINE]

Conflict of interest statement: The authors have no conflicts of interest to 
disclose.


288. Cir Esp. 2012 Mar;90(3):176-9. doi: 10.1016/j.ciresp.2011.10.015. Epub 2012 Feb 
16.

[Electrocoagulation on a fragment of anterior abdominal rectal muscle for the 
control of presacral bleeding during rectal resection].

[Article in Spanish]

Casal Núñez JE(1), Martínez MT, Poblador AR.

Author information:
(1)Hospital Meixoeiro, Complejo Hospitalario Universitario, Unidad de 
Coloproctología, Vigo, España. jose.enrique.casal.nunez@sergas.es

INTRODUCTION: Presacral venous haemorrhage during rectal movement is low, but is 
often massive, and even fatal. Our objective is the "in vitro" determination of 
the results of electrocoagulation applied to a fragment of muscle on the sacral 
bone surface during rectal resection due to a malignant neoplasm of the rectum.
MATERIAL AND METHOD: Single-pole coagulation was applied "in vitro" with the 
selector at maximum power on a 2×2 cms muscle fragment, applied to the anterior 
side of the IV sacral vertebra until reaching boiling point. The method was used 
on 6 patients with bleeding of the presacral venous plexus.
RESULTS: In the "in vitro" study, boiling point was reached in 90 seconds from 
applying the single-pole current on the muscle fragment. Electrocoagulation was 
applied to a 2×2 cm rectal muscle fragment in 6 patients with presacral venous 
haemorrhage, using pressure on the surface of the presacral bone, with the 
stopping of the bleeding being achieved in all cases.
CONCLUSIONS: The use of indirect electrocoagulation on a fragment of the rectus 
abdominis muscle is a straightforward and highly effective technique for 
controlling presacral venous haemorrhage.

Copyright © 2011 AEC. Published by Elsevier Espana. All rights reserved.

DOI: 10.1016/j.ciresp.2011.10.015
PMID: 22342004 [Indexed for MEDLINE]


289. Fed Regist. 2002 Dec 31;67(251):79965-80184.

Medicare program; revisions to payment policies under the physician fee schedule 
for calendar year 2003 and inclusion of registered nurses in the personnel 
provision of the critical access hospital emergency services requirement for 
frontier areas and remote locations. Final rule with comment period.

Centers for Medicare & Medicaid Services (CMS), HHS.

This final rule with comment period refines the resource-based practice expense 
relative value units (RVUs) and makes other changes to Medicare Part B payment 
policy. In addition, as required by statute, we are announcing the physician fee 
schedule update for CY 2003. The update to the physician fee schedule occurs as 
a result of a calculation methodology specified by law. That law required the 
Department to set annual updates based in part on estimates of several factors. 
Although subsequent after-the-fact data indicate that actual increases were 
different to some degree from earlier estimates, the law does not permit those 
estimates to be revised. A subsequent law required estimates to be revised for 
FY 2000 and beyond. Although we have exhaustively examined opportunities for a 
different interpretation of law that would allow us to correct the flaw in the 
formula administratively, current law does not permit such an interpretation. 
Accordingly, without Congressional action to address the current legal 
framework, the Department is compelled to announce herein a physician fee 
schedule update for CY 2003 of -4.4 percent. Because the Department would adopt 
a change in the formula that determines the physician update if the law 
permitted it, we have examined how proper adjustments to past data could result 
in a positive update. The Department believes that revisions of estimates used 
to establish the sustainable growth rates (SGR) for fiscal years (FY) 1998 and 
1999 and Medicare volume performance standards (MVPS) for 1990-1996 would, under 
present calculations, result in a positive update. The Department intends to 
work closely with Congress to develop legislation that could permit a positive 
update, and hopes that such legislation can be passed before the negative update 
takes effect. Because the Department wishes to change the update promptly in the 
event that Congress provides the Department legal authority to do so, we are 
requesting comments regarding how physician fee schedule rates could and should 
be recalculated prospectively in the event that Congress provides the Department 
with legal authority to revise estimates used to establish the sustainable 
growth rates (SGR) and for 1998 and 1999 and the NVPS for 1990-1996. The other 
policy changes concern: the pricing of the technical component for positron 
emission tomography (PET) scans, Medicare qualifications for clinical nurse 
specialists, a process to add or delete services to the definition of 
telehealth, the definition for ZZZ global periods, global period for surface 
radiation, and an endoscopic base for urology codes. In addition, this rule 
updates the codes subject to physician self-referral prohibitions. We are 
expanding the definition of a screening fecal-occult blood test and are 
modifying our regulations to expand coverage for additional colorectal cancer 
screening tests through our national coverage determination process. We also 
make revisions to the sustainable growth rate, the anesthesia conversion factor, 
and the work values for some gastroenterologic services. We are making these 
changes to ensure that our payment systems are updated to reflect changes in 
medical practice and the relative value of services. This final rule also 
clarifies the enrollment of physical and occupational therapists as therapists 
in private practice and clarifies the policy regarding services and supplies 
incident to a physician's professional services. In addition, this final rule 
discusses physical and occupational therapy payment caps and makes technical 
changes to the definition of outpatient rehabilitation services. In addition, we 
are finalizing the calendar year (CY) 2002 interim RVUs and are issuing interim 
RVUs for new and revised procedure codes for calendar year (CY) 2003. As 
required by the statute, we are announcing that the physician fee schedule 
update for CY 2003 is -4.4 percent, the initial estimate of the sustainable 
growth rate for CY 2003 is 7.6 percent, and the conversion factor for CY 2003 is 
$34.5920. This final rule will also allow registered nurses (RNs) to provide 
emergency care in certain critical access hospitals (CAHs) in frontier areas (an 
area with fewer than six residents per square mile) or remote locations 
(locations designated in a State's rural health plan that we have approved.) 
This policy applies if the State, following consultation with the State Boards 
of Medicine and Nursing, and in accordance with State law, requests that RNs be 
included, along with a doctor of medicine or osteopathy, a physician's 
assistant, or a nurse practitioner with training or experience in emergency 
care, as personnel authorized to provide emergency services in CAHs in frontier 
areas or remote locations.

PMID: 12510665 [Indexed for MEDLINE]


290. Health Care Financ Rev. 2002 Summer;23(4):189-200.

Screening for osteoporosis and colon cancer under Medicare.

Adler GS(1), Shatto A.

Author information:
(1)gadler@cms.hhs.gov

PMCID: PMC4194763
PMID: 12500479 [Indexed for MEDLINE]


291. Cell Biol Int. 2005 Jun;29(6):441-8. doi: 10.1016/j.cellbi.2005.01.006. Epub 
2005 Mar 25.

NMR measurements of the diffusional permeability of water in cultured colonic 
epithelial cancer cells.

Nouri-Sorkhabi MH(1), Chapman BE, O'Loughlin EV, Li Z, Kuchel PW, Gaskin KJ.

Author information:
(1)James Fairfax Institute of Paediatric Nutrition, Children's Hospital at 
Westmead, Westmead, NSW 2145, Australia.

The water residence time and diffusional water permeability in colonic 
epithelial T84 cancer cells was measured using (1)H NMR spectroscopy; the values 
estimated were 35.2+/-2.8 ms and (7.4+/-0.6)x10(-3)cms(-1), respectively. Water 
permeability was inhibited to approximately 10% of its original value by the 
mercurial diuretic, p-chloromercuribenzenesulfonate (PCMBS; 1mM), and fully 
restored by dithiothreitol (DTT; 1mM). The permeability was also inhibited 
reversibly to approximately 55%, by extracellular glibenclamide (1mM), an 
inhibitor of some ATP-binding cassette (ABC) transporters, including the cystic 
fibrosis transmembrane conductance regulator (CFTR). Addition of the 
phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IMBX; 0.1-1mM) and the 
adenylate cyclase activator, forskolin (0.1-1mM) did not alter water 
permeability. It is concluded that in T84 cells water diffuses through the 
membrane lipid bilayer and via channels that are inhibited by PCMBS, including 
the channels that are known to be inhibited by glibenclamide.

DOI: 10.1016/j.cellbi.2005.01.006
PMID: 16054561 [Indexed for MEDLINE]


292. Br J Surg. 2005 May;92(5):592-5. doi: 10.1002/bjs.4861.

Doppler assessment after right hepatectomy confirms the need to fix the remnant 
left liver in the anatomical position.

Ogata S(1), Kianmanesh R, Belghiti J.

Author information:
(1)Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, 
Hospital Beaujon (AP-HP, Paris VII University), Clichy, France.

BACKGROUND: The remnant left liver after right hepatectomy tends to rotate 
spontaneously into the right subphrenic space. This rotation might induce venous 
outflow impairment. The aim of this study was to assess immediate venous outflow 
in the left hepatic vein by intraoperative Doppler ultrasound (US) according to 
the position of the remnant liver.
METHODS: From August 2003 to February 2004, assessment of left hepatic venous 
outflow was systematically performed in 44 consecutive right hepatic resections 
by Doppler US in spontaneous and anatomical positions. The anatomical position 
was defined as the position in which the falciform ligament was in its strict 
median position.
RESULTS: The placement of the left liver from the spontaneous position to the 
anatomical position resulted in a significant increase in left hepatic venous 
outflow (20.1 +/- 5.7 versus 8.5 +/- 4.4 cm/s; P < 0.0001). In the spontaneous 
position, the decrease in left hepatic venous outflow persisted even without 
division of the left triangular ligament (10.2 +/- 5.4 versus 21.7 +/- 5.3 cm/s 
in the anatomical position) or removal of the middle hepatic vein (8.4 +/- 3.4 
versus 21.3 +/- 5.8 cm/s).
CONCLUSION: : Results of this study strongly suggest that after right 
hepatectomy the remnant left liver should always be fixed in the anatomical 
position.

Copyright (c) 2005 British Journal of Surgery Society Ltd. Published by John 
Wiley & Sons, Ltd.

DOI: 10.1002/bjs.4861
PMID: 15779074 [Indexed for MEDLINE]


293. Biochem Biophys Res Commun. 1991 Mar 29;175(3):880-5. doi: 
10.1016/0006-291x(91)91647-u.

Correlation between oral drug absorption in humans and apparent drug 
permeability coefficients in human intestinal epithelial (Caco-2) cells.

Artursson P(1), Karlsson J.

Author information:
(1)Department of Pharmaceutics, Uppsala University, Sweden.

Monolayers of a well differentiated human intestinal epithelial cell line, 
Caco-2, were used as a model to study passive drug absorption across the 
intestinal epithelium. Absorption rate constants (expressed as apparent 
permeability coefficients) were determined for 20 drugs and peptides with 
different structural properties. The permeability coefficients ranged from 
approximately 5 x 10(-8) to 5 x 10(-5) cm/s. A good correlation was obtained 
between data on oral absorption in humans and the results in the Caco-2 model. 
Drugs that are completely absorbed in humans had permeability coefficients 
greater than 1 x 10(-6) cm/s. Drugs that are absorbed to greater than 1% but 
less than 100% had permeability coefficients of 0.1-1.0 x 10(-6) cm/s while 
drugs and peptides that are absorbed to less than 1% had permeability 
coefficients of less than or equal to 1 x 10(-7) cm/s. The results indicate that 
Caco-2 monolayers can be used as a model for studies on intestinal drug 
absorption.

DOI: 10.1016/0006-291x(91)91647-u
PMID: 1673839 [Indexed for MEDLINE]


294. Colorectal Dis. 2007 Jun;9(5):469-71. doi: 10.1111/j.1463-1318.2006.01120.x.

Staged anterior resection and TEM to preserve rectal function in synchronous 
malignant and benign rectal lesions.

Betambeau N(1), Simson JN.

Author information:
(1)Department of Surgery, St Richard's Hospital, Chichester, West Sussex, UK.

BACKGROUND: Traditionally patients with a high rectosigmoid carcinoma and a 
synchronous large distal rectal adenoma would be treated by low anterior 
resection with associated loss of rectal function.
METHOD: Four patients with a carcinoma of the upper rectum or distal sigmoid 
colon and a synchronous distal rectal adenoma were treated by high anterior 
resection followed by staged Transanal Endoscopic Microsurgery (TEM) thus 
conserving the distal rectum. Preoperative and postoperative rectal function was 
assessed using the St. Mark's incontinence score.
RESULTS: The proximal carcinomas and distal adenomas were 12-18 cms and 0.5-9 
cms respectively from the dentate line. The mean surface area of the distal 
adenomas was 9.7 cms2. There were no deaths or major complications. There were 
no recurrences after a mean follow-up of 31.5 months. Rectal function was 
unchanged in three patients with a minor increase in the score in one.
CONCLUSION: Staged high anterior resection and 'rEM offers effective treatment 
of synchronous rectosigmoid carcinoma and distal rectal adenoma with 
preservation of rectal function.

DOI: 10.1111/j.1463-1318.2006.01120.x
PMID: 17504346 [Indexed for MEDLINE]


295. Eur J Histochem. 1993;37(1):43-51.

The differential expression of statin in the nuclei of human colonic crypts 
adjacent to a cancer: an immunohistochemical study.

Mitmaker B(1), Bayer I, Baytner S, Gordon PH, Wang E.

Author information:
(1)Department of Surgery, Lady Davis Institute for Medical Research, Sir 
Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.

Statin, a non-proliferation-specific nuclear antigen, was used here to assess 
the colonic crypt kinetics of the mucosa bordering a human colon cancer. Mucosal 
strips adjacent to a colon cancer obtained from operative specimens were 
immediately cut into five one cm segments and stored in liquid nitrogen. An 
immunohistological technique using the statin antibody as a nuclear marker was 
used to determine the labelling indices of the non-cycling compartment at the 
varying distances. Optical density measurements of the nuclear reaction product 
served to objectively identify the statin-positive nucleus. The results indicate 
that there is a statistically significant reduction (P < 0.0001) in the 
statin-positive labelling index in the entire crypt length for a distance of 
three cms. The division of the entire crypt into four levels (A, B, C and D) 
demonstrates that this effect is principally due to the upward extension of the 
statin-negative cell mass into levels B and C with a corresponding decrease in 
the labelling index of the statin-positive nuclei in these levels. The in vivo 
expression of nuclear statin demonstrates its usefulness in accurately 
determining the size of the non-proliferative compartment in the human colonic 
crypt adjacent to a colon cancer.

PMID: 7682866 [Indexed for MEDLINE]


296. HPB (Oxford). 2013 Apr;15(4):265-72. doi: 10.1111/j.1477-2574.2012.00540.x. Epub 
2012 Aug 20.

Magnetic resonance imaging flowmetry demonstrates portal vein dilatation 
subsequent to oxaliplatin therapy in patients with colorectal liver metastasis.

Urdzik J(1), Bjerner T, Wanders A, Duraj F, Haglund U, Norén A.

Author information:
(1)Department of Surgery, Uppsala University, 75185 Uppsala, Sweden. 
jozef.urdzik@surgsci.uu.se

OBJECTIVES: Sinusoidal injury (SI) after oxaliplatin-based therapies for 
colorectal liver metastasis (CRLM) can increase postoperative morbidity. 
Preoperative methods to estimate SI are lacking. The aim of this study was to 
identify SI by evaluating portal vein haemodynamics.
METHODS: Magnetic resonance imaging flowmetry (MRIF) was used to estimate portal 
vein haemodynamics in 29 patients with CRLM before liver surgery. Sinusoidal 
injury was evaluated from resected non-tumorous liver parenchyma according to 
the combined vascular injury (CVI) score of ≥3.
RESULTS: All patients with SI (six of 29) received oxaliplatin; however, a 
significant association could not be proven (P= 0.148). Oxaliplatin-treated 
patients showed portal vein dilatation in both the SI and non-SI groups compared 
with patients who had not received oxaliplatin (Bonferroni corrected P= 0.003 
and P= 0.039, respectively). Mean portal velocity tended to be lower in patients 
with SI compared with oxaliplatin-treated patients without SI (Bonferroni 
corrected P= 0.087). A mean portal velocity of ≤14.35 cm/s together with a 
cross-section area of ≥1.55 cm(2) was found to predict SI with sensitivity of 
100% and specificity of 78%.
CONCLUSIONS: Oxaliplatin treatment was associated with portal vein dilatation. 
Patients with SI showed a tendency towards decreased mean portal flow velocity. 
This may indicate that SI is associated with an increased resistance to blood 
flow in the liver parenchyma. Portal vein haemodynamic variables estimated by 
MRIF can identify patients without SI non-invasively.

© 2012 International Hepato-Pancreato-Biliary Association.

DOI: 10.1111/j.1477-2574.2012.00540.x
PMCID: PMC3608980
PMID: 23458313 [Indexed for MEDLINE]


297. G Chir. 1992 Apr;13(4):213-5.

[Clinical use of a new compression surgical stapler in surgery of the large 
intestine].

[Article in Italian]

Rosati R(1), Rebuffat C, Fumagalli U, Montorsi M, Olivari N, Salvaneschi S, 
Roviaro G, Pezzuoli G.

Author information:
(1)Istituto di Chirurgia Generale, Università degli Studi di Milano.

The clinical experience with the use in colorectal surgery of a new compression 
anastomotic device developed by the Authors is reported. From May 1986 through 
June 1990, 95 patients underwent large bowel anastomosis using this device. 
Operations performed included 51 left hemicolectomies or anterior resections of 
the sigmoid and rectum, 23 left colon resections, 19 right hemicolectomies, and 
two total colectomies. Twenty-nine anastomoses were performed below the pelvic 
peritoneal reflection and 18.5% of them resulted less than 4 cms from the anal 
verge while 20% were located between 4.5 and 8 cms. Five (5.2%) intraoperative 
diverting colostomies were needed. The rings were evacuated postoperatively 
after a mean of 10.9 days with none or very little discomfort. Operative 
mortality was 1.0% (one patient died of myocardial infarction). Anastomotic 
complications included five (5.2%) clinical and four (4.2%) subclinical 
leakages. No haemorrhages or stenoses were observed. This initial clinical 
experience shows the anastomotic device is reliable and justifies further 
experimentation.

PMID: 1637632 [Indexed for MEDLINE]