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Mohamed E Salem, Alberto Puccini, Axel Grothey, Derek Raghavan, Richard M Goldberg, Joanne Xiu, W Michael Korn, Benjamin A Weinberg, Jimmy J Hwang, Anthony F Shields, John L Marshall, Philip A Philip, Heinz-Josef Lenz
The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing (NGS) was performed on genomic DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor specimens using the NextSeq platform...
March 9, 2018: Molecular Cancer Research: MCR
Soo Jung Lee, Sun-Young Jun, In Hee Lee, Byung Woog Kang, Su Yeon Park, Hye Jin Kim, Jun Seok Park, Gyu-Seog Choi, Ghilsuk Yoon, Jong Gwang Kim
PURPOSE: This study attempted to reveal the prognostic impact of microsatellite instability-high (MSI-H) colon cancer with tumor-infiltrating immune cells (TIICs) and immune checkpoint protein expression, which are good candidates for immunotherapy. MATERIALS AND METHODS: The study included 89 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Chilgok Hospital. The expression status of specific inhibitory receptors, such as CD274 (programmed death-ligand 1, PD-L1), PDCD1 (programmed cell death 1, PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and indolamine 2'3'-dioxygenase 1 (IDO1), was retrospectively analyzed using immunohistochemistry (IHC)...
March 8, 2018: Journal of Cancer Research and Clinical Oncology
Camille Boulagnon-Rombi, Christophe Schneider, Chloé Leandri, Albin Jeanne, Virginie Grybek, Aude Marchal Bressenot, Coralie Barbe, Benjamin Marquet, Saviz Nasri, Christelle Coquelet, Caroline Fichel, Nicole Bouland, Arnaud Bonnomet, Reza Kianmanesh, Anne-Sophie Lebre, Olivier Bouché, Marie-Danièle Diebold, Georges Bellon, Stéphane Dedieu
LRP1 (low-density lipoprotein receptor-related protein 1), a multifunctional endocytic receptor, has recently been identified as a hub within a biomarker network for multi-cancer clinical outcome prediction. As its role in colon cancer has not yet been characterized, we here investigate the relationship between LRP1 and outcome. Materials and Methods: LRP1 mRNA expression was determined in colon adenocarcinoma and paired colon mucosa samples, as well as in stromal and tumor cells obtained after laser capture microdissection...
February 6, 2018: Oncotarget
David W Brammer, Patrick J Gillespie, Mei Tian, Daniel Young, Muthuswamy Raveendran, Lawrence E Williams, Mihai Gagea, Fernando J Benavides, Carlos J Perez, Russell R Broaddus, Bruce J Bernacky, Kirstin F Barnhart, Mian M Alauddin, Manoop S Bhutani, Richard A Gibbs, Richard L Sidman, Renata Pasqualini, Wadih Arap, Jeffrey Rogers, Christian R Abee, Juri G Gelovani
Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques ( Macaca mulatta ) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon...
February 28, 2018: Proceedings of the National Academy of Sciences of the United States of America
Adrian Frick, Vineeta Khare, Gregor Paul, Michaela Lang, Franziska Ferk, Siegfried Knasmueller, Andrea Beer, Georg Oberhuber, Christoph Gasche
Patients with inflammatory bowel disease (IBD) have a higher risk of developing colitis-associated-cancer (CAC), however, the underlying processes of disease progression are not completely understood. Here, the molecular processes of inflammation-driven colon carcinogenesis were investigated using IL-10 deficient mice (IL-10- KO). IL-10- KO mice were euthanized after development of colitis and dysplasia. Immunohistochemistry (IHC) was performed for markers of colitis-induced DNA damage (CIDD): oxidative-DNA-lesions (8-oxoG), double-strand breaks (DSB; γH2AX) and DSB-repair...
January 29, 2018: Molecular Cancer Research: MCR
Harrison M Penrose, Sandra Heller, Chloe Cable, Hani Nakhoul, Nate Ungerleider, Melody Baddoo, Zachary F Pursell, Erik K Flemington, Susan E Crawford, Suzana D Savkovic
Background: Mitochondrial reprogramming has emerged as a hallmark of cancer pathobiology. Although it is believed this reprogramming is essential for cancer cells to thrive, how it supports cancer pathobiology is unclear. We previously generated colonic ρ0 (rho0) cells with reduced mitochondrial energy function and acquired their transcriptional signature. Here, we utilized a bioinformatics approach to identify their changes linked to cancer pathobiology. Methods: Human colon cancer HCT116 cells, control and ρ0, were used for qPCR...
November 2017: Oncoscience
Bert H O'Neil, John M Wallmark, David Lorente, Elena Elez, Judith Raimbourg, Carlos Gomez-Roca, Samuel Ejadi, Sarina A Piha-Paul, Mark N Stein, Albiruni R Abdul Razak, Katia Dotti, Armando Santoro, Roger B Cohen, Marlena Gould, Sanatan Saraf, Karen Stein, Sae-Won Han
BACKGROUND: Colorectal cancers (CRCs) expressing programmed death ligand 1 (PD-L1) have poor prognosis. In the multicohort KEYNOTE-028 trial, the anti-PD-1 antibody pembrolizumab was evaluated in 20 PD-L1-positive advanced solid tumors. Herein, we report results for the advanced CRC cohort. METHODS: Patients with advanced, treatment-resistant PD-L1-positive carcinoma of the colon or rectum were enrolled, regardless of microsatellite instability (MSI) status. Pembrolizumab 10 mg/kg was administered every 2 weeks for up to 2 years or until disease progression/unacceptable toxicity...
2017: PloS One
Tamotsu Sugai, Yayoi Takahashi, Makoto Eizuka, Ryo Sugimoto, Yasuko Fujita, Wataru Habano, Kouki Otsuka, Akira Sasaki, Eiichiro Yamamoto, Takayuki Matsumoto, Hiromu Suzuki
To characterize somatic alterations in colorectal cancer (CRC), we conducted a genome-scale analysis of 106 CRC specimens. We assessed comprehensive somatic copy number alterations (SCNAs) in these CRC specimens. In addition, we examined microsatellite instability (MSI; low and high), genetic mutations (KRAS, BRAF, TP53, and PIK3CA), and DNA methylation status (classified into low, intermediate, and high type). We stratified molecular alterations in the CRCs using a hierarchical cluster analysis. The examined CRCs could be categorized into three subgroups using hierarchical cluster analysis...
March 2018: Molecular Carcinogenesis
Gabriel J LaBonia, Katelyn R Ludwig, C Bruce Mousseau, Amanda B Hummon
For a patient with metastatic colorectal cancer there are limited clinical options aside from chemotherapy. Unfortunately, the development of new chemotherapeutics is a long and costly process. New methods are needed to identify promising drug candidates earlier in the drug development process. Most chemotherapies are administered to patients in combinations. Here, an in vitro platform is used to assess the penetration and metabolism of combination chemotherapies in three-dimensional colon cancer cell cultures, or spheroids...
January 16, 2018: Analytical Chemistry
Alexandre How-Kit, Antoine Daunay, Olivier Buhard, Clément Meiller, Mourad Sahbatou, Ada Collura, Alex Duval, Jean-François Deleuze
Every colorectal cancer (CRC) patient should be tested for microsatellite instability (MSI) to screen for Lynch syndrome. Evaluation of MSI status involves screening tumor DNA for the presence of somatic deletions in DNA repeats using PCR followed by fragment analysis. While this method may lack sensitivity due to the presence of a high level of germline DNA, which frequently contaminates the core of primary colon tumors, no other method developed to date is capable of modifying the standard PCR protocol to achieve improvement of MSI detection...
March 2018: Human Mutation
David A Drew, Allen Mo, James J Grady, Richard G Stevens, Joel B Levine, Bruce M Brenner, Joseph C Anderson, Faripour Forouhar, Michael J O'Brien, Thomas J Devers, Daniel W Rosenberg
Aberrant crypt foci (ACF) are the earliest morphologically identifiable lesion found within the human colon. Despite their relatively high frequency in the distal colon, few studies have examined the molecular characteristics of ACF within the proximal colon. In the following study, clinical participants ( n = 184) were screened for ACF using high-definition chromoendoscopy with contrast dye-spray. Following pathologic confirmation, ACF biopsies were subjected to laser capture microdissection (LCM), and epithelial cells were evaluated for somatic mutations with a customized colorectal cancer mutation panel using DNA-mass spectrometry...
March 2018: Molecular Cancer Research: MCR
Sukanya Horpaopan, Jutta Kirfel, Sophia Peters, Michael Kloth, Robert Hüneburg, Janine Altmüller, Dmitriy Drichel, Margarete Odenthal, Glen Kristiansen, Christian Strassburg, Jacob Nattermann, Per Hoffmann, Peter Nürnberg, Reinhard Büttner, Holger Thiele, Philip Kahl, Isabel Spier, Stefan Aretz
Background: Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia ( BRAF , KRAS, RNF43 mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified...
2017: Hereditary Cancer in Clinical Practice
Leon Raskin, Yan Guo, Liping Du, Mark Clendenning, Christophe Rosty, Noralane M Lindor, Stephen B Gruber, Daniel D Buchanan
The underlying genetic cause of colorectal cancer (CRC) can be identified for 5-10% of all cases, while at least 20% of CRC cases are thought to be due to inherited genetic factors. Screening for highly penetrant mutations in genes associated with Mendelian cancer syndromes using next-generation sequencing (NGS) can be prohibitively expensive for studies requiring large samples sizes. The aim of the study was to identify rare single nucleotide variants and small indels in 40 established or candidate CRC susceptibility genes in 1,046 familial CRC cases (including both MSS and MSI-H tumor subtypes) and 1,006 unrelated controls from the Colon Cancer Family Registry Cohort using a robust and cost-effective DNA pooling NGS strategy...
November 7, 2017: Oncotarget
Ioannis Gkekas, Jan Novotny, Ladislav Pecen, Karin Strigård, Richard Palmqvist, Ulf Gunnarsson
BACKGROUND/AIM: The prognostic role of microsatellite instability (MSI) in stage II colon cancer patients remains controversial despite the fact that it has been investigated in a number of studies. Hazard ratios differ considerably among these studies. We performed a meta-analysis to define the significance of MSI in this group of patients. MATERIALS AND METHODS: Studies indexed in PubMed presenting separate data on MSI status and survival outcomes for stage II colon cancer patients have been analyzed using fixed-effect meta-analysis of hazard ratio (HR) according to the method of Peto...
December 2017: Anticancer Research
Jonathan M Loree, Allan A L Pereira, Michael Lam, Alexandra N Willauer, Kanwal Raghav, Arvind Dasari, Van K Morris, Shailesh Advani, David G Menter, Cathy Eng, Kenna Shaw, Russell Broaddus, Mark J Routbort, Yusha Liu, Jeffrey S Morris, Rajyalakshmi Luthra, Funda Meric-Bernstam, Michael J Overman, Dipen Maru, Scott Kopetz
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...
November 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Julien Taieb, Hampig Raphael Kourie, Jean-François Emile, Karine Le Malicot, Ralyath Balogoun, Josep Tabernero, Enrico Mini, Gunnar Folprecht, Jean-Luc Van Laethem, Claire Mulot, Olivier Bouché, Thomas Aparicio, Pierre Michel, Josef Thaler, John Bridgewater, Eric Van Cutsem, Géraldine Perkins, Come Lepage, Ramon Salazar, Pierre Laurent-Puig
Importance: We know of no data on the prognostic value of primary tumor location (PTL) according to BRAF, RAS, and microsatellite instability (MSI) status in patients who have undergone resection for colon cancer (CC) and have been treated with current standard adjuvant chemotherapy. Objective: To determine the prognostic and predictive value of PTL according to BRAF, RAS, and MSI status in patients with stage III CC receiving adjuvant treatment with FOLFOX (folinic acid [leucovorin calcium], fluorouracil, and oxaliplatin) with or without cetuximab...
November 22, 2017: JAMA Oncology
Quentin Thiebault, Gautier Defossez, Lucie Karayan-Tapon, Pierre Ingrand, Christine Silvain, David Tougeron
BACKGROUND: The aim of the study was to evaluate the current rate of molecular testing prescription (KRAS codons 12/13, BRAF and microsatellite instability (MSI)) in newly diagnosed colorectal cancer (CRC) patients and to determine which factors influence testing. METHODS: All incident CRC cases in 2010 were identified in the Poitou-Charentes General Cancer Registry. The exhaustive molecular testing performed was accessed in the French molecular genetics platform...
November 14, 2017: BMC Cancer
Martha L Slattery, Andrew J Pellatt, Frances Y Lee, Jennifer S Herrick, Wade S Samowitz, John R Stevens, Roger K Wolff, Lila E Mullany
Half of miRNAs expressed in colorectal tissue are expressed < 50% of the population. Many infrequently expressed miRNAs have low levels of expression. We hypothesize that less frequently expressed miRNAs, when expressed at higher levels, influence both disease stage and survival after diagnosis with colorectal cancer (CRC); low levels of expression may be background noise. We examine 304 infrequently expressed miRNAs in 1893 population-based cases of CRC with paired carcinoma and normal mucosa miRNA profiles...
October 13, 2017: Oncotarget
María Laura González, Natalia Causada-Calo, Juan Pablo Santino, Mev Dominguez-Valentin, Fabiana Alejandra Ferro, Inés Sammartino, Pablo Germán Kalfayan, Maria Alicia Verzura, Tamara Alejandra Piñero, Andrea Romina Cajal, Walter Pavicic, Carlos Vaccaro
Microsatellite instability (MSI) is a hallmark tool for Lynch syndrome (LS) screening and a prognostic marker for sporadic colorectal cancer (CRC). In regions with limited resources and scarce CRC molecular characterization as South America, the implementation of universal MSI screening is under debate for both its purposes. We sought to estimate the frequency of BAT26 in colorectal adenocarcinomas and to determine associated clinical and histological features. Consecutive patients from a CRC registry were included...
November 11, 2017: Familial Cancer
Raul S Gonzalez, Justin M M Cates, Frank Revetta, Loralee A McMahon, Kay Washington
Objectives: To determine whether histologic features could help identify gastric carcinomas with lymphoid stroma associated with microsatellite instability (MSI) (ie, "medullary carcinomas"), Epstein-Barr virus (EBV) infection (termed lymphoepithelioma-like carcinomas in other organ systems), or neither. Methods: We identified 17 solid-type gastric carcinomas with lymphoid stroma, assessed EBV and MSI status, and compared features across groups. We also compared them with 51 solid-type colorectal adenocarcinomas...
November 20, 2017: American Journal of Clinical Pathology
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