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JOURNAL ARTICLE
Daniel Morales Borràs, Sara Verbandt, Markus Ausserhofer, Gregor Sturm, Jinyeong Lim, Gil Arasa Verge, Isaure Vanmeerbeek, Raquel S Laureano, Jannes Govaerts, Jenny Sprooten, Yourae Hong, Rebecca Wall, Gert De Hertogh, Xavier Sagaert, Gabriele Bislenghi, André D'Hoore, Albert Wolthuis, Francesca Finotello, Woong-Yang Park, Stefan Naulaerts, Sabine Tejpar, Abhishek D Garg
CD8+ T cell activation via immune checkpoint blockade (ICB) is successful in microsatellite instable (MSI) colorectal cancer (CRC) patients. By comparison, the success of immunotherapy against microsatellite stable (MSS) CRC is limited. Little is known about the most critical features of CRC CD8+ T cells that together determine the diverse immune landscapes and contrasting ICB responses. Hence, we pursued a deep single cell mapping of CRC CD8+ T cells on transcriptomic and T cell receptor (TCR) repertoire levels in a diverse patient cohort, with additional surface proteome validation...
November 15, 2023: Cell Discovery
#2
JOURNAL ARTICLE
S Joris, H Denys, J Collignon, M Rasschaert, D T'Kint de Roodenbeke, F P Duhoux, J-L Canon, S Tejpar, J Mebis, L Decoster, P Aftimos, J De Grève
BACKGROUND: The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic next-generation sequencing in patients with advanced cancer and enhance access to molecularly guided treatment options. Academic tumor-agnostic basket phase II studies are part of this initiative. The current investigator-driven trial aimed to investigate the efficacy of olaparib in advanced cancers with a (likely) pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR)...
December 2023: ESMO Open
#3
REVIEW
David B Page, Glenn Broeckx, Chowdhury Arif Jahangir, Sara Verbandt, Rajarsi R Gupta, Jeppe Thagaard, Reena Khiroya, Zuzana Kos, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Sarah N Dudgeon, Mahmoud Elghazawy, Scott Ely, Claudio Fernandez-Martín, Susan Fineberg, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Alexandros Hardas, Steven N Hart, Johan Hartman, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S McDonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen van der Laak, Paul J van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Sylvia Adams, John Mark Seaverns Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard
Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers...
August 2023: Journal of Pathology
#4
JOURNAL ARTICLE
Shania M Corry, Amy Mb McCorry, Tamsin Rm Lannagan, Niamh A Leonard, Natalie C Fisher, Ryan M Byrne, Petros Tsantoulis, Xabier Cortes-Lavaud, Raheleh Amirkhah, Keara L Redmond, Aoife J McCooey, Sudhir B Malla, Emily Rogan, Svetlana Sakhnevych, Michael A Gillespie, Mark White, Susan D Richman, Rene-Filip Jackstadt, Andrew D Campbell, Sarah Maguire, Simon S McDade, Daniel B Longley, Maurice B Loughrey, Helen G Coleman, Emma M Kerr, Sabine Tejpar, Timothy Maughan, Simon J Leedham, Donna M Small, Aideen E Ryan, Owen J Sansom, Mark Lawler, Philip D Dunne
OBJECTIVE: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy. DESIGN: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically...
April 27, 2022: Gut
#5
JOURNAL ARTICLE
Prashanthi Ramesh, Tamsin R M Lannagan, Rene Jackstadt, Lidia Atencia Taboada, Nico Lansu, Pratyaksha Wirapati, Sander R van Hooff, Danielle Dekker, Jessica Pritchard, Aleksandar B Kirov, Sanne M van Neerven, Sabine Tejpar, Geert J P L Kops, Owen J Sansom, Jan Paul Medema
Evasion of apoptosis is a hallmark of cancer, which is frequently mediated by upregulation of the antiapoptotic BCL-2 family proteins. In colorectal cancer (CRC), previous work has highlighted differential antiapoptotic protein dependencies determined by the stage of the disease. While intestinal stem cells (ISCs) require BCL-2 for adenoma outgrowth and survival during transformation, ISC-specific MCL1 deletion results in disturbed intestinal homeostasis, eventually contributing to tumorigenesis. Colon cancer stem cells (CSCs), however, no longer require BCL-2 and depend mainly on BCL-XL for their survival...
December 2021: Cell Death and Differentiation
#6
JOURNAL ARTICLE
Joshua D G Leach, Nikola Vlahov, Petros Tsantoulis, Rachel A Ridgway, Dustin J Flanagan, Kathryn Gilroy, Nathalie Sphyris, Ester G Vázquez, David F Vincent, William J Faller, Michael C Hodder, Alexander Raven, Sigrid Fey, Arafath K Najumudeen, Douglas Strathdee, Colin Nixon, Mark Hughes, William Clark, Robin Shaw, Sander R van Hooff, David J Huels, Jan Paul Medema, Simon T Barry, Margaret C Frame, Asier Unciti-Broceta, Simon J Leedham, Gareth J Inman, Rene Jackstadt, Barry J Thompson, Andrew D Campbell, Sabine Tejpar, Owen J Sansom
Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+ ) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature...
June 8, 2021: Nature Communications
#7
RANDOMIZED CONTROLLED TRIAL
Britt B S L Houwen, Yark Hazewinkel, María Pellisé, Liseth Rivero-Sánchez, Francesc Balaguer, Raf Bisschops, Sabine Tejpar, Alessandro Repici, D Ramsoekh, Maarten A J M Jacobs, Ramon-Michel M Schreuder, Michal Filip Kaminski, Maria Rupinska, Pradeep Bhandari, Martijn G H van Oijen, Lianne Koens, Barbara A J Bastiaansen, Kristien M Tytgat, Paul Fockens, Jasper L A Vleugels, E Dekker
OBJECTIVE: Despite regular colonoscopy surveillance, colorectal cancers still occur in patients with Lynch syndrome. Thus, detection of all relevant precancerous lesions remains very important. The present study investigates Linked Colour imaging (LCI), an image-enhancing technique, as compared with high-definition white light endoscopy (HD-WLE) for the detection of polyps in this patient group. DESIGN: This prospective, randomised controlled trial was performed by 22 experienced endoscopists from eight centres in six countries...
March 2022: Gut
#8
JOURNAL ARTICLE
Sarah McCuaig, David Barras, Elizabeth H Mann, Matthias Friedrich, Samuel J Bullers, Alina Janney, Lucy C Garner, Enric Domingo, Viktor Hendrik Koelzer, Mauro Delorenzi, Sabine Tejpar, Timothy S Maughan, Nathaniel R West, Fiona Powrie
PURPOSE: The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression. EXPERIMENTAL DESIGN: Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N = 566) and verification (PETACC3 clinical trial, N = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes IL22RA1 and IL10RB ), tumor mutation status, and clinical outcome using Cox proportional hazard models...
August 15, 2020: Clinical Cancer Research
#9
JOURNAL ARTICLE
J F Seligmann, F Elliott, S Richman, G Hemmings, S Brown, B Jacobs, C Williams, S Tejpar, J H Barrett, P Quirke, M Seymour
BACKGROUND: Primary tumour location (PTL) is being adopted by clinicians to guide treatment decisions in metastatic colorectal cancer (mCRC). Here we test PTL as a predictive marker for panitumumab efficacy, and examine its relationship with an extended biomarker profile. We also examine rectal tumours as a separate location. PATIENTS AND METHODS: mCRC patients from the second-line PICCOLO trial of irinotecan versus irinotecan/panitumumab (IrPan). PTL was classified as right-PTL, left-PTL or rectal-PTL...
August 2020: Annals of Oncology: Official Journal of the European Society for Medical Oncology
#10
JOURNAL ARTICLE
Markus Germann, Nadine Zangger, Marc-Olivier Sauvain, Christine Sempoux, Amber D Bowler, Pratyaksha Wirapati, Lana E Kandalaft, Mauro Delorenzi, Sabine Tejpar, George Coukos, Freddy Radtke
High T-cell infiltration in colorectal cancer (CRC) correlates with a favorable disease outcome and immunotherapy response. This, however, is only observed in a small subset of CRC patients. A better understanding of the factors influencing tumor T-cell responses in CRC could inspire novel therapeutic approaches to achieve broader immunotherapy responsiveness. Here, we investigated T cell-suppressive properties of different myeloid cell types in an inducible colon tumor mouse model. The most potent inhibitors of T-cell activity were tumor-infiltrating neutrophils...
January 9, 2020: EMBO Molecular Medicine
#11
JOURNAL ARTICLE
Oghenekevwe M Gbenedio, Caroline Bonnans, Delphine Grun, Chih-Yang Wang, Ace J Hatch, Michelle R Mahoney, David Barras, Mary Matli, Yi Miao, K Christopher Garcia, Sabine Tejpar, Mauro Delorenzi, Alan P Venook, Andrew B Nixon, Robert S Warren, Jeroen P Roose, Philippe Depeille
Colorectal cancer (CRC) is the third most frequent neoplastic disorder and is a main cause of tumor-related mortality as many patients progress to stage IV metastatic CRC. Standard care consists of combination chemotherapy (FOLFIRI or FOLFOX). Patients with WT KRAS typing are eligible to receive anti-EGFR therapy combined with chemotherapy. Unfortunately, predicting efficacy of CRC anti-EGFR therapy has remained challenging. Here we uncover that the EGFR-pathway component RasGRP1 acts as CRC tumor suppressor in the context of aberrant Wnt signaling...
June 25, 2019: JCI Insight
#12
JOURNAL ARTICLE
Tamsin R M Lannagan, Young K Lee, Tongtong Wang, Jatin Roper, Mark L Bettington, Lochlan Fennell, Laura Vrbanac, Lisa Jonavicius, Roshini Somashekar, Krystyna Gieniec, Miao Yang, Jia Q Ng, Nobumi Suzuki, Mari Ichinose, Josephine A Wright, Hiroki Kobayashi, Tracey L Putoczki, Yoku Hayakawa, Simon J Leedham, Helen E Abud, Ömer H Yilmaz, Julie Marker, Sonja Klebe, Pratyaksha Wirapati, Siddhartha Mukherjee, Sabine Tejpar, Barbara A Leggett, Vicki L J Whitehall, Daniel L Worthley, Susan L Woods
OBJECTIVE: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumours that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen-activated kinase pathway gene, BRAF , and epigenetic modifications termed the CpG Island Methylator Phenotype, leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein...
April 2019: Gut
#13
JOURNAL ARTICLE
Philip D Dunne, Helen G Coleman, Peter Bankhead, Matthew Alderdice, Ronan T Gray, Stephen McQuaid, Victoria Bingham, Maurice B Loughrey, Jacqueline A James, Amy M B McCorry, Alan Gilmore, Caitriona Holohan, Dirk Klingbiel, Sabine Tejpar, Patrick G Johnston, Darragh G McArt, Federica Di Nicolantonio, Daniel B Longley, Mark Lawler
Purpose: BRAF mutation occurs in 8-15% of colon cancers (CC), and is associated with poor prognosis in metastatic disease. Compared to wild-type BRAF (BRAFWT) disease, stage II/III CC patients with BRAF mutant (BRAFMT) tumors have shorter overall survival after relapse; however, time-to-relapse is not significantly different. The aim of this investigation was to identify, and validate, novel predictors of relapse of stage II/III BRAFMT CC. Experimental design: We used gene expression data from a cohort of 460 patients (GSE39582) to perform a supervised classification analysis based on risk-of-relapse within BRAFMT stage II/III CC, to identify transcriptomic biomarkers associated with prognosis within this genotype...
March 2, 2018: Oncotarget
#14
JOURNAL ARTICLE
R Dienstmann, M J Mason, F A Sinicrope, A I Phipps, S Tejpar, A Nesbakken, S A Danielsen, A Sveen, D D Buchanan, M Clendenning, C Rosty, B Bot, S R Alberts, J Milburn Jessup, R A Lothe, M Delorenzi, P A Newcomb, D Sargent, J Guinney
Background: TNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation. Patients and methods: After imputation of missing at random data, a subset of patients accrued in phase 3 trials with adjuvant chemotherapy (n = 3016)-N0147 (NCT00079274) and PETACC3 (NCT00026273)-was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples (n = 1499), and also externally in different population cohorts of chemotherapy-treated (n = 949) or -untreated (n = 1080) CC patients, and an additional series without treatment annotation (n = 782)...
May 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
#15
JOURNAL ARTICLE
R Dienstmann, M J Mason, F A Sinicrope, A I Phipps, S Tejpar, A Nesbakken, S A Danielsen, A Sveen, D D Buchanan, M Clendenning, C Rosty, B Bot, S R Alberts, J Milburn Jessup, R A Lothe, M Delorenzi, P A Newcomb, D Sargent, J Guinney
No abstract text is available yet for this article.
February 9, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
#16
JOURNAL ARTICLE
Albert Bosch-Vilaró, Bart Jacobs, Valentina Pomella, Layka Abbasi Asbagh, Richard Kirkland, Joe Michel, Sharat Singh, Xinjun Liu, Phillip Kim, Gregory Weitsman, Paul R Barber, Borivoj Vojnovic, Tony Ng, Sabine Tejpar
The EGFR inhibitor cetuximab is approved for the treatment of colorectal cancer. However, both innate and acquired resistance mechanisms, including compensatory feedback loops, limit its efficacy. Nevertheless, the emergence of these feedback loops has remained largely unexplored to date. Here, we showed feedback upregulation of HER3 and induction of HER3 phosphorylation after cetuximab treatment in colon cancer cells. We also showed that this upregulation occurs, at least partly, through AKT inhibition. Together with this, we observed increased HER2:HER3 dimerization upon cetuximab treatment...
January 17, 2017: Oncotarget
#17
JOURNAL ARTICLE
Sabine Tejpar, Sebastian Stintzing, Fortunato Ciardiello, Josep Tabernero, Eric Van Cutsem, Frank Beier, Regina Esser, Heinz-Josef Lenz, Volker Heinemann
IMPORTANCE: Metastatic colorectal cancer (mCRC) is heterogeneous, and primary tumors arising from different regions of the colon are clinically and molecularly distinct. OBJECTIVE: To examine the prognostic and predictive value of primary tumor location in patients with RAS wild-type (wt) mCRC treated with first-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab in the Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial and FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer (FIRE-3) trial...
February 1, 2017: JAMA Oncology
#18
JOURNAL ARTICLE
Ida Kappel Buhl, Sarah Gerster, Mauro Delorenzi, Thomas Jensen, Peter Buhl Jensen, Fred Bosman, Sabine Tejpar, Arnaud Roth, Nils Brunner, Anker Hansen, Steen Knudsen
PURPOSE: This study evaluates whether gene signatures for chemosensitivity for irinotecan and 5-fluorouracil (5-FU) derived from in vitro grown cancer cell lines can predict clinical sensitivity to these drugs. METHODS: To test if an irinotecan signature and a SN-38 signature could identify patients who benefitted from the addition of irinotecan to 5-FU, we used gene expression profiles based on cell lines and clinical tumor material. These profiles were applied to expression data obtained from pretreatment formalin fixed paraffin embedded (FFPE) tumor tissue from 636 stage III colon cancer patients enrolled in the PETACC-3 prospective randomized clinical trial...
2016: PloS One
#19
JOURNAL ARTICLE
Loredana Vecchione, Valentina Gambino, Jonne Raaijmakers, Andreas Schlicker, Arianna Fumagalli, Mariangela Russo, Alberto Villanueva, Evelyne Beerling, Alice Bartolini, David G Mollevi, Nizar El-Murr, Marielle Chiron, Loreley Calvet, Céline Nicolazzi, Cécile Combeau, Christophe Henry, Iris M Simon, Sun Tian, Sjors in 't Veld, Giovanni D'ario, Sara Mainardi, Roderick L Beijersbergen, Cor Lieftink, Sabine Linn, Cornelia Rumpf-Kienzl, Mauro Delorenzi, Lodewyk Wessels, Ramon Salazar, Federica Di Nicolantonio, Alberto Bardelli, Jacco van Rheenen, René H Medema, Sabine Tejpar, René Bernards
BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells...
April 7, 2016: Cell
#20
JOURNAL ARTICLE
Pu Yan, Dirk Klingbiel, Zenia Saridaki, Paola Ceppa, Monica Curto, Thomas Alexander McKee, Arnaud Roth, Sabine Tejpar, Mauro Delorenzi, Fredrik T Bosman, Roberto Fiocca
PURPOSE: SMAD4 loss is associated with the development of metastases and poor prognosis. We evaluated expression of SMAD4 protein and its association with tumor characteristics, including biomarkers and outcome in terms of relapse-free survival and overall survival. EXPERIMENTAL DESIGN: We used 1,564 stage II/III colon cancer samples from PETACC-3 to evaluate SMAD4 expression by immunohistochemistry. SMAD4 protein expression was validated by assessing mRNA expression using available expression array data...
June 15, 2016: Clinical Cancer Research
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