Anti-thrombotics (antiplatelets and anticoagulants; ATs) have been identified as risk factors for upper gastrointestinal bleeding (UGIB). However few international studies have evaluated their effect on patient outcome. We aimed to assess the effects of AT use on outcome in patients with high-risk UGIB requiring endoscopic therapy.

Methods

Patients presenting with UGIB who required endoscopic therapy at eight centres (Scotland, England, USA, Canada, Denmark, Italy, Singapore & New Zealand) were prospectively included over 12 months. Data recorded included the full Rockall score (FRS); AT use (Aspirin, Adenosine Diphosphate Receptor Inhibitors (ADP-RI), Vitamin-K Antagonists (VKA), Low Molecular Weight Heparin (LMWH), Thrombin inhibitors and Factor Xa inhibitors); endoscopic findings; blood transfusion; interventional radiology; surgery; rebleeding; 30 day mortality and length of hospital stay.

Results

Out of 3154 patients, 619 required endotherapy (44% for ulcer bleeding and 21% for varices). 187 (30%) patients were on aspirin, 61 (11%) ADP-RI, 57 (9%) VKA, 8 (1%) LMWH, 7 (1%) factor Xa-inhibitor and 1 patient a thrombin-inhibitor. 63 (11%) patients were treated with >1 type of AT. Patients treated with ATs were older (p < 0.0001), had higher ASA-score (p = 0.001), lower haemoglobin (P = 0.04), higher FRS (p < 0.0001), more frequently had ischaemic heart disease (IHD; p < 0.001), less frequently had cirrhosis (P < 0.001), more frequently bled from ulcers (p < 0.001) but less frequently from varices (p < 0.001) compared with those not taking ATs. There were no differences in sex, systolic blood pressure, frequency of malignancies, need for surgery/embolisation or rebleeding rate. Patients taking ATs had lower mortality than those not taking these drugs: all cause (11/253 [4%] vs 37/315 [12%]; p = 0.006) and bleeding-related (3/253 [1%] vs 19/315 [6%]; p = 0.01). However, when excluding patients with liver cirrhosis (n = 151) there were no differences in mortality between groups.

Conclusion

Patients with UGIB who require endoscopic therapy whilst on ATs do not experience a higher rate of rebleeding or mortality compared with UGIB patients who do not use ATs. We observed excess mortality in patients not taking ATs, which is likely due to the high rates of cirrhosis (40%) and variceal bleeding (33%) in these patients. Further studies are needed to clarify the risk of adverse outcome following UGIB in patients taking novel ATs.

Disclosure of Interest

None Declared

Upper Gastrointestinal Bleeding

10.1136/gutjnl-2016-312388.17

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Supplementary Table 1 from AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer

Philip D. Dunne Darragh G. McArt Jaine K. Blayney Murugan Kalimutho Samanda Greer

PDF file - 133K, Clinicopathological features of the colorectal cancer patient cohort.

Table (database)

10.1158/1078-0432.22449098.v1

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Data from AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer

Philip D. Dunne Darragh G. McArt Jaine K. Blayney Murugan Kalimutho Samanda Greer

<div>AbstractPurpose: Despite the use of 5-fluorouracil (5-FU)–based adjuvant treatments, a large proportion of patients with high-risk stage II/III colorectal cancer will relapse. Thus, novel therapeutic strategies are needed for early-stage colorectal cancer. Residual micrometastatic disease from the primary tumor is a major cause of patient relapse.Experimental Design: To model colorectal cancer tumor cell invasion/metastasis, we have generated invasive (KRASMT/KRASWT/+chr3/p53-null) colorectal cancer cell subpopulations. Receptor tyrosine kinase (RTK) screens were used to identify novel proteins that underpin the migratory/invasive phenotype. Migration/invasion was assessed using the XCELLigence system. Tumors from patients with early-stage colorectal cancer (N = 336) were examined for AXL expression.Results: Invasive colorectal cancer cell subpopulations showed a transition from an epithelial-to-mesenchymal like phenotype with significant increases in migration, invasion, colony-forming ability, and an attenuation of EGF receptor (EGFR)/HER2 autocrine signaling. RTK arrays showed significant increases in AXL levels in all invasive sublines. Importantly, 5-FU treatment resulted in significantly increased migration and invasion, and targeting AXL using pharmacologic inhibition or RNA interference (RNAi) approaches suppressed basal and 5-FU–induced migration and invasion. Significantly, high AXL mRNA and protein expression were found to be associated with poor overall survival in early-stage colorectal cancer tissues.Conclusions: We have identified AXL as a poor prognostic marker and important mediator of cell migration/invasiveness in colorectal cancer. These findings provide support for the further investigation of AXL as a novel prognostic biomarker and therapeutic target in colorectal cancer, in particular in the adjuvant disease in which EGFR/VEGF–targeted therapies have failed. Clin Cancer Res; 20(1); 164–75. ©2013 AACR.</div>

10.1158/1078-0432.c.6521558

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Supplementary Figure 7 from AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer

Philip D. Dunne Darragh G. McArt Jaine K. Blayney Murugan Kalimutho Samanda Greer

PDF file - 94K, Sensitivity of parental and invasive CRC cells to chemotherapy and EGFR targeted therapies.

10.1158/1078-0432.22449107

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Supplementary figure S1 from EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer

Philip D. Dunne Sonali Dasgupta Jaine K. Blayney Darragh G. McArt Keara L. Redmond

EphA2 and EFNA1 expression levels in colorectal cancer cells.

EPH receptor A2

Expression (computer science)

10.1158/1078-0432.22461383

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Data from EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer

Philip D. Dunne Sonali Dasgupta Jaine K. Blayney Darragh G. McArt Keara L. Redmond

<div>AbstractPurpose: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.Experimental Design: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.Results: Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.Conclusions: These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. Clin Cancer Res; 22(1); 230–42. ©2015 AACR.</div>

EPH receptor A2

10.1158/1078-0432.c.6524777.v1

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Supplementary Table 2 from Stratification to Neoadjuvant Radiotherapy in Rectal Cancer by Regimen and Transcriptional Signatures

Umair Mahmood Andrew Blake Sanjay Rathee Leslie Samuel Graeme I. Murray

Supplementary Table 2

Regimen

Stratification (seeds)

Table (database)

Risk Stratification

10.1158/2767-9764.27016306

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

The Journal of Pathology (2018)

Matthew Alderdice Susan D. Richman Simon Gollins Peter Stewart Chris Hurt

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.

Stratification (seeds)

Risk Stratification

10.1002/path.5051

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Figure S7 from β-catenin drives butyrophilin-like molecule loss and γδ T-cell exclusion in colon cancer

Toshiyasu Suzuki Anna Kilbey Nuria Casa-Rodríguez Amy Lawlor Αναστασία Γεωργακοπούλου

Impact of Btnl1 and Btnl6 expression on Vgamma7+ cells and the tumor microenvironment

10.1158/2326-6066.27026732.v1

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Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Nature Communications (2021)

Joshua D.G. Leach Nikola Vlahov Petros Tsantoulis Rachel A. Ridgway Dustin J. Flanagan

Abstract 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. These features are recapitulated in human BRAF -mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.

ACVRL1

10.1038/s41467-021-23717-5

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