SummaryBackgroundOesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus.MethodsThe Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial had a 2 × 2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barrett's oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barrett's oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77.FindingsBetween March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2–9·8), and we collected 20 095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01–1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98–1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01–1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14–2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events.InterpretationHigh-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus.FundingCancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.

The immunocytochemical expression of cadherins and catenins was examined during the process of oral carcinogenesis by comparing their expression in normal and dysplastic epithelium with primary and metastatic carcinomas. While control epithelium showed normal distribution for P and E cadherin and the catenins, in severe dysplasia P‐cadherin was upregulated. In other cases and in carcinoma‐in‐situ adjacent to infiltrating carcinomas, membranous expression of the cadherins and catenins was reduced or lost. The changes in expression of E‐cadherin and the catenins suggest that disruption of the E‐cadherin/catenin complex is a late event associated with invasion. In primary carcinomas reduced membranous and cytoplasmic staining were observed for both cadherins and catenins. Abnormal localisation of E‐cadherin occurred in the more superficial parts of the better differentiated carcinomas, suggesting abnormality to the E‐cadherin complex(es). In contrast, membranous expression of cadherins and catenins was reduced or lost in the deep invasive margin of primary carcinomas and in most poorly differentiated carcinomas. For E‐cadherin at least, this reduction appears associated with differentiation, invasion and possibly prognosis. Possible mechanisms involved for changes in expression of the cadherins and associated catenins and areas for further study are discussed.

Esophageal and gastric cancers represent tumors with poor prognosis. Unfortunately, radiotherapy, chemotherapy, and targeted therapy have made only limited progress in recent years in improving the generally disappointing outcome. Immunotherapy with checkpoint inhibitors is a novel treatment approach that quickly entered clinical practice in malignant melanoma and renal cell cancer, but the role in esophageal and gastric cancer is still poorly defined. The principal prognostic/predictive biomarkers for immunotherapy efficacy currently considered are PD-L1 expression along with defects in mismatch repair genes resulting in microsatellite instability (MSI-H) phenotype. The new molecular classification of gastric cancer also takes these factors into consideration. Available reports regarding PD-1, PD-L1, PD-L2 expression and MSI status in gastric and esophageal cancer are reviewed to summarize the clinical prognostic and predictive role together with potential clinical implications. The most important recently published clinical trials evaluating checkpoint inhibitor efficacy in these tumors are also summarized.

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Research in Context Panel:Evidence before this study: Preclinical data, epidemiological studies, and meta-analyses of randomised data from cardiovascular trials support the hypothesis that aspirin could be an effective adjuvant cancer therapy (Langley R, et al. Br J Cancer 2011;105(8):1107-13; Algra AM et al. Lancet Oncol 2012;13(5):518-27 ). Globally, several phase III studies are ongoing to assess this, though debate continues about the safety profile of aspirin particularly after radical therapy for gastrointestinal malignancies.Added value of this study: The Add-Aspirin trial (encompassing 4 individually powered phase III studies in gastro-oesophageal, colorectal, prostate and breast cancer) is the largest of the ongoing trials and includes a pre-defined feasibility analysis to assess the acceptability of randomisation, tolerability and toxicity based on an open label run-in phase prior to double-blind randomisation. The data show that aspirin is well tolerated after radical cancer therapy, acceptable to patients, and there is no evidence to suggest there is increased toxicity in the gastro-oesophageal cohort over other tumour-specific cohorts.Implications of all the available evidence: Aspirin is a low cost generic drug with the potential to have a large impact on cancer outcomes globally. Outcomes from gastro-oesophageal cancer remain poor and there is an imperative to complete recruitment to the ongoing trials as quickly as possible. The rationale and supporting evidence for evaluating aspirin as a potential anti-cancer therapy remains strong. More generally, a run-in approach may be useful in adjuvant (or prevention) studies for reducing the risk of non-adherence and participant attrition at a later date. ABSTRACT Background: Pre-clinical, epidemiological and randomised data indicate aspirin prevents tumour development and metastases leading to reduced cancer mortality, particularly for gastro-oesophageal and colorectal cancer. Randomised trials evaluating aspirin use after primary radical therapy are ongoing. To address concerns about toxicity particularly bleeding after radical treatment for gastro-oesophageal cancer, a pre-planned feasibility analysis was incorporated into the ongoing Add-Aspirin trial. Method: The Add-Aspirin protocol includes 4 phase III randomised-controlled trials evaluating the effect of aspirin on recurrence/survival after radical therapy in 4 tumour cohorts: gastro-oesophageal (GO), colorectal (CRC), breast and prostate. An open-label run-in phase (aspirin 100mg daily for 8 weeks) precedes double-blind randomisation (1:1:1 aspirin 300mg: aspirin 100mg: matched placebo). A preplanned analysis of feasibility, including recruitment, adherence, and toxicity was performed. The trial is registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN74358648), and remains open to recruitment. Findings: After two years of recruitment (October 2015-October 2017), 3494 participants were registered on the trial (gastro-oesophageal 115, colorectal 950, breast...

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