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.

A 50-year-old man, with a known weekly alcohol intake of almost 100 units, presented to his GP feeling drowsy. Routine blood tests revealed a profound hyponatraemia of 100 mmol/litre, and he was referred to hospital for investigations. On admission he was drowsy, but had a Glasgow Coma Scale score of 15, an abbreviated mental test score of 10/10 and an entirely normal neurological examination. Liver function tests were consistent with excessive alcohol consumption. He had been prescribed bendroflumethazide and clomipramine (a tricyclic antidepressant) by his GP. In view of their potential tocause hyponatraemia these were subsequently withheld and he was fluid restricted to 1.5 litres per day. His sodium level rose gradually and on day 5 of admission it had increased to 122 mmol/litre. He was discharged on day 8 having been advised to stop drinking. Less than a week after discharge he represented to his GP with symptoms of excessive sweating, shaking, constipation, disorientation and dysarthria. He was febrile at 38.6°C , and had a blood pressure of 180/90 mmHg. Electrolytes were normal (Na+ 135 mmol/litre). Although he denied consuming any alcohol since his initial admission, his symptoms were consistent with acute alcohol withdrawal and he was treated accordingly. He failed to improve on two attempts at reducing doses of chlordiazepoxide. His dysarthria progressed until his speech was difficult to understand and his swallow became unsafe. He continued to spike temperatures throughout the admission and although a catheter specimen of urine was positive for enterococcus, treatment with a prolonged course of antibiotics had not resolved his fever. A computed tomography scan of his head and a lumbar puncture were performed. Other than cortical atrophy in keeping with alcohol abuse, neither investigation provided any answers. It was considered that his symptoms could be explained by autonomic dysfunction. In view of his corrected hyponatraemia, central pontine myelinolysis was suggested and a magnetic resonance imaging head scan was performed (Figure 1). This confirmed the presence of central hyperintensity on the water sensitive sequences within the central pons, in keeping with an osmotic demyelination syndrome. Additionally these changes were identified within the caudate nuclei, possibly accounting for the patient's inability to fully control voluntary movement. The ongoing temperatures without sepsis suggested hypothalamic involvement. Following diagnosis this patient failed to improve. Treatment became supportive, and he died 7 weeks later.

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oesophagitis delayed treatment in 12.1% and hiatus hernia repair surgery was required in 1.3% of patients. Stricture rates were 5.4% requiring a median of 2 (IQR:6) dilatations and bleeding requiring hospital admission was 0.45%. RFA failed or was abandoned in 6.3% of patients. Metachronous lesions development during RFA treatment phase warranting further therapy in 14.9% patients: BO (2.7%) LGD (0.9%) HGD (5%) and IMC (6.3%). Metachronous lesions and BO developed after CRIM in 5% requiring further therapy and 0.9% developed invasive cancer. Median follow up post CRD/CRIM was 20.1 (±28.9) months. The survival rate over the 10-year study period was 94.6% with the majority of deaths due to unrelated disease. Conclusions This 10-year data demonstrates that RFA therapy is effective in achieving eradication of BO and dysplasia with a favourable safety profile.