Background & Aims An association between gastric cancer and the rs2294008 (C>T) polymorphism in the prostate stem cell antigen (PSCA) gene has been reported for several Asian populations. We set out to determine whether such an association exists in Caucasians. Methods We genotyped 166 relatives of gastric cancer patients, including 43 H pylori-infected subjects with hypochlorhydria and gastric atrophy, 65 infected subjects without these abnormalities, 58 H pylori-negative relatives, and 100 population controls. Additionally, a population-based study of chronic atrophic gastritis provided 533 cases and 1054 controls. We then genotyped 2 population-based case-control studies of upper gastrointestinal cancer: the first included 312 gastric cancer cases and 383 controls; the second included 309 gastric cancer cases, 159 esophageal cancer cases, and 211 controls. Odds ratios were computed from logistic models and adjusted for confounding variables. Results Carriage of the risk allele (T) of rs2294008 in PSCA was associated with chronic atrophic gastritis (adjusted odds ratio [OR] = 1.5; 95% confidence interval [CI], 1.1–1.9) and non-cardia gastric cancer (OR = 1.9; 95% CI, 1.3– 2.8). The association was strongest for the diffuse histological-type (OR = 3.2; 95% CI, 1.2–10.7). An inverse association was observed between carriage of the risk allele and gastric cardia cancer (OR = 0.5; 95% CI, 0.3–0.9), esophageal adenocarcinoma (OR = 0.5; 95% CI, 0.3–0.9), and esophageal squamous cell carcinoma (OR = 0.4; 95% CI, 0.2–0.9). Conclusions The rs2294008 polymorphism in PSCA increases the risk of non-cardia gastric cancer and its precursors in Caucasians but protects against proximal cancers.

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Should patients undergoing cardiac surgery with atrial fibrillation (AF) have left atrial appendage (LAA) exclusion?' Altogether 310 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that despite finding five clinical trials including one randomised controlled trial, that studied around 1400 patients who underwent LAA occlusion, the results of these studies do not clearly show a benefit for appendage occlusion. Indeed of the five studies, only one showed a statistical benefit for LAA occlusion, with three giving neutral results and in fact one demonstrating a significantly increased risk. One reason for this may be the inability to achieve acceptably high rates of successful occlusion on echocardiography when attempting to perform this procedure. The highest success rate was only 93% but most studies reported only a 55-66% successful occlusion rate when attempting closure in a variety of methods including stapling, ligation and amputation. Currently, the evidence is insufficient to support LAA occlusion and may indeed cause harm especially if incomplete exclusion occurs.

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20–50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/−3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/−22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.