No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study.

BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.

BACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10-8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. FINDINGS: Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10-10), MSRA (rs17749155; p=5·2 × 10-10), LINC00208 and BLK (rs10108511; p=2·1 × 10-9), KHDRBS2 (rs62423175; p=3·0 × 10-9), TPPP and CEP72 (rs9918259; p=3·2 × 10-9), TMOD1 (rs7852462; p=1·5 × 10-8), SATB2 (rs139606545; p=2·0 × 10-8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10-8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10-8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10-6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. INTERPRETATION: Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. FUNDING: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council

Analysis of failed rotator cuff repair – Retrospective survey of revisions after open rotator cuff repair

Background Rotator cuff defects are frequently occurring shoulder pathologies associated with pain and movement impairment. Aims The aim of the study was to analyse the pathologies that lead to operative revisions after primary open rotator cuff repair. Methods In 216 patients who underwent primary rotator cuff repair and later required operative revision between 1996 to 2005, pathologies found intraoperatively during the primary operation and during revision surgery were collected, analysed and compared. Results The average age at the time of revision surgery was 54.3 years. The right shoulder (61.6 per cent) was more often affected than the left, males (63.4 per cent) more often than females. At primary operation – apart from rotator cuff repair – there were the following surgical procedures performed: 190 acromioplasty, 86 Acromiclavicular joint resections, 68 tenodesis, 40 adhesiolysis and 1 tenotomy. If an ACJ-resection had been performed in the primary operation, ACJ-problems were rare in revision surgery (p<0.01). Primary gleno-humeral adhesions were associated with a significant rise in re-tearing rate (p=0.049). Primary absence of adhesions went along with a significant lower rate of adhesions found at revision (p=0.018). Primary performed acromioplasty had no influence on re-tearing rate (p=0.408) or on the rate of subacromial impingement at revision surgery (p=0.709). Conclusion To avoid operative revision after rotator cuff repair relevant copathologies of the shoulder have to be identified before or during operation and treated accordingly. Therefore, even during open rotator cuff repair, the surgeon should initially start with arthroscopy of the shoulder joint and subacromial space to recognise co-pathologies

The prognostic impact of sex on surgically resected non-small cell lung cancer depends on clinicopathologic characteristics

The increasing incidence of lung cancer in women and their supposed survival advantage over men requires clarification of the significance of sex. Age, stage, histologic features, differentiation grade, and Ki-67 index were assessed in 405 surgically resected non-small cell lung cancers (NSCLCs) using a standardized tissue microarray platform. Women were associated with well/moderate tumor differentiation, a Ki-67 index of 3% or less, and adenocarcinoma histologic features. Female sex predicted increased survival time only by univariate analysis. Stratified by sex, increased survival was noted for women older than 64 years, with a tumor at postsurgical International Union Against Cancer stage I, with adenocarcinoma histologic features, with well- or moderately differentiated tumors, or with a Ki-67 index of 3% or less. Sex is not an independent prognostic parameter for patients with surgically resected NSCLC. Sex-linked differences are associated with other factors, thus simulating a prognostic impact of sex. This study elucidates sex-specific interactions between patient and tumor characteristics, which are pivotal toward improving prognostic accuracy, individualized therapies, and screening efforts

A comprehensive analysis of p16 expression, gene status, and promoter hypermethylation in surgically resected non-small cell lung carcinomas

The role of p16 is gaining importance in non-small cell lung cancer (NSCLC) because of epigenetic therapy options. Further insight into the significance of protein expression, gene status and promoter methylation is needed and has the potential to optimize existing treatment strategies

Helicobacter Infection and Gastric Adenoma

Background: We aimed to provide insight into the actual frequencies of gastric adenoma types and their association with gastritis status and associated mucosal changes with a focus on Helicobacter infection and the operative link on gastritis assessment (OLGA)/operative link on gastric intestinal metaplasia assessment (OLGIM) staging. Methods: From the archive of the Institute of Pathology in Bayreuth, we collected a consecutive series of 1058 gastric adenomas diagnosed between 1987 and 2017. Clinicopathological parameters retrieved from diagnostic reports included adenoma type and localization, associated mucosal changes in antrum and corpus (i.e., type of gastritis, the extent of intestinal metaplasia and atrophy), gender, date of birth, and date of diagnosis. Results: Intestinal-type adenoma was the most frequent adenoma (89.1%), followed by foveolar-type adenoma (4.3%), pyloric gland adenoma (3.4%), adenomas associated with hereditary tumor syndromes (2.8%), and oxyntic gland adenoma (0.4%). Adenomas were found in the background of Helicobacter pylori (H. pylori) gastritis in 23.9%, Ex-H. pylori gastritis in 36.0%, autoimmune gastritis in 24.8%, chemical reactive gastritis in 7.4%, and others in 0.1%. More than 70% of patients with gastric adenomas had low-risk stages in OLGA and OLGIM. Conclusions: We found a higher frequency of foveolar-type adenoma than anticipated from the literature. It needs to be questioned whether OLGA/OLGIM staging can be applied to all patients