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High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

Understanding the contribution of the host’s genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-β-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions. We are grateful to the Society for Immunotherapy of Cancer (SITC) for the logistical support of the investigator meeting within the SITC Cancer Immune Responsiveness Workshop (San Francisco CA, US, April 2018; Houston, TX, US, May 2019). We are also grateful to Noah Zaitlen and Andy Dahl for useful discussions on heritability interaction analyses. This work was funded in part by the National Institutes of Health R01CA227466 and K24CA169004 to EZ and T32CA221709 postdoctoral fellowship to RWS, Qatar National Research Fund (QNRF) NPRP11S-0121-180351 grant and the Sidra Precision Medicine Program internal grant (SDR100035 and SDR400023) to DB, Associazione Italiana per la Ricerca sul cancro (AIRC) grant IG2018-21846 to MC, the Cancer Research Institute funding to VT, and the Fundació Bancaria La Caixa, a La Caixa Junior Leader Fellowship (LCF/BQ/PI18/11630003) to EP-P.

BACKGROUND: Treatment options for achalasia include endoscopic and surgical techniques that carry the risk of esophageal bleeding and perforation. The rare coexistence of esophageal varices has only been anecdotally described and treatment is presumed to carry additional risk. METHODS: Experience from physicians/surgeons treating this rare combination of disorders was sought through the International Manometry Working Group. RESULTS: Fourteen patients with achalasia and varices from seven international centers were collected (mean age 61 ± 9 years). Five patients were treated with botulinum toxin injections (BTI), four had dilation, three received peroral endoscopic myotomy (POEM), one had POEM then dilation, and one patient underwent BTI followed by Heller's myotomy. Variceal eradication preceded achalasia treatment in three patients. All patients experienced a significant symptomatic improvement (median Eckardt score 7 vs 1; p

Background Advances in clinical measurement of esophageal motility and function have improved the assessment of swallowing disorders and reflux symptoms. Variation in data acquisition, analysis, and reporting exists and impacts on diagnosis and management. Aims and Methods This study examined variation in esophageal manometry methodology between institutions to establish the status in current practice. A structured survey was distributed through international NGM societies using an Internet-based platform. Questions explored infrastructure, technology, analysis, and reporting. Key Results Responses were received from 91 centers from 29 countries. Eighteen (20%) centers used “conventional” manometry, 75 (82%) high-resolution manometry, and 53 (58%) HR impedance manometry. All centers documented motility for single water swallows. The Chicago Classification was applied by 65 (71.4%) centers. In contrast, analysis of EGJ morphology varied widely. Adjunctive testing was often applied: multiple rapid swallows (77%), rapid drink challenge (77%), single solid swallows (63%), and a standard test meal (18%). Of 86 (94.5%) units that offered pH impedance (pH-Z) studies, approximately half (53.5%) performed tests on acid-suppressant medication in patients with a high pretest probability (eg, erosive esophagitis). Most (75.6%) centers manually reviewed every reflux event. Others examined pH-Z data only prior to symptoms. To assess symptom association with reflux events, 73.6% centers analyzed each symptom separately, whereas 29.7% centers pooled symptoms. Conclusions and Inferences There is marked variation in the data acquisition, analysis, and reporting of esophageal manometry studies. Further efforts to improve quality and uniformity in testing and reporting are required. This survey provides information upon which best-practice guidelines can be developed.