A phase II study of perioperative pembrolizumab plus mFOLFOX in patients with potentially resectable esophagus, gastroesophageal junction (GEJ), and stomach adenocarcinoma.

BACKGROUND: Perioperative chemotherapy/chemoradiation is standard in esophageal/gastric/gastroesophageal junction (GEJ) adenocarcinoma, immune checkpoint inhibitors (ICI) effect in setting of metastatic and postoperatively. This study is to assess ICI + chemotherapy perioperatively. METHODS: Patients with locally advanced (T1N1-3M0 or T2-3NanyM0) potentially resectable esophageal/gastric/GEJ adenocarcinoma by PET/EUS/CT and staging-laparoscopy, were treated preoperative 4 cycles mFOLFOX6 (Oxaliplatin 85 mg/m2 /Leucovorin 400 mg/m2 /5-FU bolus 400 mg/m2 then infusion 2400 mg/m2 for 46 h q2weeks) and 3 cycles pembrolizumab (200 mg q3week). Those without distal disease post-neoadjuvant and eligible for resection underwent surgery. Postoperative treatment was initiated at 4-8 weeks with 4 cycles mFOLFOX and 12 cycles pembrolizumab. The primary objective is pathological response (ypRR with tumor regression score, TRS ≤2). The expression of ICI-related markers PD-L1 (CPS), CD8, and CD20 were analyzed before and after preoperative therapy. RESULTS: Thirty-seven patients completed the preoperative treatment. Twenty-nine patients had curative R0 resection. 6/29 (21%; 95% CI: 0.08-0.40) achieved ypCR with TRS 0 in resected patients. 26/29 (90%; 95% CI: 0.73-0.98) had ypRR with TRS ≤2. Twenty-six patients finished adjuvant therapy with a median 36.3-month follow-up. Three patients had recurrence/metastatic disease (at 9-, 10-, 22 months enrollment) with one dead at 23 months, and two are still alive at 28 and 36.5 months. The remaining (23/26) are free of disease with 3 years DFS of 88.5% and 3 years OS of 92.3%. There were no unexpected toxicities. Preoperative ICI + chemotherapy enhanced immune responses significantly with increasing expression of PD-L1 (CPS ≥10, p = 0.0078) and CD8 (>5%, p = 0.0059). CONCLUSIONS: The perioperative pembrolizumab and mFOLFOX combination in resectable esophageal/gastric/GEJ adenocarcinoma is very effective with 90% ypRR, 21% ypCR, and impressive long-time survival benefits.

Predictive Model for Positive Video Capsule Endoscopy in Iron Deficiency Anemia.

BACKGROUND AND AIMS: Bleeding from the gastrointestinal tract can contribute to the development of iron deficiency anemia (IDA) among individuals without another obvious source of bleeding. In order to identify patients most likely to benefit from examination of the small bowel, our aim was to create a risk score for positive video capsule endoscopy (VCE) in IDA utilizing a multicenter collection of studies. METHODS: We performed a retrospective multicenter study utilizing VCE studies performed for an indication of IDA between 1/1/2005 and 7/31/2018. VCE findings were graded based on the P0-P2 grading system. The primary outcome of interest was a positive (P2) VCE. Data were analyzed with Student's t test for continuous variables and the Fisher's exact test for categorical variables. Logistic regression was used to identify independent associations with positive VCE. RESULTS: In total, 765 VCE procedures were included with 355 (46.5%) male subjects and a median age of 63.2 (SD 15.3) years. One hundred ninety studies (24.8%) were positive (P2) for small bowel bleeding. Four variables associated with positive VCE which were incorporated into a point scoring system: (+) 1 for age ≥ 66 years, active smoking and cardiac arrythmia and (-) 1 for preceding hemoglobin level ≥ 8.5. The risk probabilities for positive VCE-assigned scores - 1, 0, 1, and 2 + were 12.3% (95% CI 7.3-17.3%), 20% (14.9-25.1%), 34.8% (28.6-41%), and 39% (30-47.8%). CONCLUSION: In order to improve the diagnostic yield of capsule examinations, risk factors should be applied to clinical decision-making. We created a risk score for positive VCE in IDA, including the risk factors of age, smoking, history of cardiac arrythmia, and preceding hemoglobin level.

Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity. METHODS: We performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes. RESULTS: Prior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed 'futile cycling' of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity. CONCLUSIONS: APAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication. LAY SUMMARY: Only one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine.

Refined pancreatobiliary UroVysion criteria and an approach for further optimization.

Pancreatobiliary strictures are a common source of false negatives for malignancy detection. UroVysion is more sensitive than any other method but remains underutilized because of conflicting sensitivities and specificities due to a lack of standardized cutoff criteria and confusion in interpreting results in the context of primary sclerosing cholangitis. We set out to determine the sensitivities and specificities of UroVysion, brushing cytology, forceps biopsies, and fine needle aspiration (FNAs) for pancreatobiliary stricture malignancy detection. A retrospective review was performed of all biopsied pancreatobiliary strictures at our institution over 5 years. UroVysion was unquestionably the most sensitive method and all methods were highly specific. Sensitivity was highest while maintaining specificity when a malignant interpretation was limited to cases with 5+ cells with the same polysomic signal pattern and/or loss of one or both 9p21 signals. Only UroVysion detected the metastases and a neuroendocrine tumor. In reviewing and analyzing the signal patterns, we noticed trends according to location and diagnosis. Herein we describe our method for analyzing signal patterns and propose cutoff criteria based upon observations gleaned from such analysis.

Impact of feedback on adenoma detection rate: a systematic review and meta-analysis.

BACKGROUND: Adenoma detection rate (ADR) is one of the most important quality indicators of colonoscopy. Monitoring endoscopists and providing feedback has shown to improve ADR. We performed a systematic review of the literature and meta-analysis to determine the effect of any form of feedback on ADR. METHODS: A literature search for comparative studies that employed any form of feedback to assess the impact on ADR before and after the feedback was done on MEDLINE, EMBASE, and Cochrane Database. The primary outcome of interest was ADR. Secondary outcomes included polyp detection rate, advanced adenoma detection rate, sessile serrated adenoma detection rate, withdrawal time, and cecal intubation rate. Cochrane Revman 5.3 software was used for statistical analysis. RESULTS: A total of 12 studies met the inclusion criteria for the analysis of primary outcomes. There were 78,355 subjects (45.42% male) with a mean age of 59.52 years. There was a significant improvement in ADR after any form of feedback compared to no feedback: 36.18% vs. 26.75%; pooled odds ratio 1.51, 95% confidence interval 1.37-1.66; P<0.001. There was a substantial heterogeneity (I2=82%). ADR improved in both active or passive feedback, irrespective of whether endoscopists knew about being monitored for their performance or not. CONCLUSIONS: Monitoring and providing feedback to endoscopists in any form leads to improvement in ADR. Feedback is an easy and effective way of improving the ADR of endoscopists, especially in those not achieving the recommended benchmarks.

Effect of dynamic position changes on adenoma detection rate during colonoscope withdrawal: systematic review and meta-analysis.

Background and study aims The adenoma detection rate (ADR) is an important quality metric of colonoscopy. Higher ADR correlates with lower incidence of interval colorectal cancer. ADR is variable between endoscopists and depends upon the withdrawal technique amongst other factors. Dynamic position change (lateral rotation of patients with a view to keep the portion of the colon being inspected at a higher level) helps with luminal distension during the withdrawal phase. However, impact of this on ADR is not known in a pooled sample. We performed a systematic review and meta-analysis to study the impact of dynamic position changes during withdrawal phase of colonoscopy on ADR Methods A comprehensive search of MEDLINE, EMBASE, Google Scholar, and the Cochrane Database was conducted from each database's inception to search for studies comparing dynamic position changes during colonoscope withdrawal with static left lateral position (control). The primary outcome of interest was ADR. Other studied outcomes were polyp detection rate (PDR) and withdrawal time. Outcomes were reported as pooled odds ratio (OR) with 95 % confidence intervals (CI) with statistical significance ( P  < 0.05). RevMan 5.3 software was used for statistical analysis. Results Six studies were included in our analysis with 2860 patients. Of these, dynamic position change was implemented in 1177 patients while 1183 patients served as the controls. ADR was significantly higher in the dynamic position change group with pooled OR 1.36 (95 % CI, 1.15-1.61; P  < 0.01). There was low heterogeneity in inclusion studies (I 2  = 0 %). PDR was numerically higher in position change group (53.4 % vs 49.6 %) but not statistically significant ( P  = 0.16). Mean withdrawal time did not significantly change with dynamic position change (12.43 min vs 11.46 min, P  = 0.27). Conclusion Position change during the withdrawal phase of colonoscopy can increase the ADR compared to static left lateral position. This is an easy and practical technique that can be implemented to improve ADR.

The utility of immunohistochemical testing for mismatch repair proteins in fine needle aspiration specimens of pancreatic adenocarcinoma.

INTRODUCTION: Microsatellite instability (MSI) testing is recommended for all colonic and endometrial carcinomas to screen for Lynch syndrome. The role of MSI testing in pancreatic adenocarcinoma has not been well-established. Screening can be done via immunohistochemical (IHC) staining for mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2). We report our experience and the clinical utility of MMR IHC on pancreatic adenocarcinomas in fine-needle aspiration (FNA) specimens. MATERIALS AND METHODS: We performed a retrospective review to identify all patients diagnosed with pancreatic adenocarcinoma by FNA at our institution between December 2017 and September 2019. For cases with sufficient tumor cells for testing, the MMR results and morphology were summarized, as well as corresponding clinical information, including age, clinical stage, treatment, and concurrent other cancers. RESULTS: From December 2017 to September 2019, there were a total of 184 pancreatic FNAs with a diagnosis of adenocarcinoma. Of these 184 FNAs, 65 (35%) contained sufficient material in the cell block to perform IHC for MMR. The cell block material was collected in either RPMI or CytoLyt. Poor technical quality precluded interpretation of PMS2 in 4 cases and MSH6 in 2 cases. All other cases showed intact expression of all four proteins. CONCLUSIONS: IHC for MMR proteins can be done on specimens collected in RPMI or CytoLyt, but RPMI appears to be more reliable. None of the pancreatic adenocarcinomas in this study showed loss of MMR protein expression. Routine testing of MMR loss may not be indicated in pancreatic adenocarcinomas in the general patient population.

Preoperative Screening of Colorectal Cancers Is As Accurate As Postoperative Screening for Detection of Lynch Syndrome.

Lynch syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome with lifetime CRC risks of up to 70%.1 Conventionally, CRC specimens are screened for LS postoperatively but preoperative diagnosis of LS could impact decisions, such as the extent of resection and the need for additional risk-reducing surgeries for uterine and ovarian cancers. Few studies have addressed this issue2-5 and surveys indicate that most gastroenterologists are unsure that LS can be screened for preoperatively.6 We compared the yield of preoperative versus postoperative screening of LS by immunohistochemistry (IHC) and microsatellite instability (MSI) in unselected patients with newly diagnosed CRC who underwent testing under real-life laboratory conditions to mimic clinical practice.

Early Readmissions after Esophagectomy for Esophageal Adenocarcinoma: Does Facility Case-Volume Matter?

Increased esophagectomy procedures over the past four decades have correlated with the rise in incidence of esophageal adenocarcinoma. Despite advances in technology and procedural expertise, esophagectomy remains a high-risk surgical procedure. Higher volume facilities have more experience with esophagectomy and would be expected to have a lower incidence of surgical complications and attendant morbidity and mortality. By analyzing information from a nationwide United States hospital database, we sought to find out if there is a significant difference between facilities stratified by case volume, with regards to 30-day readmission after esophagectomy. The findings of this study indicated that even with a large applied differential, early readmissions did not differ significantly between high- and low-volume centers. Also, analyzed and discussed were any associated demographic and comorbidity factors as they relate to early readmissions after esophagectomy for esophageal adenocarcinoma across the country. This is the first study to specifically address these variables.

Early vs Late Use of Anti-TNFa Therapy in Adult Patients With Crohn Disease: A Systematic Review and Meta-Analysis.

OBJECTIVES: While anti-tumor necrosis factor alpha (anti-TNFa) therapies for Crohn disease (CD) were initially introduced in 1998 for biologic therapies are often introduced after a minimum of 6 years after diagnosis. The benefit of anti-TNFa early in the course of CD is still controversial, with some studies showing better outcomes but others not. To determine whether earlier introduction of anti-TNFa therapy improves efficacy in clinical trials or clinical series, we aimed to perform a meta-analysis comparing early vs late anti-TNFa use in the management of CD. METHODS: A comprehensive search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus was conducted from each database's inception to November 3, 2019. We included comparative studies of early vs late use of anti-TNFa therapy in adult patients with CD. RESULTS: Eleven studies were included in the analysis, with a total of 2501 patients. Meta-analysis demonstrated that the early use of anti-TNFa was associated with a statistically significant decrease in the need for surgery (relative risk [RR] = 0.43; 95% confidence interval [CI], 0.26-0.69; I2 = 68%) and disease progression (RR = 0.51; 95% CI, 0.35-0.75; I2 = 61%). Early use also showed an increase in early remission (RR = 1.94; 95% CI, 1.54-2.46; I2 = 0%) and clinical response. There was no statistically significant difference in achieving late remission (RR = 1.39; 95% CI, 0.94-2.05; I2 = 65%) or mucosal healing (RR = 1.10; 95% CI, 0.63-1.91; I2 = 0%). CONCLUSION: This systematic review suggests that using anti-TNFa earlier in the treatment of CD (within 3 years) may improve clinical outcomes compared to late administration in terms of achieving early clinical remission, clinical response, disease progression, and the need for surgery.

Outcome, complication and follow-up of patients with esophageal foreign body impaction: an academic institute's 15 years of experience.

Esophageal foreign body impaction (EFBI) is a gastrointestinal emergency, mostly requiring endoscopic management. The aim of this study is to evaluate the epidemiology, adverse events, and outcomes of patients following the episode of EFBI. All esophagogastroduodenoscopy (EGD) reports of admitted patients for EFBI at the University of Kansas Medical Center between 2003 and 2018 were retrospectively reviewed. Of 204 patients, who met the inclusion criteria, 60% were male and the mean age was 54.7 ± 17.7 years. The encounter was the first episode of EFBI in 76% of cases. EGD in less than 24 hours of patients' admission was required in 79% of cases. The distal esophagus was the most common site of impaction (44%). Push and pull techniques were used in 38 and 35.2% of cases, respectively, while 11% were managed by a combination of both techniques. Structural causes were the most common etiologic findings including benign strictures and stenosis in 21.5% of patients, followed by Schatzki's ring (7.8%) and hiatal hernia (6.9%). Of all cases, 45% did follow-up in up to 1 year, and biopsy was done in 34% of cases. Out of 43 patients who had endoscopic findings suspicious for eosinophilic esophagitis (EoE), the diagnosis was confirmed by pathology in 37. The rate of recurrence EFBI was significantly higher in patients with EoE (P < 0.001). EFBI-related esophageal adverse events (AEs) occurred in 4.9% of cases. Cardiovascular and pulmonary AEs occurred in 1.5 and 2.9%, respectively. Logistic regression did not find any predictor for AEs occurrence. EFBI managed very well with endoscopic treatments. Despite the emerging data about the safety of the push technique, there are still concerns regarding its adverse events especially the risk of perforations. Our study shows no significant difference in adverse events between different types of techniques.

Direct Amplification of Tissue Factor:Factor VIIa Procoagulant Activity by Bile Acids Drives Intrahepatic Coagulation.

OBJECTIVE: Regulation of TF (tissue factor):FVIIa (coagulation factor VIIa) complex procoagulant activity is especially critical in tissues where plasma can contact TF-expressing cells. One example is the liver, where hepatocytes are routinely exposed to plasma because of the fenestrated sinusoidal endothelium. Although liver-associated TF contributes to coagulation, the mechanisms controlling the TF:FVIIa complex activity in this tissue are not known. Approach and Results: Common bile duct ligation in mice triggered rapid hepatocyte TF-dependent intrahepatic coagulation coincident with increased plasma bile acids, which occurred at a time before observable liver damage. Similarly, plasma TAT (thrombin-antithrombin) levels increased in cholestatic patients without concurrent hepatocellular injury. Pathologically relevant concentrations of the bile acid glycochenodeoxycholic acid rapidly increased hepatocyte TF-dependent procoagulant activity in vitro, independent of de novo TF synthesis and necrotic or apoptotic cell death. Glycochenodeoxycholic acid increased hepatocyte TF activity even in the presence of the phosphatidylserine-blocking protein lactadherin. Interestingly, glycochenodeoxycholic acid and taurochenodeoxycholic acid increased the procoagulant activity of the TF:FVIIa complex relipidated in unilamellar phosphatidylcholine vesicles, which was linked to an apparent decrease in the Km for FX (coagulation factor X). Notably, the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a bile acid structural analog, did not increase relipidated TF:FVIIa activity. Bile acids directly enhanced factor X activation by recombinant soluble TF:FVIIa complex but had no effect on FVIIa alone. CONCLUSIONS: The results indicate that bile acids directly accelerate TF:FVIIa-driven coagulation reactions, suggesting a novel mechanism whereby elevation in a physiological mediator can directly increase TF:FVIIa procoagulant activity.

Readmissions related to short bowel syndrome: a study from a national database.

While short bowel syndrome (SBS) is the leading cause of intestinal failure in children, little objective data are available regarding hospital readmissions for children with SBS. This study sought to investigate rehospitalizations related to SBS in young children. Data for study were obtained from the 2013 Nationwide Readmissions Database (NRD). Using data from the 2013 NRD, we identified a total of 1898 hospitalizations in children with SBS aged 1-4 years. A total of 901 index cases and 997 rehospitalizations were noted. Of these, 425 children (47.2%) underwent rehospitalizations. The most frequent diagnoses and procedures associated with readmission of children with SBS were related to infections and intravenous catheter placement. This is the first study to use US nationwide data to report on the incidence of readmissions in children with SBS. The results from this study indicate that improving central line care and providing home healthcare resources to families at discharge may help in preventing SBS-related rehospitalizations.

Development and validation of a web-based electronic application in managing antithrombotic agents in patients undergoing GI endoscopy.

BACKGROUND AND AIMS: Antithrombotic therapy among patients undergoing GI procedures is frequently encountered and can impact the procedure and patient outcomes. The American Society for Gastrointestinal Endoscopy (ASGE) guidelines help to manage these medications before endoscopy depending on the patient's clinical status and the type of GI procedure. However, currently there is no readily available electronic tool that can assist in decision-making regarding preprocedural management of these agents. Our aim was to develop an electronic application, endoscopy + aid (ENDOAID), to help manage antithrombotic agents before endoscopy and to perform a validation study to test its accuracy. METHODS: ENDOAID, a web-based application, was developed using JavaScript software (Oracle Corporation, Redwood Shores, Calif, USA) based on an algorithm to categorize patients and procedures into low and high risk as outlined in the updated ASGE guidelines published in 2016. Once pertinent information regarding a patient's clinical status and the procedure are entered, the application generates recommendations for the management of antithrombotic agents based on their cardiovascular risk and published ASGE guidelines. We performed a validation study with 52 patients who were referred to endoscopy and were taking antithrombotic agents. The patients were divided into groups of 5, and in the simulation each patient had 4 procedures. Different GI procedures were used in the simulation for each group of patients to ensure the entire spectrum of procedures were covered for analysis. Every simulation was then run through ENDOAID. The results from ENDOAID were compared with recommendations based on ASGE guidelines. The latter was derived by consensus between 2 endoscopists (the criterion standard). The personnel using the ENDOAID and those using the ASGE guidelines were different to avoid bias. Any clinical scenario that was unclear or not clearly outlined in ASGE guidelines was discussed with expert endoscopists for a final decision. We evaluated ASGE recommendations and calculated concordance rates between guidelines and ENDOAID results. The Pearson correlation coefficient (r) was calculated to assess the correlation between ENDOAID results to guidelines. RESULTS: There was a total of 208 simulated encounters, including 26 procedures. Initial concordance between ENDOAID recommendations and the criterion standard was seen in 206 encounters (99.03%). The 2 encounters that needed further review occurred among patients with Factor V Leiden mutation and deep vein thrombosis from antiphospholipid antibody syndrome and who were undergoing high-risk procedures that had ambiguous guidelines. ENDOAID suggested consultations with an expert before the elective procedure. This suggestion was agreed on by expert endoscopist consensus. Thus, ENDOAID showed a 100% concordance with the ASGE guideline for managing antithrombotics. There was a high degree of correlation (r = .996, P < .01) between ENDOAID results with ASGE. CONCLUSIONS: We have developed and validated an easy-to-use web-based application that can help in periprocedural management of antithrombotics. Such an application has the potential to simplify the management of these agents and potentially prevent procedural delays, cancellations, or unnecessary consults.

PNPLA3 gene predicts clinical recovery after sustained virological response in decompensated hepatitis C cirrhosis.

BACKGROUND: Patients with decompensated hepatitis C virus (HCV) cirrhosis experience various outcomes after sustained virological response (SVR), ranging from clinical recovery to further deterioration. We hypothesised that the genetic risk for steatosis, namely the polymorphisms rs738409 of Patatin-like Phospholipase Domain-Containing 3 (PNPLA3), rs58542926 of Transmembrane-6-Superfamily-2 (TM6SF2), and rs641738 of Membrane-bound O-acyltransferase Domain-Containing 7 (MBOAT7), is predictive of recovery. METHODS: We prospectively enrolled 56 patients with Child-Pugh (CPT) B/C cirrhosis who underwent antiviral therapy. The primary outcome was change in CPT score at 12, 24, and 48 weeks after SVR. We used a linear mixed-effects model for analysis. RESULTS: Forty-five patients (PNPLA3: 21 CC, 19 CG, 5 GG) survived to the first endpoint without liver transplantation. The mean change in CPT score at 12, 24, and 48 weeks was -1.57 (SE=0.30), -1.76 (SE=0.32), and -2.0 (SE=0.36), respectively, among the patients with the PNPLA3 CC genotype and -0.50 (SE=0.20), -0.41 (SE=0.25), and -0.24 (SE=0.27), respectively, among the other 24 patients. After adjustment for baseline characteristics, the PNPLA3 CG/GG genotypes were associated with a 1.29 (SE=0.30, p<0.0001) point higher CPT score. Most of the difference came from differences in hepatic encephalopathy and bilirubin. The results for rs58542926 and rs641738 were not significant. CONCLUSION: The PNPLA3 CG/GG genotypes could identify a subgroup of patients with decompensated HCV cirrhosis that had suboptimal clinical recovery despite SVR. An understanding of the genetic factors that influence clinical outcomes will help target patients for liver transplant based on individual genetic risk factors and provide insight leading to new therapeutic approaches.

Setting minimum standards for training in EUS and ERCP: results from a prospective multicenter study evaluating learning curves and competence among advanced endoscopy trainees.

BACKGROUND AND AIMS: Minimum EUS and ERCP volumes that should be offered per trainee in "high quality" advanced endoscopy training programs (AETPs) are not established. We aimed to define the number of procedures required by an "average" advanced endoscopy trainee (AET) to achieve competence in technical and cognitive EUS and ERCP tasks to help structure AETPs. METHODS: American Society for Gastrointestinal Endoscopy (ASGE)-recognized AETPs were invited to participate; AETs were graded on every fifth EUS and ERCP examination using a validated tool. Grading for each skill was done using a 4-point scoring system, and learning curves using cumulative sum analysis for overall, technical, and cognitive components of EUS and ERCP were shared with AETs and trainers quarterly. Generalized linear mixed-effects models with a random intercept for each AET were used to generate aggregate learning curves, allowing us to use data from all AETs to estimate the average learning experience for trainees. RESULTS: Among 62 invited AETPs, 37 AETs from 32 AETPs participated. Most AETs reported hands-on EUS (52%, median 20 cases) and ERCP (68%, median 50 cases) experience before starting an AETP. The median number of EUS and ERCPs performed per AET was 400 (range, 200-750) and 361 (range, 250-650), respectively. Overall, 2616 examinations were graded (EUS, 1277; ERCP-biliary, 1143; pancreatic, 196). Most graded EUS examinations were performed for pancreatobiliary indications (69.9%) and ERCP examinations for ASGE biliary grade of difficulty 1 (72.1%). The average AET achieved competence in core EUS and ERCP skills at approximately 225 and 250 cases, respectively. However, overall technical competence was achieved for grade 2 ERCP at about 300 cases. CONCLUSION: The thresholds provided for an average AET to achieve competence in EUS and ERCP may be used by the ASGE and AETPs in establishing the minimal standards for case volume exposure for AETs during their training. (Clinical trial registration number: NCT02509416.).

Cap-assisted colonoscopy: a meta-analysis of high-quality randomized controlled trials.

Background and study aims Standard colonoscopy (SC) is the preferred modality for screening for colon cancer; however, it carries a significant polyp/adenoma miss rate. Cap-assisted colonoscopy (CC) has been shown to improve polyp/adenoma detection rate, decrease cecal intubation time and increase cecal intubation rate when compared to standard colonoscopy (SC). However, data on adenoma detection rate (ADR) are conflicting. The aim of this meta-analysis was to compare the performance of CC with SC for ADR among high-quality randomized controlled trials. Patients and methods We performed an extensive literature search using MEDLINE, EMBASE, Scopus, Cochrane and Web of Science databases and abstracts published at national meetings. Only comparative studies between CC and SC were included if they reported ADR, adenoma per person (APP), cecal intubation rate, and cecal intubation time. The exclusion criterion for comparing ADR was studies with Jadad score ≤ 2. The odds ratio (OR) was calculated using Mantel-Haenszel method. I 2 test was used to measure heterogeneity among studies. Results Analysis of high-quality studies (Jadad score ≥ 3, total of 7 studies) showed that use of cap improved the ADR with the results being statistically significant (OR 1.18, 95 % CI 1.03 - 1.33) and detection of 0.16 (0.02 - 0.30) additional APP. The cecal intubation rate in the CC group was 96.3 % compared to 94.5 % with SC (total of 17 studies). Use of cap improved cecal intubation (OR 1.61, 95 % CI 1.33 - 1.95) when compared to SC ( P value < 0.001). Use of cap decreased cecal intubation time by an average of 0.88 minutes (95 % CI 0.37 - 1.39) or 53 seconds. Conclusions Meta-analysis of high-quality studies showed that CC improved the ADR compared to SC.

Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography, From Training Through Independent Practice.

BACKGROUND & AIMS: It is unclear whether participation in competency-based fellowship programs for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) results in high-quality care in independent practice. We measured quality indicator (QI) adherence during the first year of independent practice among physicians who completed endoscopic training with a systematic assessment of competence. METHODS: We performed a prospective multicenter cohort study of invited participants from 62 training programs. In phase 1, 24 advanced endoscopy trainees (AETs), from 20 programs, were assessed using a validated competence assessment tool. We used a comprehensive data collection and reporting system to create learning curves using cumulative sum analysis that were shared with AETs and trainers quarterly. In phase 2, participating AETs entered data into a database pertaining to every EUS and ERCP examination during their first year of independent practice, anchored by key QIs. RESULTS: By the end of training, most AETs had achieved overall technical competence (EUS 91.7%, ERCP 73.9%) and cognitive competence (EUS 91.7%, ERCP 94.1%). In phase 2 of the study, 22 AETs (91.6%) participated and completed a median of 136 EUS examinations per AET and 116 ERCP examinations per AET. Most AETs met the performance thresholds for QIs in EUS (including 94.4% diagnostic rate of adequate samples and 83.8% diagnostic yield of malignancy in pancreatic masses) and ERCP (94.9% overall cannulation rate). CONCLUSIONS: In this prospective multicenter study, we found that although competence cannot be confirmed for all AETs at the end of training, most meet QI thresholds for EUS and ERCP at the end of their first year of independent practice. This finding affirms the effectiveness of training programs. Clinicaltrials.gov ID NCT02509416.

Etiology of gastrointestinal bleeding in patients on dual antiplatelet therapy.

OBJECTIVE: Dual antiplatelet therapy (DAPT) is associated with an increased risk of gastrointestinal (GI) bleeding and is thought to cause upper gastrointestinal bleeding (UGIB). However, recent reports indicate that the incidence of lower gastrointestinal bleeding (LGIB) in patients on DAPT may be increasing. We aimed to compare the endoscopic findings and etiology of GI bleeding between patients on DAPT compared with those not on DAPT. METHODS: This was a retrospective, single-center, case-control study. Cases were 114 consecutive patients admitted with a first episode of GI bleeding while on DAPT who underwent detailed GI evaluation. We chose 114 controls who had GIB but were not on DAPT. RESULTS: There was no significant difference in the incidence of UGIB or LGIB between the two groups (UGIB: 53.5% vs 51.3% and LGIB: 46.5% vs 48.7%, P = 0.10) or within groups (DAPT: 53.5% vs 46.5%, P = 0.30 and controls: 51.3% vs 48.7%, P = 0.80). Although the DAPT group had a lower prevalence of the usual UGIB risk factors, it had a higher likelihood of bleeding from varices or upper GI inflammation [odds ratio (OR) 3.54, 95% confidence interval (CI) 0.14-92.3; OR 13.98, 95% CI 1.40-140.36]. No etiology of bleeding was identified in a higher percentage of patients on DAPT than those who were not (22.8% vs 5.3%). CONCLUSION: In patients with GI bleeding, the incidences of UGIB and LGIB are similar irrespective of their DAPT use.