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Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALK F1174L ) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression of ALK F1174L and MYCN resulted in shorter latency compared to MYCN alone. MYCN tumors resembled adrenergic, while ALK/MYCN tumors resembled mesenchymal, neuroblastoma. Transcriptomic analysis revealed enrichment in focal adhesion signaling, particularly the extracellular matrix genes POSTN and FN1 in ALK/MYCN tumors. Patients with ALK-mutant tumors similarly demonstrated elevated levels of POSTN and FN1. Knockdown of POSTN, but not FN1, delayed adhesion and suppressed proliferation of ALK/MYCN tumors. Furthermore, loss of POSTN reduced ALK-dependent activation of WNT signaling. Reciprocally, inhibition of the WNT pathway reduced expression of POSTN and growth of ALK/MYCN tumor cells. Thus, ALK drives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling., Competing Interests: Declaration of interests W.C.G. and N.N. are employees and shareholders at Revolution Medicines (Redwood City, CA, USA). W.A.W. is a co-founder of StemSynergy Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Extracorporeal shock wave lithotripsy (ESWL) is performed to fragment large main pancreatic duct (MPD) stones in symptomatic patients. Subsequent endoscopic retrograde cholangiopancreatography (ERCP) is often performed to clear the stone fragments. Edema of surrounding tissue after ESWL theoretically affects the ability to perform ERCP. However, the optimal timing of ERCP after ESWL is not clearly defined. The aim of this study is to determine the efficacy and safety of same-day ERCP after ESWL and to determine if the timing of ERCP after ESWL affects outcomes., Methods: This is a retrospective study of consecutive patients from January, 2013 to September, 2019 who received ESWL for MPD stones at our center. Included patients received subsequent same-day ERCP under the same general anesthesia session or later session ERCP (1-30 days after ESWL). Demographics, anatomical findings, history, and outcomes were collected. Success was defined as complete or near complete (> 80%) stone fragmentation with clearance., Results: 218 patients were treated with ESWL and subsequent ERCP. 133 (61.0%) received ERCP on the same day immediately after ESWL, while 85 (39.0%) returned for ERCP at a later day (median 3.0 days after ESWL). Baseline characteristics demonstrated patients who received same-day ERCP had a higher rate of pain at baseline (94.7% vs 87.1%, p = 0.045). Main outcomes demonstrated an overall successful MPD stone clearance rate of 90.4%, with similar rates between same-day ERCP and later session ERCP (91.7% vs 88.2%, p = 0.394). Additionally, successful cannulation at ERCP, adverse events, and post-procedure admission rates were similar., Conclusions: Delaying ERCP to allow peripancreatic tissue recovery after ESWL does not affect outcomes. Same-day ERCP after ESWL is safe and effective., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Performing a high-quality colonoscopy is critical for optimizing the adenoma detection rate (ADR). Colonoscopy withdrawal time (a surrogate measure) of ≥6 minutes is recommended; however, a threshold of a high-quality withdrawal and its impact on ADR are not known., Methods: We examined withdrawal time (excluding polyp resection and bowel cleaning time) of subjects undergoing screening and/or surveillance colonoscopy in a prospective, multicenter, randomized controlled trial. We examined the relationship of withdrawal time in 1-minute increments on ADR and reported odds ratio (OR) with 95% confidence intervals. Linear regression analysis was performed to assess the maximal inspection time threshold that impacts the ADR., Results: A total of 1142 subjects (age, 62.3 ± 8.9 years; 80.5% men) underwent screening (45.9%) or surveillance (53.6%) colonoscopy. The screening group had a median withdrawal time of 9.0 minutes (interquartile range [IQR], 3.3) with an ADR of 49.6%, whereas the surveillance group had a median withdrawal time of 9.3 minutes (IQR, 4.3) with an ADR of 63.9%. ADR correspondingly increased for a withdrawal time of 6 minutes to 13 minutes, beyond which ADR did not increase (50.4% vs 76.6%, P < .01). For every 1-minute increase in withdrawal time, there was 6% higher odds of detecting an additional subject with an adenoma (OR, 1.06; 95% confidence interval, 1.02-1.10; P = .004)., Conclusions: Results from this multicenter, randomized controlled trial underscore the importance of a high-quality examination and efforts required to achieve this with an incremental yield in ADR based on withdrawal time. (Clinical trial registration number: NCT03952611.)., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: The cornerstone of treatment for acute cholangitis is source control with biliary drainage and early antibiotics. The primary aim of this study was to describe the microbiology of bile aspirate pathogens obtained at the time of endoscopic retrograde cholangiopancreatography (ERCP) in patients suspected of having acute cholangitis., Methods: In this single-center retrospective study, patients were included if a bile aspirate was collected at ERCP for suspicion of acute cholangitis, from 1 January 2010 to 31 December 2016., Results: There were 721 ERCP procedures for suspected acute cholangitis with bile culture results, with 662 positive bile cultures (91.8 %). Pathogens included: Enterococcus species (spp.) 448 (67.7 %); Klebsiella spp. 295 (44.6 %); Escherichia coli 269 (40.6 %); Pseudomonas spp. 52 (7.9 %); and anaerobes 64 (9.7 %). Susceptibility of Klebsiella pneumoniae and E.coli isolates to ciprofloxacin was 88 % and 64 %, respectively. Extended-spectrum beta-lactamases and carbapenem resistance were found in 7.9 % and 3.6 % of Enterobacteriaceae, respectively. There were 437 concurrent blood cultures, of which 174 were positive (39.8 % of cultures drawn). Prior biliary endoscopic sphincterotomy (ES) was evident in 459 ERCP cases (63.7 %), and was associated with increased frequency of Klebsiella spp., Pseudomonas aeruginosa , Enterobacter spp., and Enterococcus spp. Prior biliary ES significantly increased the probability of vancomycin-resistant Enterococcus (VRE)., Conclusions: The vast majority of bile cultures (91.8 %) were positive. The susceptibilities of E.coli and K.pneumoniae to ciprofloxacin are lower than historically noted. A notable portion of cultures contained pathogenic drug-resistant organisms. Prior biliary ES is associated with a higher frequency of certain organisms and higher frequency of VRE., Competing Interests: M.A. Gromski serves as a consultant for Boston Scientific. S. Sherman serves as a consultant for Boston Scientific, Cook Medical, and Olympus. G. Lehman serves as a consultant for Cook Endoscopy. J. Easler serves as a consultant for Boston Scientific. The remaining authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background and Aims: Mucosal exposure devices including distal attachments such as the cuff and cap have shown variable results in improving adenoma detection rate (ADR) compared with high-definition white light colonoscopy (HDWLE)., Methods: We performed a prospective, multicenter randomized controlled trial in patients undergoing screening or surveillance colonoscopy comparing HDWLE to 2 different types of distal attachments: cuff (CF) (Endocuff Vision) or cap (CP) (Reveal). The primary outcome was ADR. Secondary outcomes included adenomas per colonoscopy, advanced adenoma and sessile serrated lesion detection rate, right-sided ADR, withdrawal time, and adverse events. Continuous variables were compared using Student's t test and categorical variables were compared using chi-square or Fisher's exact test using statistical software Stata version16. A P value <.05 was considered significant., Results: A total of 1203 subjects were randomized to either HDWLE (n = 384; mean 62 years of age; 81.3% males), CF (n = 379; mean 62.7 years of age; 79.9% males) or CP (n = 379; mean age 62.1 years of age; 80.5% males). No significant differences were found among 3 groups for ADR (57.3%, 59.1%, and 55.7%; P = .6), adenomas per colonoscopy (1.4 ± 1.9, 1.6 ± 2.4, and 1.4 ± 2; P = .3), advanced adenoma (7.6%, 9.2%, and 8.2%; P = .7), sessile serrated lesion (6.8%, 6.3%, and 5.5%; P = .8), or right ADR (48.2%, 49.3%, and 46.2%; P = .7). The number of polyps per colonoscopy were significantly higher in the CF group compared with HDWLE and CP group (2.7 ± 3.4, 2.3 ± 2.5, and 2.2 ± 2.3; P = .013). In a multivariable model, after adjusting for age, sex, body mass index, withdrawal time, and Boston Bowel Preparation Scale score, there was no impact of device type on the primary outcome of ADR (P = .77). In screening patients, CF resulted in more neoplasms per colonoscopy (CF: 1.7 ± 2.6, HDWLE: 1.3 ± 1.7, and CP: 1.2 ± 1.8; P = .047) with a shorter withdrawal time., Conclusions: Results from this multicenter randomized controlled trial do not show any significant benefit of using either distal attachment devices (CF or CP) over HDWLE, at least in high-detector endoscopists. The Endocuff may have an advantage in the screening population. (ClinicalTrials.gov, Number: NCT03952611)., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Despite calls to increase diversity in the health care workforce, most medical fields including neurology have seen minimal advances, owing in part to the lack of developing a robust pipeline for trainees from underrepresented backgrounds. We sought to create an immersive, replicable neurology-themed summer camp and longitudinal mentorship program for underrepresented-in-medicine (URM) high-school students to encourage them to enter the training pipeline in neuroscience-related fields., Methods: We established an annual, no-cost 1-week camp for local URM students with the goals of exposing them to different health care professions within neuroscience while providing them with college application resources and long-term mentorship. A postprogram survey was distributed to assess the students' attitudes towards the camp and their desires to pursue health care careers., Results: Over the 4 years since the founding of the camp (2016-2020), a total of 96 students participated, of whom 53% were URM, 74% came from very low-income households, and 61% had parents who did not attend college. In total, 87 students (91%) completed the postcamp survey. Nearly all (97%) of the respondents were likely to recommend the camp to their peers, and the vast majority (85%) felt that Brain Camp made them more likely to pursue careers in health care., Conclusions: Brain Camp seeks to address the unmet need for low barrier-to-entry programs designed for URM high-school students interested in health care careers. We envision that our camp may serve as a blueprint for other similar programs across the nation with the goal of addressing the URM pipeline in neuroscience., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Endoscopic management of large main pancreatic ductal (MPD) stones often require treatment with lithotripsy. Extracorporeal shock wave lithotripsy (ESWL) has been the mainstay therapy, and single-operator pancreatoscopy with intraductal (intracorporeal) lithotripsy (SOPIL) is an emerging technique. However, no comparative studies between these techniques exist. We therefore aimed to compare ESWL to SOPIL for the treatment of large MPD stones., Methods: This is a retrospective cohort study comparing patients who were treated with ESWL or SOPIL from September 2013 to September 2019 at a single tertiary center. Logistic regression was performed to identify factors associated with technical success and efficient stone clearance (≤ 2 procedures to clear stones)., Results: There were 240 patients who were treated with ESWL and 18 treated with SOPIL. The overall technical success rate of stone clearance was 224/258 (86.8%), which was similar between the ESWL and SOPIL groups (86.7% vs 88.9%, p = 1.000). A SOPIL approach required fewer total procedures (1.6 ± 0.6 vs 3.1 ± 1.5, p < 0.001) and less aggregate procedure time (101.6 ± 68.2 vs 191.8 ± 111.6 min, p = 0.001). Adverse event rates were similar between the groups (6.3% vs 5.6%, p = 1.000). The use of SOPIL was independently associated with greater efficiency compared to ESWL (OR 5.241 [1.348-20.369], p = 0.017). Stone size > 10 mm was associated with less efficient stone clearance (OR 0.484 [0.256-0.912], p = 0.025)., Conclusion: Both ESWL and SOPIL are safe and effective endoscopic adjunct modalities for treating large pancreatic duct stones. SOPIL is an emerging alternative to ESWL that is potentially more efficient for lithotripsy and MPD stone clearance., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Declaration of competing interest There is no conflict of interest.

Background: A single-procedure session combining EUS and ERCP (EUS/ERCP) for tissue diagnosis and biliary decompression for pancreatic duct adenocarcinoma (PDAC) is technically feasible. While EUS/ERCP may offer expedience and convenience over an approach of separate procedures sessions, the technical success and risk for complications of a combined approach is unclear., Aims: Compare the effectiveness and safety of EUS/ERCP versus separate session approaches for PDAC., Methods: Study patients (2010-2015) were identified within our ERCP database. Patients were analyzed in three groups based on approach: Group A: Single-session EUS-FNA and ERCP (EUS/ERCP), Group B: EUS-FNA followed by separate, subsequent ERCP (EUS then ERCP), and Group C: ERCP with/without separate EUS (ERCP ± EUS). Rates of technical success, number of procedures, complications, and time to initiation of PDAC therapies were compared between groups., Results: Two hundred patients met study criteria. EUS/ERCP approach (Group A) had a longer index procedure duration (median 66 min, p = 0.023). No differences were observed between Group A versus sequential procedure approaches (Groups B and C) for complications (p = 0.109) and success of EUS-FNA (p = 0.711) and ERCP (p = 0.109). Subgroup analysis (> 2 months of follow-up, not referred to hospice, n = 126) was performed. No differences were observed for stent failure (p = 0.307) or need for subsequent procedures (p = 0.220). EUS/ERCP (Group A) was associated with a shorter time to initiation of PDAC therapies (mean, 25.2 vs 42.7 days, p = 0.046)., Conclusions: EUS/ERCP approach has comparable rates of success and complications compared to separate, sequential approaches. An EUS/ERCP approach equates to shorter time interval to initiation of PDAC therapies., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

The Greater Boston Nursing Collective, a consortium composed of university nursing deans and chief nursing officers within academic medical centers and specialty hospitals in Boston, Massachusetts, was formed in 2014. Since the group's inception, our mission has been to create and reinforce whole-person/whole-system healing environments to improve the health of all communities. Through our collaboration in navigating the dual epidemics of COVID-19 and structural racism within our respective organizations, and across the United States and the world, we share experiences and lessons learned. Our common mission is clearer than ever: to create safe and joyful work environments, to protect the dignity of those we are privileged to serve, and to generate policies to advance health equity to rectify societal forces that have shaped this dual epidemic. We are humbled by the many who persist despite limited rest and respite, and whose stories, innovations, and leadership we are honored to witness and share. They have defined our generation, just as nurses in earlier crises have done: leading through service to others as our purpose and privilege., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc.)

Background/aims: A calcineurin inhibitor may alter pancreatic function and inflammatory reaction. This study aimed to determine the possible pharmacologic effect of the calcineurin inhibitor, tacrolimus, on pancreatic function, and to determine its preventive effect on post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in liver transplantation (LT) patients., Methods: The serum amylase and lipase values before and after LT were compared. The frequency of post-ERCP pancreatitis was compared between non-LT and LT patients, using propensity score matching method., Results: Median serum amylase values (normal range, 19 to 86 U/L) were 49.0 U/L (38.0 to 68.0) before LT and 27.0 U/L (19.3 to 36.8) after LT, and median serum lipase values (normal range, 7 to 59 U/L) were 40.0 U/L (26.5 to 54.0) before LT and 10.5 U/L (6.0 to 21.0) after LT. Both serum amylase and lipase values significantly decreased after LT (p < 0.001), and to a level comparable to chronic pancreatitis. There was a marginal significant difference between the non-LT and LT groups before the propensity score matching with respect to frequency of post-ERCP pancreatitis (16 [3.2%] in non-LT group vs. 2 [0.9%] in LT group, p = 0.069). After propensity score matching, a marginal significant difference still existed with respect to frequency of post-ERCP pancreatitis (7 [4.8%] in non-LT group vs. 1 [0.7%] in LT group, p = 0.067)., Conclusion: The immunosuppression with calcineurin inhibitor may reduce not only the pancreatic enzyme dynamics but also inciting inflammatory event including post-ERCP pancreatitis.

Background: Although rectal indometacin 100 mg is effective in reducing the frequency and severity of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients, the optimal dose is unknown, and pancreatitis incidence remains high. The aim of this study was to compare the efficacy of two dose regimens of rectal indometacin on the frequency and severity of pancreatitis after ERCP in high-risk patients., Methods: In this randomised, double-blind, comparative effectiveness trial, we enrolled patients from six tertiary medical centres in the USA. Eligible patients were those at high risk for the development of pancreatitis after ERCP. We randomly assigned eligible patients (1:1) immediately after ERCP to receive either two 50 mg indometacin suppositories and a placebo suppository (standard-dose group) or three 50 mg indometacin suppositories (high-dose group). 4 h after the procedure, patients assigned to the high-dose group received an additional 50 mg indometacin suppository, whereas patients in the standard-dose group received an additional placebo suppository. The randomisation schedule, stratified according to study centre and with no other restrictions, was computer generated by an investigator who was uninvolved in the clinical care of any participants, distributed to the sites, and kept by personnel not directly involved with the study. These same personnel were responsible for packaging the drug and placebo in opaque envelopes. Patients, study personnel, and treating physicians were masked to study group assignment. The primary outcome of the study was the development of pancreatitis after ERCP. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01912716, and enrolment is complete., Findings: Between July 9, 2013, and March 22, 2018, 1037 eligible patients were enrolled and randomly assigned to receive either standard-dose (n=515) or high-dose indometacin (n=522). Pancreatitis after ERCP occurred in 141 (14%) of 1037 patients-76 (15%) of 515 patients in the standard-dose indometacin group and 65 (12%) of 522 patients in the high-dose indometacin group (risk ratio [RR] 1·19, 95% CI 0·87-1·61; p=0·32). We observed 19 adverse events that were potentially attributable to study drug. Clinically significant bleeding occurred in 14 (1%) of 1037 patients-six (1%) of 515 patients in the standard-dose indometacin group and eight (2%) of 522 patients in the high-dose indometacin group (p=0·79). Three (1%) of 522 patients in the high-dose indometacin group developed acute kidney injury versus none in the standard-dose group (p=0·25). A non-ST elevation myocardial infarction occurred in the standard-dose indometacin group 2 days after ERCP. A transient ischaemic attack occurred in the high-dose indometacin group 5 days after ERCP. All 19 adverse events, in addition to the 141 patients who developed pancreatitis after ERCP, were considered serious as all required admission to hospital. We observed no allergic reactions or deaths at 30 day follow-up., Interpretation: Dose escalation to rectal indometacin 200 mg did not confer any advantage compared with the standard 100 mg regimen, with pancreatitis incidence remaining high in high-risk patients. Current practice should continue unchanged. Further research should consider the pharmacokinetics of non-steroidal anti-inflammatory drugs to determine the optimal timing of their administration to prevent pancreatitis after ERCP., Funding: American College of Gastroenterology., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Aims: Devices for flattening colon folds can improve polyp detection at colonoscopy. However, there are few data on the endoscopic ring-fitted cap (EndoRings; EndoAid, Caesarea, Israel). We sought to compare adenoma detection with EndoRings with that of standard high-definition colonoscopy., Methods: This was a single-center, randomized controlled trial of 562 patients (284 randomized to EndoRings and 278 to standard colonoscopy) at 2 outpatient endoscopy units in the Indiana University Hospital system. Adenoma detection was the primary outcome measured as adenoma detection rate (ADR) and adenomas per colonoscopy (APC). We also compared sessile serrated polyp detection rate, insertion times, withdrawal times, and ease of passage through the sigmoid colon., Results: EndoRings was superior to standard colonoscopy in terms of APC (1.46 vs 1.06, P = .025), but there were no statistically significant differences in ADR or sessile serrated polyp detection rate. Mean withdrawal time (in patients with no polyps) was shorter and insertion time (all patients) was longer in the EndoRings arm by 1.8 minutes and 0.75 minutes, respectively. One provider had significantly higher detection with Endo-Rings and contributed substantially to the overall results., Conclusions: EndoRings can increase adenoma detection without a significant increase in procedure time, but the effect varies between operators. The use of EndoRings slows colonoscope insertion. (Clinical trial registration number: NCT03418662.)., (Copyright © 2020 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Comparative analyses of neuronal phenotypes in closely related species can shed light on neuronal changes occurring during evolution. The study of post-mortem brains of nonhuman primates (NHPs) has been limited and often does not recapitulate important species-specific developmental hallmarks. We utilize induced pluripotent stem cell (iPSC) technology to investigate the development of cortical pyramidal neurons following migration and maturation of cells grafted in the developing mouse cortex. Our results show differential migration patterns in human neural progenitor cells compared to those of chimpanzees and bonobos both in vitro and in vivo, suggesting heterochronic changes in human neurons. The strategy proposed here lays the groundwork for further comparative analyses between humans and NHPs and opens new avenues for understanding the differences in the neural underpinnings of cognition and neurological disease susceptibility between species., Competing Interests: MM, BH, BK, DY, KV, SL, IN, RS, AD, AM, RO, JC, LM, JG, KH, CF, LR, RK, RX, GC, NH, KP, KS No competing interests declared, AM is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis and cellular models focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders with genetic origins. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. FG Reviewing editor, eLife, (© 2019, Marchetto et al.)

Background and Aims: Annular pancreas is a congenital anomaly whereby pancreatic tissue encircles the duodenum. Current knowledge of endoscopic findings of annular pancreas is limited to small case series. The aim of this study was to describe the endoscopic and pancreatographic findings of patients with annular pancreas at a large tertiary care ERCP center., Methods: This is a retrospective observational study. Our Institutional Review Board-approved, prospectively collected ERCP database was queried for cases of annular pancreas. The electronic medical records were searched for patient and procedure-related data., Results: From January 1, 1994, to December 31, 2016, 46 patients with annular pancreas underwent ERCP at our institution. Index ERCP was technically successful in 42 patients (91.3%), and technical success was achieved in all 46 patients (100%) after 2 attempts, when required. A duodenal narrowing or ring was found in most patients (n = 39, 84.8%), yet only 2 (4.3%) had retained gastric contents. Pancreas divisum was found in 21 patients (45.7%), 18 of which were complete divisum. Pancreatobiliary neoplasia was the indication for ERCP in 7 patients (15.2%). Pancreatographic findings consistent with chronic pancreatitis were noted in 15 patients (32.6%) at the index ERCP., Conclusion: This is the largest series describing the endoscopic and pancreatographic findings of patients with annular pancreas. We found that 45.7% of patients had concurrent pancreas divisum. Endoscopic therapy was successful in most patients at our institution after 1 ERCP, and in all patients after a second ERCP. Nearly one-third of patients had findings consistent with chronic pancreatitis at the time of index ERCP. It is unclear whether this may be a feature of the natural history of annular pancreas., (Copyright © 2019 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Treatment and prognosis of patients with rectal adenocarcinoma (RAC) are dependent on accurate locoregional staging., Objectives: The aim of this study was to measure the performance characteristics of rectal endoscopic ultrasound (EUS) compared with surgical pathology, and to assess the interobserver variation of rectal EUS in the staging of RAC., Patients and Methods: Patients referred for rectal EUS staging of a recently diagnosed RAC were prospectively enrolled between 2012 and 2016. Tandem EUS exams were performed by two independent endosonographers (ES1 and ES2) blinded to each other's findings., Results: Ninety-five patients were enrolled. Seventy-five (79%) underwent curative intent tumor resection, including 30 without neoadjuvant therapy. In this latter group, the sensitivity, specificity, and accuracy of transrectal ultrasonography staging were 75, 83, and 82% for uT1; 50, 65, and 58% for uT2; 56, 81, and 73% for T3; 72, 44, and 63% for N0, and 38, 75, and 63% for N1, respectively. Experienced operators rendered a more accurate N stage and were less likely to overstage compared with less experienced ones (P=0.01 and 0.02, respectively). Overall, T staging agreement between endosonographers was substantial (κ=0.61) and N stage agreement was moderate (κ=0.45)., Conclusion: Rectal EUS is more accurate in staging T1 and T3 tumors compared with T2 tumors. Interobserver agreement of rectal EUS in rectal cancer staging is generally good.

Background and Study Aim: Duodenoscopes have been the source of serious infection, despite correct performance of high-level disinfection (HLD). This study aimed to observe the impact of performing HLD twice on the rate of positive cultures from duodenoscope elevators., Methods: We performed double HLD (DHLD; i. e. complete manual cleaning followed by automated reprocessing, with the entire process repeated) and then randomly cultured the elevators of our duodenoscopes on about 30 % of occasions., Results: DHLD was associated with positive elevator cultures for any microorganism in 9.4 % of cases, with a 0.8 % rate of known pathogens (627 cultures) between May 2015 and February 2016. After February 2016, and in association with changing the precleaning fluid, as well as use of a new FDA-recommended cleaning brush, the rate of positive cultures for any microorganism after DHLD was 4.8 % and 0.2 % for known pathogens (420 cultures). In a third phase, characterized by a change in personnel performing DHLD and retirement of a duodenoscope with a high rate of positive cultures, the rate of positive cultures for any microorganism was 4.9 % (783 cultures) and the rate of positive culture for known pathogens was 0.3 %. To our knowledge, no duodenoscope transmission of infection occurred during the study interval., Conclusions: DHLD resulted in a low rate of positive cultures for known pathogens and for organisms of low pathogenic potential, but did not eliminate these, from duodenoscope elevators. Additional improvements in HLD protocols and/or duodenoscope design are needed., Competing Interests: Douglas K. Rex is a consultant for Olympus Corporation., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Study Aims: In plastic stent insertion for treatment of post-cholecystectomy bile leak, stent migration may be more common due to the absence of a shelf to anchor the stent. We evaluated how adding a flap to straight plastic stents for this indication might influence the rate of stent migration when compared to use of conventional plastic stents., Patients and Methods: This is a retrospective study including patients referred for ERCP for treatment of post-cholecystectomy bile leak. Patients with a customized anti-migration flap stent had the additional flap created on the distal end of straight plastic stents, intended to aid in anchoring in the distal supra-sphincteric biliary duct. The primary endpoint is stent migration events. The secondary endpoint is bile leak resolution after first ERCP session., Results: Thirty-two patients were treated with the experimental additional flap stents and 225 patients were treated with standard straight biliary stents. The total failure rate of bile leak resolution after a single endoscopic treatment for all treated was 10.5 % (27/257) and the total stent migration rate for all enrolled was 15.2 % (39/257). Stent migration rate was lower in the additional flap stent group than in the conventional group (3.1 % vs. 16.9 %, respectively, P  = 0.04). Furthermore, significantly more patients had resolution of their bile leak after the first ERCP session in the group with the additional flap (100 % vs. 88 %, respectively, P  = 0.03)., Conclusion: A plastic biliary stent with an extra flap may have improved performance with regard to stent migration and resolution of bile leak over standard plastic biliary stents.

Background/aims: This study aimed to determine the risk of post-endoscopic retrograde cholangiopancreatography (post-ERCP) bleeding among patients taking antiplatelet agents (APAs), particularly in the era of multiple APAs., Methods: The primary outcomes were the frequency, type, and severity of ERCP-related bleeding according to the use of APAs., Results: The frequencies of post-ERCP bleeding among the four different groups were 16 of 2,083 (0.8%) in the no drug group, 12 of 256 (4.7%) in the aspirin group, 3 of 48 (6.3%) in the single APA group, and 4 of 48 (8.3%) in the multiple APA group (p＜0.001). In the univariate analysis, post-ERCP bleeding was associated with age, pull-type sphincterotomy, and APA and was inversely associated with balloon dilation of the biliary orifice. In the multivariate analysis, pull-type sphincterotomy (odds ratio [OR], 7.829; 95% confidence interval [CI], 1.411 to 43.453; p=0.019) and country (Korea: OR, 0.124; 95% CI, 0.042 to 0.361; p＜0.001) were associated with post-ERCP bleeding., Conclusions: The frequency of post-ERCP bleeding was statistically higher in patients on any APA within 6 days prior to ERCP. However, in the multivariate analysis, APA use was not associated with post-ERCP bleeding. Until a large, adequately powered study to detect differences is performed, caution is recommended when considering invasive procedures during ERCP in patients on APAs.

Background/aims: This study aimed to evaluate the diagnostic role of low serum amylase and lipase values in the detection of chronic pancreatitis., Methods: Patients underwent endoscopic retrograde cholangiopancreatography and were diagnosed with non-calcific chronic pancreatitis (NCCP; n=99) and calcific chronic pancreatitis (CCP; n=112). Patient serum amylase and lipase values were compared with those of healthy controls (H; n=170)., Results: The median serum amylase (normal range, 19 to 86 U/L) and lipase values (7 to 59 U/L) (P₂₅-P₇₅) were 47.0 (39.8 to 55.3) and 25.0 (18.0 to 35.0) for H, 34.0 (24.5 to 49.0) and 19.0 (9.0 to 30.0) for NCCP, and 30.0 (20.0 to 40.8) and 10.0 (3.0 to 19.0) for CCP, respectively. The cutoff values with the highest diagnostic accuracy for discriminating NCCP from H were 40 U/L for amylase and 20 U/L for lipase, respectively, and for CCP from H were 38 U/L for amylase and 15 U/L for lipase, respectively. For the diagnosis of NCCP with a criterion of serum amylase <40 and lipase <20 U/L, the sensitivity, specificity, positive predictive value, and negative predictive values were 37.4%, 88.8%, 66.1%, and 70.9%, respectively., Conclusions: Serum amylase and/or lipase levels below the normal serum range are highly specific for chronic pancreatitis patients. Clinicians should not ignore low serum pancreatic enzyme values.

Background: There is a paucity of data regarding the safety and efficacy of percutaneous endoscopic gastrostomy with jejunal extension (PEG-J). We evaluated adverse events related to PEG-J and determined the clinical impact of PEG-J in those with chronic pancreatitis (CP)., Methods: This cohort study included all patients who underwent PEG-J placement in a tertiary-care academic medical center between 2010 and 2012. Main outcome measurements were (1) short- and long-term complications related to PEG-J and (2) changes in weight and hospitalizations during the 12-month period before and after PEG-J in the CP subgroup., Results: Of 102 patients undergoing PEG-J placement, the overall technical success rate was 97 %. During a median follow-up period of 22 months (1-46 months, n = 90), at least one tube malfunction occurred in 52/90 (58 %; 177 episodes) after a median of 53 days (3-350 days), requiring a median of two tube replacements. Short-term (<30 days) tube malfunction occurred in 28/90 (31 %) and delayed in 24/90 (27 %); these included dislodgement (29 %), clogging (26 %) and kinking (14 %). In the CP subgroup (n = 58), mean body weight (kg) (70 vs. 71, p = 0.06) and body mass index (kg/m 2 , 26 vs. 27, p = 0.05) increased post-PEG-J. Mean number of hospitalizations (5 vs. 2, p < 0.0001) and inpatient days per 12 months (22 vs. 12, p = 0.005) decreased., Conclusions: While we observed no major complications related to PEG-J, half of patients had at least one episode of tube malfunction. In the CP subgroup, jejunal feeding via PEG-J significantly reduced the number of hospitalizations and inpatients days, while improving nutritional parameters.

Background and study aims  Complete stone removal from the main pancreatic duct might not be achieved in all patients with obstructive chronic calcific pancreatitis. We report our results for endoscopic dorsal pancreatic duct (DPD) bypass of obstructing stones in the ventral pancreatic duct (VPD). Patients and methods  16 patients with obstructive chronic calcific pancreatitis were treated with a DPD bypass. Clinical success was defined as significant pain relief and no hospital admissions for pain management during the ongoing treatment period. Results  Among 16 patients meeting entry criteria, 10 (62.5 %) had a history of unsuccessful endoscopic therapy, and 8 had failed extracorporeal shockwave lithotripsy (ESWL). Clinical success was achieved in 12 patients (75 %). Among these responders, 10 patients (83.3 %) had markedly improved or complete pain relief after the first stent placement, which persisted throughout the follow-up period; 11 patients (91.7 %) were able to discontinue their daily analgesics. Conclusions  In selected patients with obstructive chronic calcific pancreatitis, the DPD bypass may be considered as a rescue endoscopic therapy, potentially obviating the need for surgery when standard endoscopic methods and ESWL fail., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: The aims of this study were to evaluate whether serum pancreatic enzyme levels could be used to aid screening for chronic pancreatitis (CP)., Methods: 170 healthy volunteers were screened and prospectively enrolled in the control group. 150 patients who were diagnosed with calcific CP were enrolled in the patient group by retrospective review. Serum amylase and lipase levels were compared between the 2 groups., Results: The mean values ± SD of the control group were compared with those of the patient group for serum amylase level (48.1 ± 13.2 vs 34.8 ± 17.2 U/L, P < 0.001) and serum lipase level (26.4 ± 11.3 vs 16.3 ± 11.2 U/L, P < 0.001). On the receiver operating characteristic curve analysis for amylase level, area under the curve was 0.740 (95% confidence interval), and sensitivity and specificity were 38.7% and 94.1%, respectively, with a cutoff value of 27.5 U/L. On the receiver operating characteristic curve analysis for lipase level, area under the curve was 0.748 (95% confidence interval), and sensitivity and specificity were 33.3% and 95.9%, respectively, with a cutoff value of 10.5 U/L., Conclusions: Our results suggest that low serum pancreatic enzyme levels can be used to aid in detection of CP.

Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain., Competing Interests: The authors declare no competing financial interests.

Background and Aims: Multiple factors can affect the occlusion of plastic stents. Previous data demonstrate that side holes may induce more biofilm formation probably via microturbulence and bile flow disturbances that could lead to occlusion. These results, however, have not been replicated in subsequent clinical studies with different methods. The objective of this study is to evaluate the physical characteristics of plastic stent occlusion over time., Methods: This is a plastic stent sequential analysis study. Biliary stents removed via ERCP from February 24, 2015, to June 2, 2015, were included. One hundred and forty-eight retrieved straight-type plastic stents were longitudinally cut by a custom-made cutting device. These dissected stents were then evaluated in detail with regard to the location of stent occlusion and the stent patency period. Location of stent occlusive debris was the primary outcome in this study., Results: Biofilm formations and occlusions by debris were sequentially but separately tallied. Biofilm formations were initially seen around the side hole areas within 30 days and spread to the entire stent by 60 days. Then, occlusion process by debris was mainly initiated by 80 days and progressed to full occlusion by median of 90 days. Although some occlusions were also observed around the side hole areas within 30 days, affected areas were more widely observed after biofilm formation., Conclusions: This study is the first to attempt to describe the distribution of stent occlusions over time. These observations may help guide future stent development.

Aim: To evaluate pain control in chronic pancreatitis patients who underwent total pancreatectomy with islet cell transplantation or intrathecal narcotic pump infusion., Methods: We recognized 13 patients who underwent intrathecal narcotic pump (ITNP) infusion and 57 patients who underwent total pancreatectomy with autologous islet cell transplantation (TP + ICT) for chronic pancreatitis (CP) pain control between 1998 and 2008 at Indiana University Hospital. All patients had already failed multiple other modalities for pain control and the decision to proceed with either intervention was made at the discretion of the patients and their treating physicians. All patients were evaluated retrospectively using a questionnaire inquiring about their pain control (using a 0-10 pain scale), daily narcotic dose usage, and hospital admission days for pain control before each intervention and during their last follow-up., Results: All 13 ITNP patients and 30 available TP + ICT patients were evaluated. The mean age was approximately 40 years in both groups. The median duration of pain before intervention was 6 years and 7 years in the ITNP and TP + ICT groups, respectively. The median pain score dropped from 8 to 2.5 (on a scale of 0-10) in both groups on their last follow up. The median daily dose of narcotics also decreased from 393 mg equivalent of morphine sulfate to 8 mg in the ITNP group and from 300 mg to 40 mg in the TP + ICT group. No patient had diabetes mellitus (DM) before either procedure whereas 85% of those who underwent pancreatectomy were insulin dependent on their last evaluation despite ICT., Conclusion: ITNP and TP + ICT are comparable for pain control in patients with CP however with high incidence of DM among those who underwent TP + ICT. Prospective comparative studies and longer follow up are needed to better define treatment outcomes.

Importance: Endoscopic placement of multiple plastic stents in parallel is the first-line treatment for most benign biliary strictures; it is possible that fully covered, self-expandable metallic stents (cSEMS) may require fewer endoscopic retrograde cholangiopancreatography procedures (ERCPs) to achieve resolution., Objective: To assess whether use of cSEMS is noninferior to plastic stents with respect to stricture resolution., Design, Setting, and Participants: Multicenter (8 endoscopic referral centers), open-label, parallel, randomized clinical trial involving patients with treatment-naive, benign biliary strictures (N = 112) due to orthotopic liver transplant (n = 73), chronic pancreatitis (n = 35), or postoperative injury (n = 4), who were enrolled between April 2011 and September 2014 (with follow-up ending October 2015). Patients with a bile duct diameter less than 6 mm and those with an intact gallbladder in whom the cystic duct would be overlapped by a cSEMS were excluded., Interventions: Patients (N = 112) were randomized to receive multiple plastic stents or a single cSEMS, stratified by stricture etiology and with endoscopic reassessment for resolution every 3 months (plastic stents) or every 6 months (cSEMS). Patients were followed up for 12 months after stricture resolution to assess for recurrence., Main Outcomes and Measures: Primary outcome was stricture resolution after no more than 12 months of endoscopic therapy. The sample size was estimated based on the noninferiority of cSEMS to plastic stents, with a noninferiority margin of -15%., Results: There were 55 patients in the plastic stent group (mean [SD] age, 57 [11] years; 17 women [31%]) and 57 patients in the cSEMS group (mean [SD] age, 55 [10] years; 19 women [33%]). Compared with plastic stents (41/48, 85.4%), the cSEMS resolution rate was 50 of 54 patients (92.6%), with a rate difference of 7.2% (1-sided 95% CI, -3.0% to ∞; P < .001). Given the prespecified noninferiority margin of -15%, the null hypothesis that cSEMS is less effective than plastic stents was rejected. The mean number of ERCPs to achieve resolution was lower for cSEMS (2.14) vs plastic (3.24; mean difference, 1.10; 95% CI, 0.74 to 1.46; P < .001)., Conclusions and Relevance: Among patients with benign biliary strictures and a bile duct diameter 6 mm or more in whom the covered metallic stent would not overlap the cystic duct, cSEMS were not inferior to multiple plastic stents after 12 months in achieving stricture resolution. Metallic stents should be considered an appropriate option in patients such as these., Trial Registration: clinicaltrials.gov Identifier: NCT01221311.

Background: The value of narrow-band imaging (NBI) for detecting serrated lesions is unknown., Objective: To assess NBI for the detection of proximal colon serrated lesions., Design: Randomized, controlled trial., Setting: Two academic hospital outpatient units., Patients: Eight hundred outpatients 50 years of age and older with intact colons undergoing routine screening, surveillance, or diagnostic examinations., Interventions: Randomization to colon inspection in NBI versus white-light colonoscopy., Main Outcome Measurements: The number of serrated lesions (sessile serrated polyps plus hyperplastic polyps) proximal to the sigmoid colon., Results: The mean inspection times for the whole colon and proximal colon were the same for the NBI and white-light groups. There were 204 proximal colon lesions in the NBI group and 158 in the white light group (P = .085). Detection of conventional adenomas was comparable in the 2 groups., Limitations: Lack of blinding, endoscopic estimation of polyp location., Conclusion: NBI may increase the detection of proximal colon serrated lesions, but the result in this trial did not reach significance. Additional study of this issue is warranted. (, Clinical Trial Registration Number: NCT01572428.)., (Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Objective: Incidental pancreatic cysts are often detected during abdominal imaging and require follow-up since some have malignant potential. Endoscopic ultrasound (EUS) is highly sensitive for pancreatic diseases, yet the prevalence of incidental pancreatic cysts discovered with EUS is unknown. The objective of the study was to determine its prevalence by EUS., Methods: A prospective cross-sectional study was conducted. Patients undergoing EUS for nonpancreatic indications and without known pancreatic abnormality were recruited to assess the prevalence of pancreatic cysts and its characteristics. Risk factors were determined by logistic regression., Results: We enrolled 341 patients (mean age, 59 years; 187 females) and found 46 incidental pancreatic cysts (median [range], 5 [2-80] mm) in 32 patients (9.4%). Branch duct intraductal papillary mucinous neoplasm was the most common finding. Seven cysts were larger than 1 cm and 1 adenocarcinoma was discovered. Multivariate logistic regression showed an association between pancreatic cysts and older age (odds ratio, 1.04 per year; 95% confidence interval, 1.01-1.08) and female sex (odds ratio, 3.08; 95% confidence interval, 1.25-7.45)., Conclusions: In our population, the prevalence of incidental pancreatic cyst discovered on EUS was 9.4% and the majority were less than 1 cm. Increasing age and female sex were associated with the development of pancreatic cysts.

Background and Study Aims: The role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the diagnosis and management of cystic pancreatic neuroendocrine tumors (PNETs) is unclear. We aimed to compare clinical/endosonographic characteristics of cystic with solid PNETs, determine diagnostic accuracy of preoperative EUS-FNA, and evaluate recurrence rates after resection., Patients and Methods: All patients with cystic or solid PNET confirmed by EUS-FNA between 2000 and 2014 were identified. A matched case-control study compared 50 consecutive patients with cystic PNETs with 50 consecutive patients with solid PNETs, matched by gender and age at diagnosis of index cystic PNET. We compared clinical/endosonographic characteristics, assessed diagnostic accuracy of preoperative EUS-FNA for identifying malignancy, and analyzed tumor-free survival of patients with cystic and solid PNETs., Results: Cystic PNETs tended to be larger than solid PNETs (mean 26.8 vs. 20.1 mm, P = 0.05), more frequently nonfunctional (96 % vs. 80 %, P = 0.03), and less frequently associated with multiple endocrine neoplasia type 1 (10 % vs. 28 %, P = 0.04). With surgical pathology as reference standard, EUS-FNA accuracies for malignancy of cystic and solid PNETs were 89.3 % and 90 %, respectively; cystic PNETs were less associated with metastatic adenopathy (22 % vs. 42 %, P = 0.03) and liver metastasis (0 % vs. 26 %, P < 0.001). Cystic fluid analysis (n = 13), showed benign cystic PNETs had low carcinoembryonic antigen (CEA), Ki-67 ≤ 2 %, and no loss of heterozygosity. Patients with cystic and solid PNETs had similar recurrence risk up to 5 years after complete resection., Conclusions: Cystic PNETs have distinct clinical and EUS characteristics, but were associated with less aggressive biological behavior compared with solid PNETs. EUS-FNA is accurate for determining malignant potential on preoperative evaluation. Despite complete resection, recurrence is observed up to 5 years following surgery., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The utility of endoscopic ultrasound (EUS) compared with standard white light endoscopy (WLE) following recent polypectomy of high-risk colorectal polyps is unknown., Objective: To assess the incremental yield of EUS after endoscopic polypectomy of a high-risk rectal lesion., Design: Retrospective cohort., Setting: Tertiary referral center., Materials and Methods: Patients referred for EUS following attempted endoscopic resection of a high-risk rectal neoplasm, defined as a tubulovillous adenoma, tubular adenoma with high-grade dysplasia, carcinoid, carcinoma in-situ or adenocarcinoma (CA)., Interventions: Sigmoidoscopy ± mucosal biopsy and EUS ± fine-needle aspiration (FNA) to evaluate for: (1) Residual polyp/tumor in the rectal wall or (2) peritumoral adenopathy., Main Outcome: Sensitivity and specificity for detection of residual neoplasia for WLE ± biopsy (WLE/BX) and EUS ± FNA for cancer (CA group) or benign disease (non-CA group). The incremental yield of EUS defined as: (1) Residual intramural neoplasia not present on WLE ± BX and; (2) abnormal peritumoral adenopathy., Results: A total of 70 patients (mean age 64 ± 11 years, 61% male) with a final diagnosis of CA (n = 38) and non-CA (n = 32) were identified. There was no difference between the sensitivity and specificity of WLE alone (65% and 84%), WLE with biopsy (71% and 95%), and EUS (59% and 84%), for the detection of residual neoplasia (P > 0.05 for all). EUS identified 3 masses missed by WLE, all in the CA group. A malignant (n = 2) or benign (n = 3) node was identified in 5 (13%) CA patients; EUS-FNA in two showed residual malignancy in one and a reactive lymph node (LN) in one. No LNs were identified in the non-CA patients., Limitations: Retrospective design, incomplete follow-up in some patients., Conclusion: Following endoscopic polypectomy of high-risk rectal neoplasia, the incremental yield of EUS compared with WLE/BX for evaluation of residual disease appears limited, especially in patients with benign disease.

Background: The accuracy of EUS in the locoregional assessment of ampullary lesions is unclear., Objectives: To compare EUS with ERCP and surgical pathology for the evaluation of intraductal extension and local staging of ampullary lesions., Design: Retrospective cohort study., Setting: Tertiary-care referral center., Patients: All patients who underwent EUS primarily for the evaluation of an ampullary lesion between 1998 and 2012., Intervention: EUS., Main Outcome Measurements: Comparison of EUS sensitivity/specificity for intraductal and local extension with ERCP and surgical pathology by using the area under the receiver-operating characteristic (AUROC) curves and outcomes of the subgroup referred for endoscopic papillectomy., Results: We identified 119 patients who underwent EUS for an ampullary lesion, of whom 99 (83%) had an adenoma or adenocarcinoma. Compared with ERCP (n = 90), the sensitivity/specificity of EUS for any intraductal extension was 56%/97% (AUROC = 0.77; 95% confidence interval [CI], 0.64-0.89). However, when using surgical pathology as the reference (n = 102), the sensitivity/specificity of EUS (80%/93%; AUROC = 0.87; 95% CI, 0.76-0.97) and ERCP (83%/93%; AUROC = 0.88; 95% CI, 0.77-0.99) were comparable. The overall accuracy of EUS for local staging was 90%. Of 58 patients referred for endoscopic papillectomy, complete resection was achieved in 53 (91%); in those having intraductal extension by EUS or ERCP, complete resection was achieved in 4 of 5 (80%) and 4 of 7 (57%), respectively., Limitation: Retrospective design., Conclusions: EUS and ERCP perform similarly in evaluating intraductal extension of ampullary adenomas. Additionally, EUS is accurate in T-staging ampullary adenocarcinomas. Future prospective studies should evaluate whether EUS can identify characteristics of ampullary lesions that appropriately direct patients to endoscopic or surgical resection., (Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: There are limited data regarding work-related injury among endoscopists., Objective: To define the prevalence of endoscopy-related musculoskeletal injuries and their impact on clinical practice and to identify physician and practice characteristics associated with their development., Design: Survey., Setting: Electronic survey of active members of the American Society for Gastrointestinal Endoscopy with registered e-mail addresses., Participants: Physicians who currently or ever performed endoscopy and responded to the survey between February 2013 and November 2013., Intervention: A 25-question, self-administered, electronic survey., Main Outcome Measurements: Prevalence, location, and ramifications of work-related injuries and endoscopist characteristics and workload parameters associated with endoscopy-related injury., Results: The survey was completed by 684 endoscopists. Of those, 362 (53%) experienced a musculoskeletal injury perceived definitely (n = 204) or possibly (n = 158) related to endoscopy. Factors associated with a higher rate of endoscopy-related injury included higher procedure volume (>20 cases/week; P < .001), greater number of hours per week spent performing endoscopy (>16 hours/week; P < .001), and total number of years performing endoscopy (P = .004). The most common sites of injury were neck and/or upper back (29%) and thumb (28%). Only 55% of injured endoscopists used practice modifications in response to injuries. Specific treatments included medications (57%), steroid injection (27%), physiotherapy (45%), rest (34%), splinting (23%), and surgery (13%)., Limitations: Self-reported data of endoscopy-related injury., Conclusion: Among endoscopists there is a high prevalence of injuries definitely or potentially related to endoscopy. Higher procedure volume, more time doing endoscopy per week, and cumulative years performing endoscopy are associated with more work-related injuries., (Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background and Study Aims: Endoscopic ultrasound - guided celiac plexus block (EUS-CPB) is an established treatment for pain in patients with chronic pancreatitis (CP), but the effectiveness and safety of repeated procedures are unknown. Our objective is to report our experience of repeated EUS-CPB procedures within a single patient., Patients and Methods: A prospectively maintained EUS database was retrospectively analyzed to identify patients who had undergone more than one EUS-CPB procedure over a 17-year period. The main outcome measures included number of EUS-CPB procedures for each patient, self-reported pain relief, duration of pain relief, and procedure-related adverse events., Results: A total of 248 patients underwent more than one EUS-CPB procedure and were included in our study. Patients with known or suspected CP (N = 248) underwent a mean (SD) of 3.1 (1.6) EUS-CPB procedures. In 76 % of the patients with CP, the median (range) duration of the response to the first EUS-CPB procedure was 10 (1 - 54) weeks. Lack of pain relief after the initial EUS-CPB was associated with failure of the next EUS-CPB (OR 0.17, 95 %CI 0.06 - 0.54). Older age at first EUS-CPB and pain relief after the first EUS-CPB were significantly associated with pain relief after subsequent blocks (P = 0.026 and P = 0.002, respectively). Adverse events included peri-procedural hypoxia (n = 2) and hypotension (n = 1) and post-procedural orthostasis (n = 2) and diarrhea (n = 4). No major adverse events occurred., Conclusions: Repeated EUS-CPB procedures in a single patient appear to be safe. Response to the first EUS-CPB is associated with response to subsequent blocks.

Objectives: In adults with unexplained pancreatitis, the yield of complete gene versus select exosome sequencing on mutation detection and distinguishing clinical characteristics associated with mutations requires clarification. We sought to (1) compare frequency of mutations identified using different techniques and (2) compare clinical characteristics between adults with and without mutations., Methods: This is a cohort study of adults with unexplained pancreatitis who underwent genetic testing between January 2008 and December 2012. We compare probabilities of having a positive mutation with complete gene sequencing versus alternatives and describe differences in characteristics among patients with and without mutations., Results: Of the 370 patients, 67 (18%) had a genetic mutation; 24 (6%) were of high risk. Mutations were significantly more prevalent with use of complete sequencing (42%) versus other approaches (8%, P < 0.0001). Most (44/67, 66%) with a mutation had no family history. Those with high-risk mutations were more likely to have a family history of chronic pancreatitis (21% vs 4%, P = 0.002). Patients with pancreas divisum were more likely to have mutations (27% vs 14%, P = 0.0007)., Conclusion: Among individuals with adult-onset pancreatic disease, the probability of finding any mutation, including high risk, is significantly higher using complete gene sequencing. The impact on patients and providers requires further investigation.

Objective: This study aimed to evaluate associations between endoscopic ultrasound (EUS) criteria for chronic pancreatitis (CP) and coexisting pancreatic intraepithelial neoplasia (PanIN) lesions., Methods: Patients with known or suspected CP who underwent pancreatic resection within a year of EUS were selected. Histology slides and EUS images were reviewed for evidence of pancreatic fibrosis., Results: Ninety-seven (51 men; mean age, 53 [12] years) underwent EUS within a 1 year or less of EUS. Pancreatic intraepithelial neoplasia lesions were found in 84 (87%) patients. Pancreatic intraepithelial neoplasia 1, 2, and 3 lesions were seen in 71 (83%), 10 (14%), and 1 (2%), respectively. Two patients had more than 1 PanIN grade (one had PanIN 1 and 2 and the other had PanIN 1 and 3). The mean number of EUS criteria for PanIN 1, 2, and 3 lesions were 3.9, 4.5, and 5.5, respectively. The odds ratio for the association between PanIN 2 and hyperechoic foci without shadowing in the pancreas head was 8.5 (P = 0.05). The odds ratio for the association between PanIN 2 and lobularity with honeycombing was 2.7 (P = ns). Advanced PanIN lesions had greater than or equal to 4 EUS criteria for CP., Conclusions: Pancreatic intraepithelial neoplasia lesions were highly prevalent in CP resections. Increasing PanIN grade is observed with increasing fibrosis score and increasing number of EUS criteria for CP.

Background and Aim: There are no data specifically correlating early intravenous volume infusion (IVI) with the length of hospitalization for postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP)., Methods: We conducted a retrospective cohort study of patients admitted within 24 h after ERCP to our institute with PEP. IVI during the first 24 h after ERCP was assessed. Primary outcome was severity of PEP, defined by length of hospitalization according to consensus guidelines: mild ≤ 3, moderate 4-10, and severe > 10 days., Results: Of 72 eligible patients, 41 (56.9%) had mild and 31 (43.1%) moderate/severe PEP. Both groups had comparable demographics, indications, and procedural factors except patients with moderate/severe PEP were older (median age 49 vs 36 years, P = 0.05) and more likely to be discharged and readmitted within the first 24 h (41.9% vs 14.6%, P < 0.01). Patients with mild PEP received significantly greater IVI during the first 24 h (2834 mL [2046, 3570] vs 2044 mL [1227, 2875], P < 0.02) and 50% more fluid post-ERCP (2270 mL [1435, 2961] vs 1515 [950-2350], P < 0.02) compared with those with at least moderate PEP., Conclusion: In patients with PEP, greater IVI during the first 24 h after ERCP is associated with reduced length of hospitalization. Lower IVI was more commonly observed in individuals who were discharged and then readmitted during the first 24 h., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Objectives: This study aimed to correlate endoscopic ultrasound (EUS) criteria and pathology in patients with chronic pancreatitis (CP)., Methods: Endoscopic ultrasound reports and pathology specimens were reviewed from patients with known or suspected CP who underwent surgery within 1 year of EUS. The following information was abstracted: EUS criteria for CP, corresponding pathology results, and histologic features. The EUS and pathology results were correlated., Results: One hundred patients (55 men; mean age, 54 years) underwent a pancreatic resection, median of 50 days (range, 1-363 days). The mean (SD) fibrosis scores in the head and body/tail specimens were 7.9 (3.0) and 6.4 (3.8), respectively (P = 0.02). The main pancreatic duct (MPD) dilation and irregularity were associated with moderate and severe fibrosis. Lobularity with honeycombing was associated with intralobular and interlobular fibrosis. Severe CP was associated with the following: lobularity with honeycombing, hyperechoic foci with shadowing, hyperechoic foci without shadowing, MPD dilation, MPD irregularity, and dilated side branches., Conclusions: Endoscopic ultrasound of the pancreas head may be considered in the evaluation of CP. The EUS criteria that were associated with severe CP included the following: lobularity with honeycombing, hyperechoic foci with shadowing, dilated MPD, irregular MPD, and dilated side branches. The importance of pancreatic ductal changes should not be minimized in the evaluation of CP.

The availability of human pluripotent stem cells (hPSCs) offers the opportunity to generate lineage-specific cells to investigate mechanisms of human diseases specific to brain regions. Here, we report a differentiation paradigm for hPSCs that enriches for hippocampal dentate gyrus (DG) granule neurons. This differentiation paradigm recapitulates the expression patterns of key developmental genes during hippocampal neurogenesis, exhibits characteristics of neuronal network maturation, and produces PROX1+ neurons that functionally integrate into the DG. Because hippocampal neurogenesis has been implicated in schizophrenia (SCZD), we applied our protocol to SCZD patient-derived human induced pluripotent stem cells (hiPSCs). We found deficits in the generation of DG granule neurons from SCZD hiPSC-derived hippocampal NPCs with lowered levels of NEUROD1, PROX1, and TBR1, reduced neuronal activity, and reduced levels of spontaneous neurotransmitter release. Our approach offers important insights into the neurodevelopmental aspects of SCZD and may be a promising tool for drug screening and personalized medicine.

Background: Endoscopic papillectomy is increasingly used as an alternative to surgery for ampullary adenomas and other noninvasive ampullary lesions., Objective: To measure short-term safety and efficacy of endoscopic papillectomy, define patient and lesion characteristics associated with incomplete endoscopic resection, and measure adenoma recurrence rates during long-term follow-up., Design: Retrospective cohort study., Setting: Tertiary-care academic medical center., Patients: All patients who underwent endoscopic papillectomy for ampullary lesions between July 1995 and June 2012., Intervention: Endoscopic papillectomy., Main Outcome Measurements: Patient and lesion characteristics associated with incomplete endoscopic resection and ampullary adenoma-free survival analysis., Results: We identified 182 patients who underwent endoscopic papillectomy, 134 (73.6%) having complete resection. Short-term adverse events occurred in 34 (18.7%). Risk factors for incomplete resection were jaundice at presentation (odds ratio [OR] 0.21; 95% confidence interval [CI] 0.07-0.69; P = .009), occult adenocarcinoma (OR 0.06; 95% CI, 0.01-0.36; P = .002), and intraductal involvement (OR 0.29; 95% CI, 0.11-0.75; P = .011). The en bloc resection technique was strongly associated with a higher rate of complete resection (OR 4.05; 95% CI, 1.71-9.59; P = .001). Among patients with ampullary adenoma who had complete resection (n = 107), 16 patients (15%) developed recurrence up to 65 months after resection., Limitations: Retrospective analysis., Conclusion: Jaundice at presentation, occult adenocarcinoma in the resected specimen, and intraductal involvement are associated with a lower rate of complete resection, whereas en bloc papillectomy increases the odds of complete endoscopic resection. Despite complete resection, recurrence was observed up to 5 years after papillectomy, confirming the need for long-term surveillance., (Copyright © 2014 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Background: Diagnosis of mucinous pancreatic cysts (MPCs) is challenging due to the poor sensitivity of cytology provided by EUS-guided-FNA (EUS-FNA)., Objective: To quantify the test characteristics of molecular (DNA) analysis in suspected low-risk MPCs., Design: A prospective cohort study performed in between 2008 and 2011., Setting: Academic referral center., Patients: Consecutive patients who underwent EUS-FNA of suspected MPCs., Intervention: EUS-FNA and molecular (DNA) analysis of cyst fluid., Main Outcome Measurements: The sensitivity and specificity of molecular analysis in the diagnosis of MPCs using the criterion standard of surgical pathology in resected cysts., Results: Patients with suspected MPCs underwent EUS-FNA and cyst fluid DNA analysis. Surgical resection was performed in 48 patients (17%), confirming a mucinous pathology in 38 (79%). In this group, molecular analysis had a sensitivity of 50% and a specificity of 80% in identifying MPCs (accuracy of 56.3%). The combination of molecular analysis with cyst fluid carcinoembryonic antigen (CEA) and cytology resulted in higher MPC diagnostic performance than either one of its individual components, with a sensitivity, specificity, and accuracy of 73.7%, 70%, and 72.9%, respectively. There was no significant difference in accuracy between molecular analysis and CEA/cytology in this group., Limitations: Single-center experience., Conclusion: Molecular analysis aids in the diagnosis of MPCs when cytology is nondiagnostic or cyst fluid is insufficient for CEA or its level is indeterminate. Our results do not support the routine use of molecular analysis, which should be used selectively after review of imaging findings and cyst fluid studies. Further studies are needed to assess DNA's performance in malignant cysts., (Copyright © 2014 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

This article presents an overlooked case of research misconduct and violations of basic principles of medical and business ethics. When Bayer's Cutter Laboratories realized that their blood products, Factor VIII and IX or antihemophiliac factor (AHF), were contaminated with human immunodeficiency virus (HIV), the financial investment in the product was considered too high to destroy the inventory. Cutter misrepresented the results of its own research and sold the contaminated AHF to overseas markets in Asia and Latin America without the precaution of heat treating the product recommended for eliminating the risk. As a consequence, hemophiliacs who infused the HIV-contaminated Factor VIII and IX tested positive for HIV and developed AIDS.

Background and Study Aim: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is frequently performed for suspected biliary tumors for diagnosis and staging but carries a theoretical risk of needle-track seeding. We aimed to evaluate the impact of preoperative EUS-FNA on long-term outcomes for patients with cholangiocarcinoma (CCA)., Patients and Methods: In a retrospective single-center study of consecutive patients with CCA with preoperative EUS-FNA, main outcome measures were overall survival and progression-free survival., Results: In 150 patients with confirmed CCA, 61 underwent preoperative FNA. Median overall survival was 18.5 months (95% confidence limits [CL] 15.4, 25.7): 111 patients died and 39 survived. Of the 150 patients, 119 underwent curative-intent surgical resection, with median progression-free survival of 17.8 months (95% CL 14.5, 22.8); 89/119 patients had tumor recurrence or died, and 30/119 remained alive and disease-free. On multivariable analysis, overall survival was associated with: undergoing curative-intent surgery (hazard ratio [HR] 5.79, P = 0.001), lack of lymph node involvement (HR 1.89, P = 0.011), younger age (HR 1.51 for every 10 years, P < 0.0015), and small tumor size (HR 1.11 for every 1 cm, P = 0.029). For patients undergoing curative-intent surgery, on multivariable analysis, improved progression-free survival was associated with: lack of lymph node involvement (HR 1.88, P = 0.010), smaller tumor size (HR 1.16 for every 1 cm smaller, P = 0.003), and younger age (HR 1.53 for every 10 years, P < 0.001). Number of needle passes showed no statistically significant impact on overall survival., Conclusion: Preoperative EUS-FNA in patients with CCA does not appear to adversely affect overall or progression-free survival., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Roux-en-Y gastric bypass (RYGB) is the most common bariatric surgery. The performance of ERCP in bariatric RYGB is challenging due to the long Roux limb. We herein compared the indications and technical outcomes of ERCP via percutaneous gastrostomy (GERCP) and double balloon enteroscopy (DBERCP) for patients with prior bariatric RYGB anatomy., Methods: Between December 2005 and November 2011, consecutive ERCP patients who had undergone RYGB were identified using a prospectively maintained electronic ERCP database. Medical records were abstracted for ERCP indications and outcomes. In most cases, the gastrostomy was done by either laparoscopic or open surgery and allowed to mature at least 1 month before performing ERCP. The choice of route for ERCP was at discretion of managing physician., Results: Forty-four patients (F = 42) with GERCP and 28 patients (F = 26) with DBERCP were identified. The mean age was younger in GERCP than DBERCP (44.8 vs. 56.1, p < 0.001). GERCP patients were more likely to have suspected sphincter of Oddi dysfunction (77 %) as the primary indication whereas DBERCP was suspected CBD stone (57 %). The mean total number of sessions/patient in GERCP and DBERCP was 1.7 ± 1.0 and 1.1 ± 0.4, respectively (p = 0.004). GERCP access to the major papilla was successful in all but two (97 %), whereas duct cannulation and interventions were successful in all. In DBERCP, the success rate of accessing major papilla, cannulation and therapeutic intervention was 78, 63, 56 %, respectively. There was one (3.1 %) post-ERCP pancreatitis in DBERCP. Complications occurred in 11 GERCP procedures (14.5 %) and 10 were related to the gastrostomy. This was significantly higher than that of DBERCP (p = 0.022)., Conclusions: GERCP is more effective than DBERCP in gaining access to the pancreatobiliary tree in patients with RYGB, but it is hindered by the gastrostomy maturation delay and a higher morbidity. Technical improvements in each method are needed.