The Diagnostic Yield of Malignancy Comparing Cytology, FISH, and Molecular Analysis of Cell Free Cytology Brush Supernatant in Patients With Biliary Strictures Undergoing Endoscopic Retrograde Cholangiography (ERC): A Prospective Study.

BACKGROUND: Routine cytology of biliary stricture brushings obtained during endoscopic retrograde cholangiopancreatography (ERCP) has suboptimal sensitivity for malignancy. We compared the individual and combined ability of cytology, fluorescence in situ hybridization (FISH) analysis and PCR-based mutation profiling (MP) to detect malignancy in standard biliary brushings. METHODS: We performed a prospective study of patients undergoing ERCP using histology or 1 year follow-up to determine patient outcomes. MP was performed on free-DNA from biliary brushing specimens using normally discarded supernatant fluid. MP examined KRAS point mutations and tumor suppressor gene associated loss of heterozygosity mutations at 10 genomic loci. FISH examined chromosome specific gains or losses. RESULTS: A total of 101 patients were included in final analysis and 69% had malignancy. Cytology had 26% sensitivity and 100% specificity for malignancy. Using either FISH or MP in combination with cytology increased sensitivity to 44% and 56%, respectively. The combination of all 3 tests (cytology, FISH, and MP) had the highest sensitivity for malignancy (66%). There was no difference in the specificity of cytology, FISH or MP testing when examined alone or in combination. MP improved diagnostic yield of each procedure from 22% to 100%; FISH improved yield to 90%. MP detected 21 malignancies beyond that identified by cytology; FISH detected an additional 13. The combination of FISH and MP testing detected an additional 28 malignancies. CONCLUSIONS: Both MP and FISH are complimentary molecular tests that can significantly increase detection of biliary malignancies when used in combination with routine cytology of standard biliary brush specimens.

Utility of Endoscopic Ultrasound in Evaluating Local Recurrence After Surgery for Pancreatic Cancer.

Pancreatic adenocarcinoma recurrence after surgery (PARaS) is associated with poor outcomes. PARaS is locoregional in 50%-80%, effecting the resection bed and adjacent lymphatics.1-3 Detection of PARaS via endoscopic ultrasound (EUS) is challenging because recurrent malignancy is difficult to distinguish from normal postoperative changes. Diagnosing PARaS is important, because salvage chemotherapy/radiation improves survival.4,5 The purpose of this investigation is to determine the clinical utility of EUS fine-needle aspiration (FNA) in patients with suspected PARaS.

EUS-guided drainage of peripancreatic fluid collections with lumen-apposing metal stents and plastic double-pigtail stents: comparison of efficacy and adverse event rates.

BACKGROUND AND AIMS: Transmural drainage with double-pigtail plastic stents (DPPSs) was the mainstay of endoscopic therapy for symptomatic peripancreatic fluid collections (PPFCs) until the introduction of lumen-apposing covered self-expanding metal stents (LAMSs). Currently, there are limited data regarding the efficacy and adverse event rate of LAMSs compared with DPPSs. METHODS: A retrospective analysis of EUS-guided PPFC drainage at a single tertiary care center between 2008 and 2015 was performed. Patients were classified based on drainage method: DPPSs and LAMSs. Adverse event rates, unplanned endoscopic procedures/necrosectomies, and PPFC resolution within 6 months were recorded. Significant bleeding was defined as necessitating transfusion or requiring endoscopic treatment/radiographic embolization. Subsequent endoscopic procedures were defined as unplanned procedures; stent removals were excluded. RESULTS: A total of 103 patients met inclusion criteria (84 DPPSs, 19 LAMSs). PPFCs were classified as walled-off necrosis (WON) in 23 (14 DPPSs, 9 LAMSs). There were significantly more bleeding episodes in the LAMS group (4 [19%]: 2 splenic artery pseudo-aneurysms, 1 collateral vessel bleed, 1 intracavitary variceal bleed; P = .0003) than in the DPPS group (1 (1%]: stent erosion into the gastric wall). One perforation occurred in the DPPS group. Unplanned repeat endoscopy was more frequent in the LAMS group (10% vs 26%, P = .07). Among retreated LAMS patients in with WON, 5 (56%) had obstruction by necrotic debris. In patients for whom follow-up was available, 67 of 70 (96%) with DPPSs and 16 of 17 (94%) with LAMSs had resolution of PPFCs within 6 months (P = .78). CONCLUSIONS: DPPSs and LAMSs are effective methods for treatment of PPFCs. In our cohort, use of LAMSs was associated with significantly higher rates of procedure-related bleeding and greater need for repeat endoscopic intervention.

Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections.

BACKGROUND AND AIMS: Peripancreatic fat necrosis occurs frequently in necrotising pancreatitis. Distinguishing markers from mediators of severe acute pancreatitis (SAP) is important since targeting mediators may improve outcomes. We evaluated potential agents in human pancreatic necrotic collections (NCs), pseudocysts (PCs) and pancreatic cystic neoplasms and used pancreatic acini, peripheral blood mononuclear cells (PBMC) and an acute pancreatitis (AP) model to determine SAP mediators. METHODS: We measured acinar and PBMC injury induced by agents increased in NCs and PCs. Outcomes of caerulein pancreatitis were studied in lean rats coadministered interleukin (IL)-1ß and keratinocyte chemoattractant/growth-regulated oncogene, triolein alone or with the lipase inhibitor orlistat. RESULTS: NCs had higher fatty acids, IL-8 and IL-1ß versus other fluids. Lipolysis of unsaturated triglyceride and resulting unsaturated fatty acids (UFA) oleic and linoleic acids induced necro-apoptosis at less than half the concentration in NCs but other agents did not do so at more than two times these concentrations. Cytokine coadministration resulted in higher pancreatic and lung inflammation than caerulein alone, but only triolein coadministration caused peripancreatic fat stranding, higher cytokines, UFAs, multisystem organ failure (MSOF) and mortality in 97% animals, which were prevented by orlistat. CONCLUSIONS: UFAs, IL-1ß and IL-8 are elevated in NCs. However, UFAs generated via peripancreatic fat lipolysis causes worse inflammation and MSOF, converting mild AP to SAP.

Variation in learning curves and competence for ERCP among advanced endoscopy trainees by using cumulative sum analysis.

BACKGROUND AND AIMS: There are limited data on learning curves and competence in ERCP. By using a standardized data collection tool, we aimed to prospectively define learning curves and measure competence among advanced endoscopy trainees (AETs) by using cumulative sum (CUSUM) analysis. METHODS: AETs were evaluated by attending endoscopists starting with the 26th hands-on ERCP examination and then every ERCP examination during the 12-month training period. A standardized ERCP competency assessment tool (using a 4-point scoring system) was used to grade the examination. CUSUM analysis was applied to produce learning curves for individual technical and cognitive components of ERCP performance (success defined as a score of 1, acceptable and unacceptable failures [p1] of 10% and 20%, respectively). Sensitivity analyses varying p1 and by using a less-stringent definition of success were performed. RESULTS: Five AETs were included with a total of 1049 graded ERCPs (mean ± SD, 209.8 ± 91.6/AET). The majority of cases were performed for a biliary indication (80%). The overall and native papilla allowed cannulation times were 3.1 ± 3.6 and 5.7 ± 4, respectively. Overall learning curves demonstrated substantial variability for individual technical and cognitive endpoints. Although nearly all AETs achieved competence in overall cannulation, none achieved competence for cannulation in cases with a native papilla. Sensitivity analyses increased the proportion of AETs who achieved competence. CONCLUSION: This study demonstrates that there is substantial variability in ERCP learning curves among AETs. A specific case volume does not ensure competence, especially for native papilla cannulation.

Variation in Aptitude of Trainees in Endoscopic Ultrasonography, Based on Cumulative Sum Analysis.

BACKGROUND & AIMS: Studies have reported substantial variation in the competency of advanced endoscopy trainees, indicating a need for more supervised training in endoscopic ultrasound (EUS). We used a standardized, validated, data collection tool to evaluate learning curves and measure competency in EUS among trainees at multiple centers. METHODS: In a prospective study performed at 15 centers, 17 trainees with no prior EUS experience were evaluated by experienced attending endosonographers at the 25th and then every 10th upper EUS examination, over a 12-month training period. A standardized data collection form was used (using a 5-point scoring system) to grade the EUS examination. Cumulative sum analysis was applied to produce a learning curve for each trainee; it tracked the overall performance based on median scores at different stations and also at each station. Competency was defined by a median score of 1, with acceptable and unacceptable failure rates of 10% and 20%, respectively. RESULTS: Twelve trainees were included in the final analysis. Each of the trainees performed 265 to 540 EUS examinations (total, 4257 examinations). There was a large amount of variation in their learning curves: 2 trainees crossed the threshold for acceptable performance (at cases 225 and 245), 2 trainees had a trend toward acceptable performance (after 289 and 355 cases) but required continued observation, and 8 trainees needed additional training and observation. Similar results were observed at individual stations. CONCLUSIONS: A specific case load does not ensure competency in EUS; 225 cases should be considered the minimum caseload for training because we found that no trainee achieved competency before this point. Ongoing training should be provided for trainees until competency is confirmed using objective measures.

Impact of retroflexion vs. second forward view examination of the right colon on adenoma detection: a comparison study.

OBJECTIVES: Although screening colonoscopy is effective in preventing distal colon cancers, effectiveness in preventing right-sided colon cancers is less clear. Previous studies have reported that retroflexion in the right colon improves adenoma detection. We aimed to determine whether a second withdrawal from the right colon in retroflexion vs. forward view alone leads to the detection of additional adenomas. METHODS: Patients undergoing screening or surveillance colonoscopy were invited to participate in a parallel, randomized, controlled trial at two centers. After cecal intubation, the colonoscope was withdrawn to the hepatic flexure, all visualized polyps removed, and endoscopist confidence recorded on a 5-point Likert scale. Patients were randomized to a second exam of the proximal colon in forward (FV) or retroflexion view (RV), and adenoma detection rates (ADRs) compared. Logistic regression analysis was used to evaluate predictors of identifying adenomas on the second withdrawal from the proximal colon. RESULTS: A total of 850 patients (mean age 59.1±8.3 years, 59% female) were randomly assigned to FV (N=400) or RV (N=450). Retroflexion was successful in 93.5%. The ADR (46% FV and 47% RV) and numbers of adenomas per patient (0.9±1.4 FV and 1.1±2.1 RV) were similar (P=0.75 for both). At least one additional adenoma was detected on second withdrawal in similar proportions (10.5% FV and 7.5% RV, P=0.13). Predictors of identifying adenomas on the second withdrawal included older age (odds ratio (OR)=1.04, 95% confidence interval (CI)=1.01-1.08), adenomas seen on initial withdrawal (OR=2.8, 95% CI=1.7-4.7), and low endoscopist confidence in quality of first examination of the right colon (OR=4.8, 95% CI=1.9-12.1). There were no adverse events. CONCLUSIONS: Retroflexion in the right colon can be safely achieved in the majority of patients undergoing colonoscopy for colorectal cancer screening. Reexamination of the right colon in either retroflexed or forward view yielded similar, incremental ADRs. A second exam of the right colon should be strongly considered in patients who have adenomas discovered in the right colon, particularly when endoscopist confidence in the quality of initial examination is low.

Acute lipotoxicity regulates severity of biliary acute pancreatitis without affecting its initiation.

Obese patients have worse outcomes during acute pancreatitis (AP). Previous animal models of AP have found worse outcomes in obese rodents who may have a baseline proinflammatory state. Our aim was to study the role of acute lipolytic generation of fatty acids on local severity and systemic complications of AP. Human postpancreatitis necrotic collections were analyzed for unsaturated fatty acids (UFAs) and saturated fatty acids. A model of biliary AP was designed to replicate the human variables by intraductal injection of the triglyceride glyceryl trilinoleate alone or with the chemically distinct lipase inhibitors orlistat or cetilistat. Parameters of AP etiology and outcomes of local and systemic severity were measured. Patients with postpancreatitis necrotic collections were obese, and 13 of 15 had biliary AP. Postpancreatitis necrotic collections were enriched in UFAs. Intraductal glyceryl trilinoleate with or without the lipase inhibitors resulted in oil red O-positive areas, resembling intrapancreatic fat. Both lipase inhibitors reduced the glyceryl trilinoleate-induced increase in serum lipase, UFAs, pancreatic necrosis, serum inflammatory markers, systemic injury, and mortality but not serum alanine aminotransferase, bilirubin, or amylase. We conclude that UFAs are enriched in human necrotic collections and acute UFA generation via lipolysis worsens pancreatic necrosis, systemic inflammation, and injury associated with severe AP. Inhibition of lipolysis reduces UFA generation and improves these outcomes of AP without interfering with its induction.

Compliance with surveillance recommendations for foregut subepithelial tumors is poor: results of a prospective multicenter study.

BACKGROUND: American Gastroenterological Association guidelines recommend performing EUS to characterize subepithelial lesions (SELs) discovered on upper endoscopy (EGD), followed by surveillance if no high-risk features are identified. However, limited data are available on the impact of and compliance with surveillance recommendations. OBJECTIVE: To determine the natural history of SELs<30 mm in size evaluated by EUS and to determine the degree of patient compliance with surveillance recommendations. DESIGN: Prospective registry. SETTING: Two tertiary centers. PATIENTS: We studied 187 consecutive adult patients referred for EUS evaluation of foregut SELs. MAIN OUTCOME MEASUREMENTS: Proportion of patients in whom SELs change in size or echo-features and compliance with follow-up recommendations. RESULTS: Surveillance was recommended in 65 patients with hypoechoic SELs (44.6% women, age 59.5±13.2 years); of these, 29 (44.6%) underwent surveillance EUS as recommended and were followed for a median of 30 months (range, 12-105). During follow-up, 16 SELs (25%) increased in size, with a mean increase of 3.4±3.9 mm (range, 1-15). No changes in echo-texture of the SELs were observed. One patient was referred to surgery during follow-up (because of SEL growth>30 mm). LIMITATIONS: Short follow-up duration; compliance was a secondary aim. CONCLUSIONS: During a median follow-up of 30 months, growth in size was observed in 25% of small foregut SELs. However, change in size was minimal, and only 1 patient was referred for surgery based on surveillance EUS findings. Compliance with surveillance recommendations is poor, with fewer than 50% of patients undergoing surveillance EUS as recommended.

Endoscopic mucosal resection.

EMR has become an established therapeutic option for premalignant and early-stage GI malignancies, particularly in the esophagus and colon. EMR can also aid in the diagnosis and therapy of subepithelial lesions localized to the muscularis mucosa or submucosa. Several dedicated EMR devices are available to facilitate these procedures. Adverse event rates, particularly bleeding and perforation, are higher after EMR relative to other basic endoscopic interventions but lower than adverse event rates for ESD. Endoscopists performing EMR should be knowledgeable and skilled in managing potential adverse events resulting from EMR.

Echoendoscopes.

Advances in echoendoscopes and their processors have significantly expanded the role of EUS and its clinical applications.The diagnostic and therapeutic capabilities of EUS continue to evolve and improve. EUS has made a large impact on patient care but comes with significant startup and maintenance costs. As improved technology continues to enhance image resolution while decreasing the size of EUS processors, use of endosonography will become more widespread. EUS will continue to be a vital part of patient care and complement currently available cross-sectional imaging.

Enteroscopy.

Noninvasive imaging with CT and magnetic resonance enterography or direct visualization with wireless capsule endoscopy can provide valuable diagnostic information and direct therapy. Enteroscopy technology and techniques have evolved significantly and allow diagnosis and therapy deep within the small bowel, previously attainable only with intraoperative enteroscopy. Push enteroscopy, readily available in most endoscopy units, plays an important role in the evaluation and management of lesions located up to the proximal jejunum. Currently available device-assisted enteroscopy systems, DBE, SBE, and spiral enteroscopy each have their technical nuances, clinical advantages, and limitations. Newer, on-demand enteroscopy systems appear promising, but further studies are needed. Despite slight differences in parameters such as procedural times, depths of insertion, and rates of complete enteroscopy, the overall clinical outcomes with all overtube-assisted systems appear to be similar. Endoscopists should therefore master the enteroscopy technology based on institutional availability and their level of technical expertise.

Endoscopic submucosal dissection.

ESD is an established effective treatment modality for premalignant and early-stage malignant lesions of the stomach, esophagus, and colorectum. Compared with EMR, ESD is generally associated with higher rates of en bloc, R0, and curative resections and a lower rate of local recurrence. Oncologic outcomes with ESD compare favorably with competing surgical interventions, and ESD also serves as an excellent T-staging tool to identify noncurative resections that will require further treatment. ESD is technically demanding and has a higher rate of adverse events than most endoscopic procedures including EMR. As such,sufficient training is critical to ensure safe conduct and high-quality resections. A standardized training model for Western endoscopists has not been clearly established,but will be self-directed and include courses, animal model training, and optimally an observership at an expert center.Numerous dedicated ESD devices are now available in the United States from different manufacturers. Although the use of ESD in the United States is increasing, issues related to technical difficulty, limited training opportunities and mentors, risk of adverse events, long procedure duration,and suboptimal reimbursement may limit ESD adoption in the United States to a modest number of academic referral centers for the foreseeable future.

ASGE Technology Committee systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting real-time endoscopic assessment of the histology of diminutive colorectal polyps.

In vivo real-time assessment of the histology of diminutive (≤5 mm) colorectal polyps detected at colonoscopy can be achieved by means of an "optical biopsy" by using currently available endoscopic technologies. This systematic review and meta-analysis was performed by the American Society for Gastrointestinal Endoscopy (ASGE) Technology Committee to specifically assess whether acceptable performance thresholds outlined by an ASGE Preservation and Incorporation of Valuable endoscopic Innovations (PIVI) document for clinical adoption of these technologies have been met. We conducted direct meta-analyses calculating the pooled negative predictive value (NPV) for narrow-band imaging (NBI), i-SCAN, and Fujinon Intelligent Color Enhancement (FICE)-assisted optical biopsy for predicting adenomatous polyp histology of small/diminutive colorectal polyps. We also calculated the pooled percentage agreement with histopathology when assigning postpolypectomy surveillance intervals based on combining real-time optical biopsy of colorectal polyps 5 mm or smaller with histopathologic assessment of polyps larger than 5 mm. Random-effects meta-analysis models were used. Statistical heterogeneity was evaluated by means of I(2) statistics. Our meta-analyses indicate that optical biopsy with NBI, exceeds the NPV threshold for adenomatous polyp histology, supporting a "diagnose-and-leave" strategy for diminutive predicted nonneoplastic polyps in the rectosigmoid colon. The pooled NPV of NBI for adenomatous polyp histology by using the random-effects model was 91% (95% confidence interval [CI], 88-94). This finding was associated with a high degree of heterogeneity (I(2) = 89%). Subgroup analysis indicated that the pooled NPV was greater than 90% for academic medical centers (91.8%; 95% CI, 89-94), for experts (93%; 95% CI, 91-96), and when the optical biopsy assessment was made with high confidence (93%; 95% CI, 90-96). Our meta-analyses also indicate that the agreement in assignment of postpolypectomy surveillance intervals based on optical biopsy with NBI of diminutive colorectal polyps is 90% or greater in academic settings (91%; 95% CI, 86-95), with experienced endoscopists (92%; 95% CI, 88-96) and when optical biopsy assessments are made with high confidence (91%; 95% CI, 88-95). Our systematic review and meta-analysis confirms that the thresholds established by the ASGE PIVI for real-time endoscopic assessment of the histology of diminutive polyps have been met, at least with NBI optical biopsy, with endoscopists who are expert in using this advanced imaging technology and when assessments are made with high confidence.

Electronic chromoendoscopy.

Electronic chromoendoscopy technologies provide image enhancement and may improve the diagnosis of mucosal lesions. Although strides have been made in standardization of image characterization, especially with NBI, further image-to-pathology correlation and validation are required. There is promise for the development of a resect and discard policy for diminutive adenomas by using electronic chromoendoscopy; however, before this can be adopted, further community-based studies are needed. Further validated training tools for NBI, FICE, and i-SCAN will also be required for the use of these techniques to become widespread.

Suboptimal accuracy of carcinoembryonic antigen in differentiation of mucinous and nonmucinous pancreatic cysts: results of a large multicenter study.

BACKGROUND AND AIMS: The exact cutoff value at which pancreatic cyst fluid carcinoembryonic antigen (CEA) level distinguishes pancreatic mucinous cystic neoplasms (MCNs) from pancreatic nonmucinous cystic neoplasms (NMCNs) is unclear. The aim of this multicenter retrospective study was to evaluate the diagnostic accuracy of cyst fluid CEA levels in differentiating between MCNs and NMCNs. METHODS: Consecutive patients who underwent EUS with FNA at 3 tertiary care centers were identified. Patients with histologic confirmation of cyst type based on surgical specimens served as the criterion standard for this analysis. Demographic characteristics, EUS morphology, FNA fluid, and cytology results were recorded. Multivariate logistic regression analysis to identify predictors of MCNs was performed. Receiver-operating characteristic (ROC) curves were generated for CEA levels. RESULTS: A total of 226 patients underwent surgery (mean age, 61 years, 96% white patients, 39% female patients) of whom 88% underwent Whipple's procedure or distal pancreatectomy. Based on surgical histopathology, there were 150 MCNs and 76 NMCNs cases. The median CEA level was 165 ng/mL. The area under the ROC curve for CEA levels in differentiating between MCNs and NMCNs was 0.77 (95% confidence interval, 0.71-0.84, P < .01) with a cutoff of 105 ng/mL, demonstrating a sensitivity and specificity of 70% and 63%, respectively. The cutoff value of 192 ng/mL yielded a sensitivity of 61% and a specificity of 77% and would misdiagnose 39% of MCN cases. CONCLUSIONS: Cyst fluid CEA levels have a clinically suboptimal accuracy level in differentiating MCNs from NMCNs. Future studies should focus on novel cyst fluid markers to improve risk stratification of pancreatic cystic neoplasms.

Devices for the endoscopic treatment of hemorrhoids.

Multiple endoscopic methods are available to treat symptomatic internal hemorrhoids. Because of its low cost, ease of use, low rate of adverse events, and relative effectiveness, RBL is currently the most widely used technique.

Wireless capsule endoscopy.

Over the last decade, WCE has established itself as a valuable test for imaging the small intestine. It is a safe and relatively easy procedure to perform that can provide valuable information in the diagnosis of small-bowel conditions. Its applications still remain limited within the esophagus and colon. Future developments may include improving visualization within the esophagus and developing technologies that may allow manipulation of the capsule within the GI tract and biopsy capabilities.

Learning curves for EUS by using cumulative sum analysis: implications for American Society for Gastrointestinal Endoscopy recommendations for training.

BACKGROUND: American Society for Gastrointestinal Endsocopy (ASGE) guidelines for assessing minimal competence in EUS are based on expert opinion and retrospective studies. OBJECTIVE: To prospectively define learning curves in EUS among advanced endoscopy trainees (AETs). DESIGN: Prospective trial. SETTING: Three tertiary-care referral centers. PATIENTS: AETs with no prior EUS experience. INTERVENTION: AETs were evaluated by attending endosonographers at intervals of 10 EUS examinations (beginning at the 25th examination) during a 12-month training period. A standardized data collection form was used to grade examination of EUS anatomic stations and, when applicable, lesion of interest, accurate uTNM staging, wall layer origin of subepithelial lesions, and technical success with FNA. MAIN OUTCOME MEASUREMENTS: Cumulative sum analysis was applied to assess competency and produce a learning curve for each trainee for overall performance and for each anatomic station. Acceptable and unacceptable failure rates of 10% and 20%, respectively, were used. RESULTS: Five AETs were included, with a total of 1412 EUS examinations (AET1-225, T2-175, T3-402, T4-315, T5-295). Two AETs crossed the threshold for acceptable performance at cases number 255 and 295, two AETs showed a trend toward acceptable performance after 225 and 196 cases but needed ongoing training, and 1 AET demonstrated the need for ongoing training after 402 cases. Similar variable results were noted for individual stations. LIMITATIONS: Results from this study may not be generalizable to other centers' AETs. CONCLUSION: We observed substantial variability in achieving competency and a consistent need for more supervision in all AETs than current recommendations (150 cases). Future studies should focus on standardization of trainee performance, definition of competency, and widespread applicability of AET evaluation.