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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A Prospective Multicenter Study Evaluating Learning Curves and Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography Among Advanced Endoscopy Trainees: The Rapid Assessment of Trainee Endoscopy Skills Study.

BACKGROUND & AIMS: On the basis of the Next Accreditation System, trainee assessment should occur on a continuous basis with individualized feedback. We aimed to validate endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) learning curves among advanced endoscopy trainees (AETs) by using a large national sample of training programs and to develop a centralized database that allows assessment of performance in relation to peers. METHODS: ASGE recognized training programs were invited to participate, and AETs were graded on ERCP and EUS exams by using a validated competency assessment tool that assesses technical and cognitive competence in a continuous fashion. Grading for each skill was done by using a 4-point scoring system, and a comprehensive data collection and reporting system was built to create learning curves by using cumulative sum analysis. Individual results and benchmarking to peers were shared with AETs and trainers quarterly. RESULTS: Of the 62 programs invited, 20 programs and 22 AETs participated in this study. At the end of training, median number of EUS and ERCP performed/AET was 300 (range, 155-650) and 350 (125-500), respectively. Overall, 3786 exams were graded (EUS, 1137; ERCP-biliary, 2280; ERCP-pancreatic, 369). Learning curves for individual end points and overall technical/cognitive aspects in EUS and ERCP demonstrated substantial variability and were successfully shared with all programs. The majority of trainees achieved overall technical (EUS, 82%; ERCP, 60%) and cognitive (EUS, 76%; ERCP, 100%) competence at conclusion of training. CONCLUSIONS: These results demonstrate the feasibility of establishing a centralized database to report individualized learning curves and confirm the substantial variability in time to achieve competence among AETs in EUS and ERCP. ClinicalTrials.gov: NCT02509416.