Iatrogenic Portobiliary Fistula following Endoscopic Biliary Stent Placement: A Case Series and Review of the Literature.

Iatrogenic portobiliary fistula is a rare adverse event following endoscopic biliary stent placement. Damage to the portal vein following endoscopic biliary stent placement has previously only been reported as single case reports. Management has ranged from conservative monitoring to surgery. Here, the authors present 4 cases of inadvertent endoscopic placement of a biliary stent into the portal vein. Interventional radiology was called to assist in the management of each of these cases. The experience presented here in conjunction with review of the previously reported cases helps shed light on potential management strategies if this adverse event is encountered in the future.

Diphenyleneiodonium enhances oxidative stress and inhibits Japanese encephalitis virus induced autophagy and ER stress pathways.

Diphenyleneiodonium (DPI) and N-acetyl-l-cysteine (NAC), two widely used anti-oxidants, were employed to evaluate the role of oxidative stress in Japanese encephalitis virus (JEV) induced autophagy, stress responses and replication. DPI and NAC exerted opposite effects on ROS levels in JEV infected mouse neuronal cells (Neuro2a), mouse embryonic fibroblasts (MEFs) and human epithelial cells (HeLa). While NAC effectively quenched ROS, DPI enhanced ROS levels, suggesting that DPI induces oxidative stress in JEV infected cells. DPI treatment of JEV infected Neuro2a cells further blocked autophagy induction and activation of all three arms of the ER stress pathway, and, inhibited virus particle release. Autophagy induction in JEV infection has been previously shown to be linked to the activation of XBP1 and ATF6 ER stress sensors. Our data suggests that DPI mediated block of autophagy is a result of inhibition of ER stress responses and is not associated with an anti-oxidative effect. Since DPI has a wide inhibitory potential for all Flavin dependent enzymes, it is likely that the signalling pathways for ER stress and autophagy during JEV infection are modulated by DPI sensitive enzymes.

Japanese encephalitis virus activates autophagy through XBP1 and ATF6 ER stress sensors in neuronal cells.

Endoplasmic reticulum (ER) stress and autophagy are key cellular responses to RNA virus infection. Recent studies have shown that Japanese encephalitis virus (JEV)-induced autophagy negatively influences virus replication in mouse neuronal cells and embryonic fibroblasts, and delays virus-induced cell death. Here, we evaluated the role of ER stress pathways in inducing autophagy during JEV infection. We observed that JEV infection of neuronal cells led to activation of all three sensors of ER stress mediated by eIF2α/PERK, IRE1/XBP1 and ATF6. The kinetics of autophagy induction as monitored by levels of SQSTM1 and LC3-II paralleled activation of ER stress. Inhibition of the eIF2α/PERK pathway by siRNA-mediated depletion of proteins and by the PERK inhibitor had no effect on autophagy and JEV replication. However, depletion of XBP1 and ATF6, alone or in combination, prevented autophagy induction and significantly enhanced JEV-induced cell death. JEV-infected cells depleted of XBP1 or ATF6 showed reduced transcription of ER chaperones, ERAD components and autophagy genes, resulting in reduced protein levels of the crucial autophagy effectors ATG3 and BECLIN-1. Conversely, pharmacological induction of ER stress in JEV-infected cells further enhanced autophagy and reduced virus titres. Our study thus demonstrates that a crucial link exists between the ER stress pathways and autophagy in virus-infected cells, and that these processes are highly regulated during virus infection.

Lumen-apposing covered self-expandable metal stents for short benign gastrointestinal strictures: a multicenter study.

Background and study aim Use of the fully covered self-expandable metal stent (SEMS) for benign luminal gastrointestinal (GI) stricture (BLGS) has been limited by the migration rate. The role of the lumen-apposing metal stent (LAMS) for BLGS is not well defined. We assessed the safety, feasibility, and efficacy of LAMS for the treatment of BLGS. Patients and methods This was an observational, open-label, retrospective, single-arm, multicenter consecutive case series of patients undergoing LAMS placement for BLGS. Technical success was defined as successful placement of the LAMS. Short- and long-term clinical success rates were defined as symptom improvement/resolution with indwelling stent and after stent removal, respectively. All adverse events and additional interventions were recorded. Results A total of 30 patients (mean age 51.6 years; 63.3 % women) underwent LAMS placement for GI strictures (83.9 % anastomotic). Median stricture diameter and length were 4.5 mm (range 2 - 10 mm) and 8 mm (range 5 - 10 mm), respectively. Technical success was achieved in 29 patients (96.7 %), with an adverse event rate of 13.3 %. The stent migration rate was 8.0 % (2/25) on follow-up endoscopy. Short-term clinical success was achieved in 90.0 % (27/30) at a median of 60 days (interquartile range [IQR] 40 - 90 days). Most patients (19/23; 82.6 %) experienced sustained symptom improvement/resolution without the need for additional interventions at a median follow-up of 100 days (IQR 60 - 139 days) after LAMS removal. Conclusion This multicenter study demonstrated that LAMS placement represents a safe, feasible, and effective therapeutic option for patients with BLGS and is associated with a low stent migration rate. Our initial findings suggest that future prospective comparative studies are needed on the use of LAMS, endoscopic dilation, and conventional SEMS. .

Impact of Endotracheal Intubation on Interventional Endoscopy Unit Efficiency Metrics at a Tertiary Academic Medical Center.

OBJECTIVES: Measures for evaluating interventional endoscopy unit efficiency have not been adequately validated, especially in reference to the involvement of anesthesia services for endoscopy. Primary aim was to compare process measures/metrics of interventional endoscopy unit efficiency between intubated and non-intubated patients. Secondary aim was to assess variables associated with the need for endotracheal intubation. METHODS: The prospectively collected endoscopy unit metrics database at UF Health was reviewed for procedures performed in the interventional endoscopy unit for 6 months. Parameters included hospital-mandated metrics available from the database. RESULTS: A total of 1,421 patients underwent 1,635 interventional endoscopic procedures and 271/1,421 patients (19.1%) were intubated. There was no significant difference between intubated and non-intubated cohorts with respect to age, gender, BMI, ASA Score, Mallampati Score, or the Charlson Comorbidity Index. Patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) were more frequently intubated than those undergoing non-ERCP procedures (41.3 vs. 12.4%, P<0.0001). Inpatients comprised 48.3% of all intubated patients, whereas only 29.2% of non-intubated patients were inpatients (P<0.0001). Most patients (159/271, 58.7%) were intubated per anesthesiologist preference. All process efficiency metrics were significantly prolonged in the intubated compared with the non-intubated patient cohort, except the time interval between successive procedures. Multivariate analysis revealed that patients with an anesthesiologist who had performed a greater number of total endoscopic sedations were less likely to be intubated than patients with an anesthesiologist who had performed fewer total procedures (P=0.0066). CONCLUSIONS: Endotracheal intubation negatively impacts efficiency metrics in an interventional endoscopy unit. Careful assessment for the need for intubation should be emphasized.

Utility of clinical suspicion and endoscopic re-examination for detection of esophagogastric perforation after pneumatic dilation for achalasia.

BACKGROUND AND STUDY AIMS: Esophagrams are often obtained routinely after pneumatic balloon dilation for achalasia, even in asymptomatic patients, as there is a risk of postprocedure esophagogastric perforation, which is a potentially life-threatening complication. The aim of this study was to determine whether the combination of a clinical suspicion of perforation and endoscopic re-examination after pneumatic dilation for achalasia can detect esophagogastric perforation, and thereby preclude the need for routine esophagrams in all patients. PATIENTS AND METHODS: All patients who underwent pneumatic dilation between January 2002 and June 2012 at our single tertiary referral center were identified retrospectively. Procedures were categorized into two groups: Group 1 underwent routine esophagograms after pneumatic dilation, and Group 2 underwent esophagograms only if there was a clinical suspicion of perforation. The detection rate of esophageal perforation after pneumatic dilation was compared between the two groups. RESULTS: A total of 119 achalasia dilation procedures were performed in 70 patients. Group 1 included 49/119 procedures (41.2 %), all of which were followed by routine esophagograms. Group 2 included 70/119 procedures (58.8 %), 12 of which were followed by esophagograms based on a clinical suspicion of perforation. No esophageal perforations were found in Group 1, whereas three were found in Group 2. No perforations occurred in the 58 procedures that were not followed by esophagograms. The overall rate of perforation was 3/119 (2.5 %). CONCLUSIONS: Esophagrams obtained routinely after pneumatic dilation for achalasia did not reveal unsuspected esophagogastric perforations. No esophageal perforations were missed after procedures that were not followed by esophagograms. Obtaining an esophagram only in cases of clinical suspicion of perforation and endoscopic evaluation may be an alternative to routine esophagograms in patients undergoing pneumatic dilation for achalasia.

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 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.

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.

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.

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.

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.

Diagnostic accuracy of conventional and cholangioscopy-guided sampling of indeterminate biliary lesions at the time of ERCP: a prospective, long-term follow-up study.

BACKGROUND: The diagnostic accuracy of cholangioscopy-guided sampling has not been rigorously evaluated. OBJECTIVE: To prospectively evaluate the accuracy of cholangioscopy-guided mini-forceps sampling and compare it with standard cytology brushings and forceps biopsies for the tissue diagnosis of indeterminate biliary lesions. DESIGN: Prospective, long-term follow-up, paired design cohort study. SETTING: Tertiary center. PATIENTS: Patients undergoing cholangioscopy for the evaluation of indeterminate biliary lesions. INTERVENTIONS: Each patient underwent triple sampling with cholangioscopy-guided mini-forceps, cytology brushing, and standard forceps. MAIN OUTCOME MEASUREMENTS: Diagnostic accuracy of each sampling method compared with the patient final status (cancer vs no cancer). RESULTS: A total of 26 patients (17 cancer positive/9 cancer negative) were enrolled. The mean follow-up in the patients with no cancer was 21.78 (SD ±6.78) months. The procedure was technically successful in all cases (100%). Sample quality was adequate in 25 of 26 (96.2%) of the cytology brushings, in 26 of 26 (100%) of the standard forceps biopsies, and in 25 of 26 (96.2%) of the mini-forceps biopsies. The sensitivity, accuracy, and negative predictive values were 5.9%, 38.5%, and 36% for standard cytology brushings; 29.4%, 53.8%, and 42.8% for standard forceps biopsies; and 76.5%, 84.6%, and 69.2% for mini-forceps biopsies, respectively. When comparing the 3 methods of sampling, mini-forceps biopsy provided significantly better sensitivity and overall accuracy compared with standard cytology brushing (P < .0001) and standard forceps biopsy (P = .0215). LIMITATIONS: Potential for selection bias. CONCLUSIONS: Cholangioscopy-guided biopsies of indeterminate biliary lesions have significantly higher accuracy compared with ERCP-guided cytology brushings and standard forceps biopsies, but negative findings on mini-forceps biopsy cannot rule out malignancy with a high degree of certainty. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01227382.).

Prospective evaluation of the long-term outcomes after deep small-bowel spiral enteroscopy in patients with obscure GI bleeding.

BACKGROUND: Spiral enteroscopy can be safe and effective in the short term for evaluation of obscure GI bleeding, but long-term data are lacking. OBJECTIVE: To assess the long-term clinical outcomes after deep small-bowel spiral enteroscopy performed for obscure GI bleeding. DESIGN: Prospective cohort study. SETTING: Academic referral center. PATIENTS: This study included 78 patients who underwent antegrade spiral enteroscopy for evaluation of obscure GI bleeding. INTERVENTION: Diagnostic spiral enteroscopy with hemostatic therapeutic maneuvers applied as indicated. MAIN OUTCOME MEASUREMENTS: Postprocedure evidence of recurrent overt GI bleeding, blood transfusion requirements, need for iron supplementation, serum hemoglobin values, and the need for additional therapeutic procedures. RESULTS: Long-term follow-up data (mean [± standard deviation] 25.3 ± 7.5 months; range 12.9-38.8 months) were obtained in 61 patients (78%). Among those with long-term follow-up data, overt bleeding before spiral enteroscopy was present in 62%, compared with 26% in the follow-up period (P < .0001). The mean (± SD) hemoglobin value increased from 10.6 ± 1.8 to 12.6 ± 1.9 g/dL (P < .0001). Blood transfusion requirements decreased by a mean of 4.19 units per patient (P = .0002), and the need for iron supplementation (P = .0487) and additional procedures (P < .0001) decreased in the follow-up period. There were 8 adverse events (9%) (7 mild, 1 moderate). LIMITATIONS: Single-center study, intervention bias. CONCLUSION: In patients with obscure GI bleeding, deep small-bowel spiral enteroscopy is safe and effective in reducing the incidence of overt bleeding. An increase in hemoglobin values along with a decrease in blood transfusion requirement, need for iron supplementation, and need for additional therapeutic procedures were found over long-term follow-up. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00861263.).

Algorithm for the management of endoscopic perforations: a quality improvement project.

Perforations are an uncommon but serious complication of endoscopy. Although they are well recognized, no universally accepted strategy for their management exists. The need for management algorithms in situations that call for multiple interventions in a short time, with coordinated effort encompassing multiple providers from different specialties, has long been recognized, but no such clinical care pathway has been developed for the management of endoscopic perforations. Since perforations are uncommon, a predetermined plan of action can streamline patient management. Furthermore, such a plan demonstrates preparedness on the part of the gastroenterologist. We developed an endoscopic perforation management strategy based on the best available scientific evidence and our specific resources. We report our experience in the hope that it may form a useful framework for gastroenterologists attempting to do the same at their own institution.

Prospective evaluation of the clinical utility of ERCP-guided cholangiopancreatoscopy with a new direct visualization system.

BACKGROUND: Older systems for cholangiopancreatoscopy have demonstrated improved diagnostic and therapeutic abilities over standard ERCP but have shown limited feasibility. The SpyGlass Direct Visualization System addresses many of the shortcomings of the older platforms, but its potential advantages have not been rigorously evaluated. OBJECTIVE: To prospectively evaluate the feasibility, clinical efficacy, and safety of the SpyGlass system. DESIGN: Prospective cohort study. SETTING: Tertiary care center. PATIENTS: All patients undergoing cholangiopancreatoscopy at our institution. INTERVENTIONS: Cholangiopancreatoscopy with the SpyGlass system. MAIN OUTCOME MEASUREMENTS: Procedure success, defined as complete stone clearance for stone cases. For nonstone-related lesions, success was defined when all 3 of the following were met: (1) advancement of the SpyScope to the desired target, (2) adequate visualization, and (3) successful applications of all necessary diagnostic and/or therapeutic maneuvers. RESULTS: Overall, SpyGlass was successful in 70 of 75 patients (93.3%). In patients with biliary stones, complete stone clearance was achieved in 24 of 26 patients (92.3%). Cholangioscopy for nonstone-related indications was successful in 43 of 44 patients (97.7%). Pancreatoscopy was attempted in 5 patients and was successful in 3 (60%). The mean total procedure time (standard ERCP plus SpyGlass) was 64.3 minutes, the total SpyGlass time was 27.5 minutes, the mean SpyGlass visualization time was 14.2 minutes, the mean SpyBite sampling time was 12.1 minutes, the mean Spy therapy time was 8.4 minutes, and the mean set-up time was 5 minutes. There were 4 adverse events (4.8%). LIMITATIONS: Single-center experience, no comparison group, potential for selection bias. CONCLUSIONS: ERCP-guided cholangiopancreatoscopy with the SpyGlass system is technically feasible and can be successfully and safely performed in the vast majority of patients. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00861198.).

Japanese Encephalitis Virus Infected Human Monocyte-Derived Dendritic Cells Activate a Transcriptional Network Leading to an Antiviral Inflammatory Response.

A comprehensive understanding of the human immune response to virus infection is imperative for developing effective therapies, antivirals, and vaccines. Dendritic cells (DCs) are among the first cells to encounter the virus and are also key antigen-presenting cells that link the innate and adaptive immune system. In this study, we focus on the human immune response to the mosquito-borne Japanese encephalitis virus (JEV), which is the leading cause of virus-induced encephalitis in south-east Asia and has the potential to become a global pathogen. We describe the gene regulatory circuit of JEV infection in human monocyte-derived DCs (moDCs) along with its functional validation. We observe that JEV can productively infect human moDCs leading to robust transcriptional activation of the interferon and NF-κB-mediated antiviral and inflammatory pathways. This is accompanied with DC maturation and release of pro-inflammatory cytokines and chemokines TNFα, IL-6, IL-8, IL-12, MCP-1. and RANTES. JEV-infected moDCs activated T-regulatory cells (Tregs) in allogenic mixed lymphocyte reactions (MLR) as seen by upregulated FOXP3 mRNA expression, suggestive of a host response to reduce virus-induced immunopathology. The virus also downregulated transcripts involved in Peroxisome Proliferator Activated Receptor (PPAR) signalling and fatty acid metabolism pathways suggesting that changes in cellular metabolism play a crucial role in driving the DC maturation and antiviral responses. Collectively, our data describe and corroborate the human DC transcriptional network that is engaged upon JEV sensing.