Somatic Mutational Analysis in Endoscopic Ultrasound-Guided Biopsy of Pancreatic Adenocarcinoma: Assessing Yield and Impact.

INTRODUCTION: We sought to determine the yield of somatic mutational analysis from endoscopic ultrasound (EUS)-guided biopsies of pancreatic adenocarcinoma compared with that of surgical resection and to assess the impact of these results on oncologic treatment. METHODS: We determined the yield of EUS sampling and surgical resection. We evaluated the potential impact of mutational analysis by identifying actionable mutations and its direct impact by reviewing actual treatment decisions. RESULTS: Yield of EUS sampling was 89.5%, comparable with the 95.8% yield of surgical resection. More than a quarter in the EUS cohort carried actionable mutations, and of these, more than 1 in 6 had treatment impacted by mutational analysis. DISCUSSION: EUS sampling is nearly always adequate for somatic testing and may have substantial potential and real impact on treatment decisions.

Prognostic Factors for Non-anastomotic Biliary Strictures Following Adult Liver Transplantation: A Systematic Review and Meta-Analysis.

INTRODUCTION: The development of non-anastomotic biliary strictures (NAS) following orthotopic adult liver transplantation (OLT) is associated with significant morbidity. We performed a systematic review and meta-analysis to identify all prognostic factors for the development of NAS. METHODS: A systematic review was conducted following preferred reporting items for systematic reviews and meta-analyses (PRISMA) and the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. We used the Newcastle-Ottawa scale to assess the quality of the included studies. Using the random-effects model, we calculated the weighted pooled odds ratios (OR), mean differences (MD), hazard ratios (HR), and 95% confidence intervals (CI) of the risk factors. RESULTS: Based on 19 international studies that included a total of 8269 adult LT patients, we calculated an 8% overall incidence of NAS. In this study, 7 potential prognostic factors were associated with a statistically significant hazard ratio for NAS in pooled analyses including (1) DCD donors compared to DBD donors (2) PSC as an indication for a liver transplant (3) Roux-en-Y bile duct reconstruction compared to duct-to-duct reconstruction (4) hepatic artery thrombosis (5) longer cold ischemia time (6) longer warm ischemia time (7) and total operative times. CONCLUSION: In this systematic review and meta-analysis, we identified 7 prognostic factors for the development of NAS following OLT. These findings might lay the groundwork for development of diagnostic algorithms to better risk stratify patients at risk for development of NAS.

Post-Transplant Biliary Strictures: An Updated Review.

Liver transplantation (LT) is the only curative therapy in patients with end-stage liver disease with excellent long-term survival; however, LT recipients are at risk of significant complications. Among these complications are biliary complications with an incidence ranging from 5 to 32% and associated with significant post-LT morbidity and mortality. Prompt recognition and management are critical as these complications have been associated with mortality rates up to 19% and retransplantation rates up to 13%. An important limitation of published studies is that a large proportion does not discriminate between anastomotic strictures and nonanastomotic strictures. This review aims to summarize our current understanding of risk factors and natural history, diagnostic testing, and treatment options for post-LT biliary strictures.

Sarcopenia in Chronic Pancreatitis - Prevalence, Diagnosis, Mechanisms and Potential Therapies.

PURPOSE OF REVIEW: To investigate the prevalence, pathogenesis, diagnosis, clinical sequelae, and management of sarcopenia to improve mortality and quality of life in those with Chronic Pancreatitis. RECENT FINDINGS: Sarcopenia is prevalent in chronic pancreatitis and can significantly affect clinical outcomes. Sarcopenia is prevalent in chronic pancreatitis. While effects on some clinical outcomes is has been shown, there is a significant gap in knowledge regarding effects on outcomes, pathophysiology, and options for management.

Outcomes of Radiofrequency Ablation Compared to Liquid Nitrogen Spray Cryotherapy for the Eradication of Dysplasia in Barrett's Esophagus.

INTRODUCTION: Current guidelines recommend endoscopic eradication therapy (EET) for Barrett's esophagus (BE) with dysplasia and intramucosal adenocarcinoma using either radiofrequency ablation (RFA) or liquid nitrogen spray cryotherapy (LNSC). The aims of this multicenter study are to compare the rate and number of treatment sessions of RFA vs. LNSC to achieve CE-D and CE-IM and assess outcomes for those who switched therapy. METHODS: This is a retrospective cohort study of patients with BE undergoing EET. Demographics, baseline variables, endoscopy details, and histology information were abstracted. RESULTS: One hundred and sixty-two patients were included in this study with 100 patients in the RFA group and 62 patients in the LNSC group. The rate of CE-D and CE-IM did not differ between the RFA group and LNSC group (81% vs. 71.0%, p = 0.14) and (64% vs. 66%, p = 0.78), respectively. The number of sessions to achieve CE-D and CE-IM was higher with LNSC compared to RFA (4.2 vs. 3.2, p = 0.05) and (4.8 vs. 3.5, p = 0.04), respectively. The likelihood of developing recurrent dysplasia was higher among patients who did not achieve CE-IM (12%) compared to those who did achieve CE-IM (4%), p = 0.04. Similar findings were found in those who switched treatment modalities. DISCUSSION: EET is highly effective in eradication of Barrett's associated dysplasia and neoplasia. Both RFA and LNSC achieved similar rates of CE-D and CE-IM although LNSC required more sessions. Also, achievement of CE-IM was associated with less recurrence rates of dysplasia.

Correlation of Probe-Based Confocal Laser Endomicroscopy (pCLE) and Mucosal Integrity Testing (MIT) with Epithelial Barrier Function and Presence of Gastroesophageal Reflux Disease (GERD).

INTRODUCTION: Epithelial barrier function (EBF) disruption is a key mechanism underlying gastroesophageal reflux disease (GERD). Our aim was to assess whether two novel technologies, probe-based confocal laser endomicroscopy (pCLE) and mucosal integrity testing (MIT), could assess EBF. METHODS: We prospectively enrolled patients undergoing upper endoscopy for refractory GERD or non-GERD conditions. Patients underwent esophagogastroduodenoscopy, pCLE, MIT, esophageal biopsy at 2 cm and 6 cm above the esophagogastric junction, and wireless pH testing. To assess EBF in vitro, biopsies were mounted in a mini-Ussing chamber, 1 ml of fluorescein was instilled on the mucosal side, and concentration of fluorescein on the serosal side was measured at 3 h. RESULTS: We enrolled 54 subjects (28 GERD, 26 non-GERD based on Lyon consensus criteria). In vivo permeability assessed by pCLE did not differ significantly between GERD vs. non-GERD patients and did not correlate with in vitro permeability. Mean MIT at 2 cm was lower in GERD compared to non-GERD (1914 vs. 3727 ohms). MIT correlated inversely with in vitro permeability at 2 cm and at 6 cm. Using a predictive model that used slope and intercept of MIT at 2 cm and 6 cm, sensitivity and specificity of MIT at identifying GERD was 76% and 72%, respectively. CONCLUSION: pCLE did not differentiate GERD vs non-GERD and did not correlate with EBF measured in vitro. MIT, on the other hand, may be more promising as it differentiated GERD vs non-GERD and correlated with EBF measured in vitro.

Post-transplant biliary complications: advances in pathophysiology, diagnosis, and treatment.

Liver transplantation (LT) is the only curative therapy in patients with end-stage liver disease. Long-term survival is excellent, yet LT recipients are at risk of significant complications. Biliary complications are an important source of morbidity after LT, with an estimated incidence of 5%-32%. Post-LT biliary complications include strictures (anastomotic and non-anastomotic), bile leaks, stones, and sphincter of Oddi dysfunction. Prompt recognition and management is critical as these complications are associated with mortality rates up to 20% and retransplantation rates up to 13%. This review aims to summarise our current understanding of risk factors, natural history, diagnostic testing, and treatment options for post-transplant biliary complications.

Early laboratory values after liver transplantation are associated with anastomotic biliary strictures.

BACKGROUNDS/AIMS: The aim of this study was to evaluate longitudinal changes of post-liver transplantation (LT) biliary anatomy and to assess the association of increased laboratory values after LT with the development of post-LT anastomotic biliary stricture (ABS). METHODS: Adult deceased donor LT recipients from 2008 and 2019 were evaluated. ABS was defined after blinded review of endoscopic cholangiograms. Controls were patients who underwent LT for hepatocellular carcinoma who did not have any clinical or biochemical concerns for ABS. RESULTS: Of 534 patients who underwent LT, 57 patients had ABS and 57 patients served as controls. On MRI, ABS patients had a narrower anastomosis (2.47 ± 1.32 mm vs. 3.38 ± 1.05 mm; p < 0.01) and wider bile duct at 1-cm proximal to the anastomosis (6.73 ± 2.45 mm vs. 5.66 ± 1.95 mm; p = 0.01) than controls. Association between labs at day 7 and ABS formation was as follows: aspartate aminotransferase hazard ratio (HR): 1.014; 95% confidence interval (CI): 1.008-1.020, p = 0.001; total bilirubin HR: 1.292, 95% CI: 1.100-1.517, p = 0.002; and conjugated bilirubin HR: 1.467, 95% CI: 1.216-1.768, p = 0.001. Corresponding analysis results for day 28 were alanine aminotransferase HR: 1.004, 95% CI: 1.002-1.006, p = 0.001; alkaline phosphatase HR: 1.005, 95% CI: 1.003-1.007, p = 0.001; total bilirubin HR: 1.233, 95% CI: 1.110-1.369, p = 0.001; and conjugated bilirubin HR: 1.272, 95% CI: 1.126-1.437, p = 0.001. CONCLUSIONS: Elevation of laboratory values early after LT is associated with ABS formation.

Deep learning systems detect dysplasia with human-like accuracy using histopathology and probe-based confocal laser endomicroscopy.

Probe-based confocal laser endomicroscopy (pCLE) allows for real-time diagnosis of dysplasia and cancer in Barrett's esophagus (BE) but is limited by low sensitivity. Even the gold standard of histopathology is hindered by poor agreement between pathologists. We deployed deep-learning-based image and video analysis in order to improve diagnostic accuracy of pCLE videos and biopsy images. Blinded experts categorized biopsies and pCLE videos as squamous, non-dysplastic BE, or dysplasia/cancer, and deep learning models were trained to classify the data into these three categories. Biopsy classification was conducted using two distinct approaches-a patch-level model and a whole-slide-image-level model. Gradient-weighted class activation maps (Grad-CAMs) were extracted from pCLE and biopsy models in order to determine tissue structures deemed relevant by the models. 1970 pCLE videos, 897,931 biopsy patches, and 387 whole-slide images were used to train, test, and validate the models. In pCLE analysis, models achieved a high sensitivity for dysplasia (71%) and an overall accuracy of 90% for all classes. For biopsies at the patch level, the model achieved a sensitivity of 72% for dysplasia and an overall accuracy of 90%. The whole-slide-image-level model achieved a sensitivity of 90% for dysplasia and 94% overall accuracy. Grad-CAMs for all models showed activation in medically relevant tissue regions. Our deep learning models achieved high diagnostic accuracy for both pCLE-based and histopathologic diagnosis of esophageal dysplasia and its precursors, similar to human accuracy in prior studies. These machine learning approaches may improve accuracy and efficiency of current screening protocols.

Co-existing inflammatory bowel disease and Barrett's esophagus is associated with esophageal dysplasia: a propensity score-matched cohort.

Background and study aims Barrett's esophagus (BE) and inflammatory bowel disease (IBD) predispose to the development of dysplasia and cancer. It is unclear if the inflammatory cascade seen in IBD affects disease progression in BE. We aimed to determine if patients with BE who have co-existing IBD had a higher risk of dysplasia, nodular disease, or longer segments than BE patients without IBD. Patients and methods This was a multicenter, retrospective propensity score-matched cohort study. We compared rates of dysplasia, nodular disease, and segment length in patients with BE and IBD (cases) to patients with BE who did not have IBD (controls). Controls were 1:1 propensity score matched with controls for age, sex, body mass index (BMI), smoking, and hiatal hernia. Results A total of 132 patients were included in the IBD + BE group and 132 patients in the BE group. Patients with IBD + BE had higher rates of esophageal dysplasia compared to controls (15.9 % vs. 6.1 % [adjusted odds ratio [OR]: 2.9, 95 % CI: 1.2-6.9]) and more nodules (9.8 % vs. 3.0 % [adjusted OR: 3.5, 95 % CI: 1.1-11.0]). IBD + BE group was also associated with longer BE segments (43.9 % vs. 12.1 % [OR: 5.7, 95 % CI: 3.0-10.6]). Conclusions Co-existing IBD may increase the risk of dysplasia and esophageal nodules in patients with BE. Our findings may have implications for BE surveillance intervals in IBD patients. Prospective studies are needed to confirm our findings.

Semi-Supervised Classification of Noisy, Gigapixel Histology Images.

One of the greatest obstacles in the adoption of deep neural networks for new medical applications is that training these models typically require a large amount of manually labeled training samples. In this body of work, we investigate the semi-supervised scenario where one has access to large amounts of unlabeled data and only a few labeled samples. We study the performance of MixMatch and FixMatch-two popular semi-supervised learning methods-on a histology dataset. More specifically, we study these models' impact under a highly noisy and imbalanced setting. The findings here motivate the development of semi-supervised methods to ameliorate problems commonly encountered in medical data applications.

Sarcopenia is associated with longer hospital stay and multiorgan dysfunction in alcoholic hepatitis.

INTRODUCTION: Excessive alcohol consumption has steadily risen to become the third leading cause of preventable death in the USA. One consequence of heavy alcohol use recently under considerable investigation is alcoholic hepatitis. Although many risk factors for developing alcoholic hepatitis have been documented, our aim in this study was to examine the potential association between sarcopenia and severity, mortality, 30 days readmission rate, complication, infections and length of hospital stay in alcoholic hepatitis patients. METHODS: A retrospective analysis was performed at a large, academic hospital in 194 alcoholic hepatitis patients aged 18-60 who had cross-sectional computed tomography imaging and met our clinical definition of alcoholic hepatitis. The fifth percentile of the psoas muscle index was used as a cutoff for sarcopenia. RESULTS: One hundred ninety-four patients met the criteria for alcoholic hepatitis and had cross-sectional imaging. Higher Model for End-Stage Liver disease score was found in the sarcopenia group when compared to the non-sarcopenia group (mean Model for End-Stage Liver disease 21.5 and 24.2, respectively, P = 0.03). Sarcopenia also correlated with significantly longer hospital stay; the average length of stay in the sarcopenia group was 17.2 days while the non-sarcopenia patients had an average of 12.4 days. We found higher risk of developing pneumonia, sepsis and hepatic encephalopathy in sarcopenic patients. CONCLUSION: Alcoholic hepatitis patients with sarcopenia have significantly worse outcomes when compared with the patients without sarcopenia, including a severe form of alcoholic hepatitis, longer hospital stays, higher risk of developing pneumonia, sepsis and hepatic encephalopathy.

Proton pump inhibitors increase the severity of hepatic encephalopathy in cirrhotic patients.

BACKGROUND: Liver cirrhosis is the late stage of hepatic fibrosis and is characterized by portal hypertension that can clinically lead to decompensation in the form of ascites, esophageal/gastric varices or encephalopathy. The most common sequelae associated with liver cirrhosis are neurologic and neuropsychiatric impairments labeled as hepatic encephalopathy (HE). Well established triggers for HE include infection, gastrointestinal bleeding, constipation, and medications. Alterations to the gut microbiome is one of the leading ammonia producers in the body, and therefore may make patients more susceptible to HE. AIM: To investigate the relationship between the use of proton pump inhibitors (PPIs) and HE in patients with cirrhosis. METHODS: This is a single center, retrospective analysis. Patients were included in the study with an admitting diagnosis of HE. The degree of HE was determined from subjective and objective portions of hospital admission notes using the West Haven Criteria. The primary outcome of the study was to evaluate the grade of HE in PPI users versus non-users at admission to the hospital and throughout their hospital course. Secondary outcomes included rate of infection, gastrointestinal bleeding within the last 12 mo, mean ammonia level, and model for end-stage liver disease scores at admission. RESULTS: The HE grade at admission using the West Haven Criteria was 2.3 in the PPI group compared to 1.7 in the PPI nonuser group (P = 0.001). The average length of hospital stay in PPI group was 8.3 d compared to 6.5 d in PPI nonusers (P = 0.046). Twenty-seven (31.8%) patients in the PPI user group required an Intensive Care Unit admission during their hospital course compared to 6 in the PPI nonuser group (16.7%) (P = 0.138). Finally, 10 (11.8%) patients in the PPI group expired during their hospital stay compared to 1 in the PPI nonuser group (2.8%) (P = 0.220). CONCLUSION: Chronic PPI use in cirrhotic patients is associated with significantly higher average West Haven Criteria for HE compared to patients that do not use PPIs.

The Morbidity and Mortality of Laparoscopic Appendectomy in Patients with Cirrhosis.

INTRODUCTION: The perioperative mortality is significantly higher in patients with cirrhosis undergoing certain surgical procedures. In this study, we examined the inpatient perioperative mortality and morbidities in cirrhotic people who underwent laparoscopic appendectomy. METHODS: We performed a retrospective analysis using the National Inpatient Sample database for 2010. Inclusion criteria were all race and sex who are 18 years or older. Those who have laparoscopic appendectomy and have a history of liver cirrhosis were assigned to case group. An equal random number of appendectomy-related admissions and those who have no history of liver cirrhosis were selected and placed in the control group. A binary logistic regression statistical test was used to examine the odds ratio for the mortality difference and postoperative complication including pneumonia, urinary tract infection (UTI), surgical site infection, postoperative bleeding. IBM SPSS statistics was used to execute the analysis. A confidence interval of 95% and P value less than .05 were determined to define the statistical significance. RESULT: A total of 754 appendectomy-related admissions were identified-376 appendectomy-related admissions and history of cirrhosis and 378 admissions with appendectomy and no history of cirrhosis. Control group was not found to be statistically different from the case group when it comes to age, race, and sex. Of 754, 520 were white (73.5%), 334 (44.3%) were men. The mean age was 43.75 years for the case group and 46.68 years for the control group. Comparing cirrhotic with noncirrhotic group, the mean length of stay was 1.1 vs 1.52 days, inpatient mortality was 2 (0.5%) vs 1 (0.3%) (P = .56), pneumonia 8 (2.1%) vs 3 (0.8%) (P = .142), surgical site infection 3 (0.8%) vs 2 (0.5%) (P = .652), UTI 18 (4.8%) vs 12 (3.2%) (P = .26), and postoperative bleeding 3 (0.8%) vs 2 (0.5%) (P = .65). CONCLUSIONS: Appendectomy-related morbidity and mortality in cirrhotic patients are not different from noncirrhotic patients.

Comparing efficacy of lumen-apposing stents to plastic stents in the endoscopic management of mature peripancreatic fluid collections: a single-center experience.

INTRODUCTION: Mature peripancreatic fluid collection (MPFC) is a known and often challenging consequence of acute pancreatitis and often requires intervention. The most common method accepted is the "step-up approach," which consists of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy. Our paper aims to distinguish between plastic stents and lumen-apposing stents in the endoscopic management of MPFC in terms of morbidity, mortality, and haste of fluid collection resolution. METHODS: A retrospective analysis was performed at UMass Memorial Medical Center in patients with a diagnosis of MPFC. Utilizing medical records, clinical data, radiology, as well as endoscopic evidence, patients were differentiated by stent type used (plastic versus lumen-apposing) for the management of the MPFC. The primary outcome of the study was to assess the time to MPFC resolution following the placement of either plastic or lumen-apposing stents (on endoscopic ultrasound or computerized tomography scan) using a multivariate analysis with a logistic regression model. RESULTS: A total of 54 patients were included in this study from UMass Memorial Medical Center between 2012 and 2015. Twelve (22%) of these patients received lumen-apposing stents and 42 (78%) of these patients received plastic pigtail stents. For the lumen-apposing stent group, the mean interval between stent placement and resolution of MPFC was 57 days as compared to 102 days for plastic pigtail stents (p=0.02). The mean interval for placement/removal of lumen-apposing stents was 48 days as compared to 81 days for plastic pigtail stents (p=0.01). Stent migration was seen in 5 patients (11%) who received a plastic pigtail stent compared to 0 (0%) patients who received a lumen-apposing stent. DISCUSSION: Our study demonstrates that lumen-apposing stents result in a significant reduction in the interval between stent placement and MPFC resolution as well as the time from stent placement to removal, when compared to plastic pigtail stents, the prior standard-of-care. Our study reached similar conclusions regarding the number of stents placed. However, we did not find a significant difference between the complication rates, specifically peri- and postprocedural bleeding or perforation, between the 2 study groups, as demonstrated in prior papers.

The Outcome of Thoracentesis versus Chest Tube Placement for Hepatic Hydrothorax in Patients with Cirrhosis: A Nationwide Analysis of the National Inpatient Sample.

There are only a few studies with a small sample size of patients that have compared the risks of using chest tubes versus thoracentesis in hepatic hydrothorax. It has been shown that many complications may arise secondary to chest tube placement and is associated with increased morbidity and mortality. In this retrospective study, patients with cirrhosis were identified from the 2009 National Inpatient Sample by using ICD-9 codes; we evaluated the risk of chest tube versus thoracentesis in a largest population with hepatic hydrothorax to date to measure the mortality and the length of stay. A total of 140,573 patients with liver cirrhosis were identified. Of this, 1981 patients had a hepatic hydrothorax and ended up with either thoracentesis (1776) or chest tube (205). The mortality in those who received a chest tube was two times higher than that in thoracentesis group with a P value of ≤0.001 (CI 1.43-312). In addition, the length of hospital stay of the chest tube group was longer than that of the thoracentesis subset (7.2 days versus 3.8 days, resp.). We concluded that chest tube placement has two times higher mortality rate and longer hospital length of stay when compared to patients who underwent thoracentesis.

Microscopic Colitis After Fecal Microbiota Transplant.

Microscopic colitis (MC) is an inflammatory condition of the large bowel that is associated with chronic, nonbloody diarrhea. Colonoscopy usually demonstrates normal mucosa, while tissue biopsy reveals intraepithelial lymphocytes or a subepithelial collagen band. Although no specific antibody has been discovered, MC is associated with several autoimmune disorders such as celiac disease, Hashimoto's thyroiditis, and rheumatoid arthritis. There are only a small number of case reports documenting possible hereditary MC cases, but up to 12% of patients with MC have a family history of inflammatory bowel disease. Other associations include proton pump inhibitor use, cigarette smoking, HLA-DQ2/86, and possibly some gastrointestinal infections.