Abstract Background Placement of covered self-expandable metallic stent (CSEMS) for post-endoscopic sphincterotomy (ES) bleeding achieves excellent hemostasis results. Although CSEMS placement is typically performed after failure of conventional endoscopic combination therapy, its excellent outcomes may justify earlier placement. Aims We aimed to examine the efficacy of “early” CSEMS placement for massive post-ES bleeding. Methods The medical records of 2750 patients who underwent ES between 2005 and 2019 were reviewed retrospectively, and 61 patients who developed massive post-ES bleeding were enrolled. These patients were divided into those who underwent early CSEMS placement (E-CSEMS group) and those who underwent conventional endoscopic combination therapy (Conventional group). The outcomes of hemostasis procedures were compared between the groups. Results The primary success rates of endoscopic hemostasis were 100% (21/21) and 98% (39/40) in the E-CSEMS group and Conventional group, respectively, without significant differences (P = 1.000). However, in the E-CSEMS group, re-bleeding was significantly less frequent (5% vs. 31%; P = 0.023), the median hemostasis procedure time was significantly shorter (14 min vs. 26 min; P < 0.001), and transfusion after initial hemostasis treatment was less commonly required (10% vs. 38%; P = 0.034). Multivariate analyses showed that hemodialysis was associated with a significantly higher re-bleeding rate (P = 0.029), while CSEMS placement was associated with a significantly lower re-bleeding rate (P = 0.039). Conclusions Early CSEMS placement may be effective for improving the clinical outcomes of massive post-ES bleeding by decreasing re-bleeding and the extent of bleeding.

Background and Aims Conventional endoscopic mucosal resection (EMR) using hot snare is the standard of care for resection of large (≥20 mm) nonmalignant sessile colonic polyps. Serious adverse events are predominantly due to electrocautery. This could potentially be avoided by cold snare piecemeal EMR (CSP-EMR). The study aimed to evaluate the safety and efficacy of CSP-EMR of sessile colonic polyps sized ≥20 mm. Methods All cases of CSP-EMR at 5 Australian academic hospitals for sessile polyps ≥20 mm over a 2-year period, from January 2016 to December 2017 were identified retrospectively. Efficacy was defined as the absence of residual or recurrent polyp tissue during the first surveillance colonoscopy (SC1) and second surveillance colonoscopy (SC2). Clinically significant intraprocedural or delayed adverse events and surveillance colonoscopy findings were assessed by reviewing medical records. Results CSP-EMR was performed on 204 polyps sized ≥20 mm in 186 patients (men 33.8%; median age 68 years). SC1 for 164 (80.4%) polyps at a median interval of 150 days showed residual or recurrent polyp in 9 cases (5.5%; 95% CI, 3%-11%). SC2 for 113 (72.9%) polyps at a median interval of 18 months showed late residual or recurrent polyp in 4 cases (3.5%; 95% CI, 0.9%-8.5%) after a normal SC1. Intra-procedural bleeding was successfully treated in 4 (2.2%) patients, 7 (3.8%) patients experienced self-limiting clinically significant post-EMR bleeding (CSPEB) and 1 patient (0.5%) required overnight observation for nonspecific abdominal pain that resolved spontaneously. None experienced other adverse events. Conclusion CSP-EMR of sessile colonic polyps ≥20 mm is technically feasible, effective, and safe. The adverse event rate and polyp recurrence rate were low. Randomized or large prospective trials are required to confirm the noninferiority and improved safety of CSP-EMR compared with conventional EMR, and to further determine the polyp morphologies that are best suited for CSP-EMR.

Background and Aims Previous meta-analysis showed marginal benefit of high-definition white-light endoscopy (HD-WLE) over standard-definition (SDC) colonoscopy for adenoma detection, but with residual uncertainty due to inclusion of nonrandomized studies. We aimed to further assess the effect of HD-WLE on adenoma detection by including only randomized controlled trials (RCTs). Methods A literature search was performed for RCTs evaluating HD-WLE versus SDC in terms of adenoma, advanced adenoma, and serrated sessile adenoma detection rates as well as mean number of adenomas (MAC), advanced adenomas (MAAC), and sessile serrated adenomas per colonoscopy (MSSAC). The effect size on study outcomes is presented as risk ratio (RR; 95% CI) or mean difference (MD; 95% CI). We assessed the strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Six RCTs involving 4594 individuals (HD-WLE 2323; SDC 2271) were included. Clinical indications were screening (1 study), positive FOBT and personal/family history of colorectal cancer (1 study), and mixed indications (4 studies). Withdrawal time was similar between the 2 arms (MD, -0.06; 95% CI, -0.25 to 0.12; p=0.50). Adenoma detection rate was significantly higher in the HD-WLE compared with SDC arm (40% vs 35%; RR, 1.13; 95% CI, 1.05-1.22; p=0.001; I2=0%; GRADE: low). This effect was consistent for advanced and sessile serrated adenoma detection rates (RR, 1.33; 95% CI, 1.03-1.72; p=0.03; I2=0%; GRADE: low and RR, 1.55; 95% CI, 1.05-2.28; p=0.03; I2=0%; GRADE: low, respectively). On the contrary, the difference was not significant for MAC, MAAC, and MSSAC. Conclusions Meta-analysis of RCT data support the use of HD-WLE in clinical practice, although the additional benefit is limited.

Gankyrin (GK) is an oncoprotein which regulates inflammatory responses and its inhibition is considered as a possible anti-inflammatory therapy for inflammatory bowel disease (IBD). In this study, we investigated the role of GK in epithelial cells using mice with intestinal epithelial cell-specific GK deletion in (i) the entire small intestine and colon (Villin-Cre;Gankyrinf/f) and (ii) the distal intestine and colon (Cdx2-Cre;Gankyrinf/f). Unexpectedly, GK-deficiency in the upper small bowel augmented inflammatory activity compared with control mice when colitis was induced with dextran sodium sulfate. Biochemical analyses have revealed GK-deficiency to have caused reduction in the expression of antimicrobial peptides, α-Defensin-5 and -6, in the upper small bowel. Examination of human samples have further confirmed that the reduction of GK expression in the small bowel is associated with colonic involvement in human Crohn’s disease. Through the sequencing of bacterial 16S rRNA gene amplicons, bacteria potentially deleterious to intestinal homeostasis such as Helicobacter japonicum and Bilophila were found to be over-represented in colitis induced Villin-Cre;Gankyrinf/f mice when compared to Gankyrinf/f control mice under the same condition. These results highlight the distinct site dependence of the pro- and anti-inflammatory functions of GK and provide important insights into the pathogenesis of IBD.

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has high accuracy and a low complication rate; therefore, it has been widely used as a useful tool for diagnosis of and to determine treatment strategies for pancreatic tumors. Recently, reports of the recurrence of needle tract seeding after EUS-FNA are emerging. An 83-year-old woman was referred to our hospital to undergo further examination of her pancreatic tumor. Multidetector computed tomography (MDCT) revealed a 25-mm-diameter mass in the pancreatic body. She underwent EUS-FNA (transgastric, 22-G needle, 2 passes) and was subsequently diagnosed with adenocarcinoma. Distal pancreatosplenectomy followed by adjuvant chemotherapy with S-1 for 6 months was performed. The level of carbohydrate antigen 19–9 gradually increased 22 months after surgery, and MDCT, which was performed 3 months later, revealed a 23-mm low-density mass in the stomach and paragastric lymph node swelling. Gastroendoscopy revealed a submucosal tumor, and endoscopic ultrasound revealed a hypoechoic mass in the submucosa of the gastric wall. Partial gastrectomy with lymph node resection was performed. The pathological findings showed adenocarcinoma extending from the subserosa to the submucosa and lymph node metastasis, consistent with a tumor recurrence from the resected pancreatic tumor. She received adjuvant chemotherapy with S-1; recurrence was not observed for 5 months, at the time of this writing. It is important to pay careful attention to the development of needle tract seeding in patients with pancreatic cancer diagnosed by EUS-FNA. This is the first case of needle tract seeding with lymph node metastasis, highlighting the need for caution and providing novel insight in the postoperative follow-up of patients with pancreatic body/tail cancer.

To investigate the merit of T1rho relaxation for the evaluation of liver fibrosis, inflammatory activity, and liver injury monitoring in a carbon tetrachloride (CCl4)-induced rat model. Model rats from CCl4-induced liver fibrosis (fibrosis group: n = 41; regression group: n = 20) and control (n = 11) groups underwent black blood T1rho magnetic resonance (MR) imaging (MRI). Injection of CCl4 was done twice weekly for up to 12 weeks in the fibrosis group and for up to 6 weeks in the regression group. MR scanning time points were at baseline and at 2, 4, 6, 8, 10 and 12 weeks after CCl4 injection in the fibrosis group and at baseline and at 2, 4, 6 (CCl4 withdrawal), 7, 8, 10 and 12 weeks in the regression group. In the fibrosis group, liver T1rho values increased gradually within week 8 and then decreased. In the regression group, T1rho values dropped gradually after the withdrawal of CCl4 and fell below those at baseline. The T1rho values at S0 were lower than those at any other stage (all P < 0.05). The T1rho values at G0 were significantly lower than those at any other grade, and G1 was lower than G2 (all P < 0.01). The T1rho values mildly correlated with fibrosis stages (r = 0.362) and moderately correlated with grades of inflammation (r = 0.568). The T1rho values of rats with the same inflammation grades showed no significant difference among different fibrosis stages, and the T1rho values at S3 showed a significant difference among different grades of inflammation (P = 0.024). Inflammation grade was an independent variable associated with T1rho values (P < 0.001). T1rho MRI can be used to monitor CCl4-induced liver injury, and inflammatory activity had a greater impact on liver T1rho values than fibrosis.

OBJECTIVES: Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with constipation-predominant irritable bowel syndrome (IBS-C). METHODS: In this phase 3, double-blind study (ClinicalTrials.gov identifier NCT02621892), patients with IBS-C were randomized to tenapanor 50 mg b.i.d. or placebo b.i.d. for 12 weeks followed by a 4-week randomized withdrawal period. The primary efficacy variable was the proportion of patients who reported a reduction in average weekly worst abdominal pain of ≥30.0% and an increase of ≥1 complete spontaneous bowel movement from baseline, both in the same week, for ≥6 weeks of the 12-week treatment period. RESULTS: Of the 629 randomized patients with IBS-C, 606 (96.3%) were included in the intention-to-treat analysis set (tenapanor: n = 307; placebo: n = 299) and 533 (84.7%) completed the 12-week treatment period. In the intention-to-treat analysis set (mean age 45 years, 81.4% women), a significantly greater proportion of patients treated with tenapanor met the primary endpoint than patients treated with placebo (27.0% vs 18.7%, P = 0.020). Abdominal symptoms and global symptoms of IBS also improved with tenapanor (P < 0.05 vs placebo). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in 6.5% and 0.7% of patients receiving tenapanor and placebo, respectively, during the 12-week treatment period. DISCUSSION: Tenapanor 50 mg b.i.d. improved IBS-C symptoms and was generally well tolerated, offering a potential new treatment option for patients with IBS-C. Correspondence: William D. Chey, MD, AGAF, FACG, RFF. E-mail: wchey@umich.edu. Received June 21, 2019 Accepted December 05, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

Background and aims The efficacy of celiac plexus neurolysis (CPN) with EUS guidance has not been confirmed in the era of developed opioids. The aim of this study was to evaluate the efficacy of EUS-guided CPN (EUS-CPN) for patients with pancreatic cancer-associated pain to compare medication using oxycodone and/or fentanyl with and without EUS-CPN. Methods In this randomized control study involving patients who underwent EUS-CPN and those who did not, pain, quality of life (QOL), and opioid consumption were compared. Standard medicinal treatment using oxycodone and/or fentanyl was performed for both groups. The primary endpoint was defined as the pain evaluated by using a 0 to10 visual analogue scale (VAS) 4 weeks after the baseline. Results For 48 registered patients, the outcomes of 24 patients in the EUS-CPN group and 22 patients in the control group were analyzed. EUS-CPN was successfully performed and did not induce severe procedure-related adverse events for all patients in the EUS-CPN group. Although the average pain VAS scores for both groups significantly decreased in comparison with the baseline, they were not statistically different between the groups at week 4 (1.3 ± 1.3 for the EUS-CPN group vs 2.3 ± 2.3 for the control group, P = 0.10). There was no statistical difference nor tendency in favor of EUS-CPN at evaluation points of weeks 1, 2, 8, and 12. Moreover, the average VAS scores for QOL and the average opioid consumption between the groups were not different at all evaluation points. Conclusions EUS-CPN for patients with pancreatic cancer-associated pain did not appear to improve pain, QOL, nor opioid consumption in comparison to those who did not undergo EUS-CPN being medicated with oxycodone/fentanyl. Although EUS-CPN can be an option, it was not found to have a large enough impact to be routinely performed for all patients with pain.

Background and Aims The treatment of submucosal (T1b) esophageal adenocarcinoma (EAC) remains in evolution with some evidence supporting endoscopic management of low-risk lesions. Using a multicenter cohort, we evaluated outcomes of patients with T1b EAC and predictors of survival. Methods Patients diagnosed between 2001 and 2016 with T1b EAC were identified from 3 academic medical centers in the United States. Demographic, clinical and outcome data were collected. Outcomes studied included overall and cancer-free survival. Cox proportional hazards models were constructed to assess independent predictors of survival. Results One hundred forty-one patients were included, of whom 68 (48%) underwent esophagectomy and 73 (52%) were treated endoscopically. Most (85.8%) patients had high-risk histological features. Thirty-day operative mortality was 2.9%. Median follow-up in the esophagectomy and endoscopic cohorts was 49.4 and 43.4 months, respectively. Patients treated endoscopically were older with higher comorbidity scores. 46 (63%) patients treated endoscopically achieved histologic remission. Nineteen (26.0%) patients also received chemoradiation. Five-year overall survival rates in the surgical and endoscopic cohorts were 89% and 59% respectively whereas 5-year cancer free survival rates were 92 and 69%. Presence of high-risk histological features was associated with reduced overall survival. Conclusions In this large multicenter study of patients with T1b EAC, esophagectomy was associated with improved overall but not cancer-free survival. High-risk histological features were associated with poorer survival.

ALT value is often used to reflect the hepatic inflammation and injury in NAFLD patients, but many studies proved that ALT values were normal in many NAFLD patients. The aim of this study was to identify the summarized proportion of NAFLD patients with normal ALT value in the overall NAFLD patients. Electronic databases PubMed, EMBASE, Ovid, and the Cochrane Library were searched for potential studies published from January 1, 2000 to September 30, 2019. Studies that have reported the number of NAFLD or NASH patients with normal and abnormal ALT value were included and analyzed. Abstracts, reviews, case reports, and letters were excluded. A total of 11 studies with 4084 patients were included for assessing the summarized proportion of NAFLD patients with normal ALT in overall NAFLD patients. As the results shown, the summarized proportion of NAFLD patients with normal ALT value in overall NAFLD patients was 25% (95%CI: 20–31%) which was calculated by the random-effects model. The summarized proportion of NASH patients with normal ALT value in overall NASH patients was 19% (95%CI: 13–27%). Subgroup analysis includes region, study type, diagnostic method, and group size were conducted to investigate the resource of heterogeneity in the summarized proportion of NAFLD and NASH patients with normal ALT value. 25% NAFLD patients and 19% NASH patients possess the normal ALT value in the clinical manifestation. The value of ALT in the clinical diagnosis of NAFLD and NASH remains need be further testified.

Previous studies have indicated that disease activity, psychological symptoms and social support were associated with health-related quality of life (HRQoL) in patients with inflammatory bowel diseases(IBD). However, it is unclear how disease activity, psychological symptoms and social support interact to affect HRQoL. The main purpose of this study was to examine the mediation effect of psychological symptoms in the relationship between disease activity, social support and HRQoL. This was a cross-sectional study, which collected data using convenience sampling, between December 2016 and March 2018, from the Third XiangyaHospital of Central South University in Changsha, China. An online self-administered questionnaire (including demographic and clinical information), Inflammatory Bowel Disease Questionnaire, Disease Activity Indices scale, Hospital Anxiety and Depression Scale and Social Support Rating Scale, were administered to each participant. Descriptive statistics and Pearson’s correlations were used to summarize data, whereas PROCESS analysis was performed to examine the pre-specified mediation effect. A total of 199 patients with IBD were included. Disease activity indices (DAI) and hospital anxiety and depression (HAD) were negatively correlated with HRQoL (β = − 3.37, − 2.54 respectively, P < 0.001), while social support was positively correlated with HRQoL (β = 1.38, P < 0.01). HAD partially mediated the negative relationship between DAI and HRQoL (β = − 0.83, P < 0.001) with the mediation effect ratio of 24.6%, and completely mediated the positive relationship between social support and HRQoL (β = 1.20, P < 0.001). Psychological symptoms acted as a mediator in the relationship between disease activity, social support and HRQoL. Interventions to improve HRQoL in patients with IBD should take into account the mediation effect of psychological symptoms.

Approximately 60% of adults over the age of 60 have diverticulosis, of whom 5% will experience complications such as diverticulitis or diverticular bleeding. There are an estimated 300,000 hospital admissions per year in the United States for diverticulitis (Clin Gastroenterol Hepatol 2013;11:1609-13). Despite this burden of disease, risk stratification and prevention strategies for diverticulitis are lacking. Based on the observation that diverticulitis prevalence is significantly higher in developed countries where diets are typically low in fiber, it has been hypothesized that high fiber intake is protective. However, the relationship between specific fiber sources and diverticulitis risk has been difficult to elucidate, as studies have used patient-reported diet data and have quantified fiber intake indirectly. Therefore, the paper by Ma et al. addresses a knowledge gap by evaluating whether subtypes of fiber, and/or particular foods, are associated with the risk for diverticulitis.

Abstract Aims Inhibitor for the apoptosis-stimulating protein of p53 (iASPP) has been reported to be correlated with 5-fluorouracil (5-Fu) resistance in renal cell carcinoma. Here, we uncover mechanisms of iASPP-Nrf2-ROS regulation of 5-Fu resistance which are important for the development of alternative treatment strategies for gastric adenocarcinoma treatment. Methods We analyzed iASPP and Nrf2 through TCGA RNA-seq data, UALCAN analysis, and cBioPortal datasets. Intracellular ROS generation was determined by 2′,7′-dichloro-fluorescin diacetate staining. Transwell was used to evaluate the invasion. The expression of iASPP, Nrf2, HO-1, and GSTP1 was tested using western blot. Results We found that iASPP KD led to an apparent 5-Fu-induced ROS accumulation in MGC803 and SCG790 cells. Accompanied by iASPP KD, Nrf2 was markedly decreased. iASPP-induced ROS inhibition relies on Nrf2, and due to both knocked down iASPP and Nrf2, the level of ROS did not show an obvious difference with Nrf2 KD solely. Similarly, iASPP KD failed to enhance the Nrf2 KD-mediated ROS accumulation after 5-Fu treatment, suggesting that iASPP-induced antioxidative effects related to 5-Fu resistance are partially dependent on Nrf2. Also, the combination of iASPP KD and Nrf2 KD did not show any synergistic effect on apoptosis after 5-Fu treatment in MGC803 and SCG790 cells. Further studies revealed that iASPP KD or Nrf2 KD could decrease the expression of HO-1 and GSTP1. Conclusions Our data highlight that iASPP plays a crucial role in the inhibition of 5-Fu-induced apoptosis resistance by removing ROS accumulation in gastric adenocarcinoma, and that the removal of ROS induced by iASPP is Nrf2 signaling dependent.

Despite the high efficacy and safety associated with direct-acting antivirals (DAAs), access to HCV treatment has been frequently restricted because of the high DAA drug costs.

Objective Intestinal metaplasia (IM) is a premalignant stage that poses a greater risk for subsequent gastric cancer (GC). However, factors regulating IM to GC progression remain unclear. Previously, activated DNA damage response (DDR) signalling factors were shown to engage tumour-suppressive networks in premalignant lesions. Here, we interrogate the relationship of DDR signalling to mutational accumulation in IM lesions. Design IM biopsies were procured from the gastric cancer epidemiology programme, an endoscopic surveillance programme where biopsies have been subjected to (epi)genomic characterisation. IM samples were classified as genome-stable or genome-unstable based on their mutational burden/somatic copy-number alteration (CNA) profiles. Samples were probed for DDR signalling and cell proliferation, using the markers γH2AX and MCM2, respectively. The expression of the gastric stem cell marker, CD44v9, was also assessed. Tissue microarrays representing the GC progression spectrum were included. Results MCM2-positivity increased during GC progression, while γH2AX-positivity showed modest increase from normal to gastritis and IM stages, with further increase in GC. γH2AX levels correlated with the extent of chronic inflammation. Interestingly, genome-stable IM lesions had higher γH2AX levels underscoring a protective anti-cancer role for DDR signalling. In contrast, genome-unstable IM lesions with higher mutational burden/CNAs had lower γH2AX levels, elevated CD44v9 expression and modest promoter hypermethylation of DNA repair genes WRN, MLH1 and RAD52 . Conclusions Our data suggest that IM lesions with active DDR will likely experience a longer latency at the premalignant state until additional hits that override DDR signalling clonally expand and promote progression. These observations provide insights on the factors governing IM progression.

With great interest, we have read the article by Backes et al ,1 on the pre-resection accuracy of the real-time optical diagnosis of T1 colorectal cancer (T1CRC) in large non-pedunculated colorectal polyps. In this multicentre, prospective study, the authors developed and validated the OPTICAL model, in which a sensitivity of 78.7% (95% CI: 64.3 to 89.3) for optical diagnosis of T1CRC was obtained. With the implementation of the Dutch bowel cancer screening programme (BCSP) in 2014, a shift has occurred towards the more frequent diagnoses of early AJCC (American Joint Committee on Cancer) stage I cancers.2 Estimating the risk of a T1CRC is crucial to determine the optimal treatment strategy, and to select cases for more elaborative and expensive endoscopic en bloc resection techniques such as endoscopic submucosal dissection, transanal minimally invasive surgery or endoscopic full-thickness resection. Current studies mainly report on the outcomes of advanced imaging by expert centres with dedicated endoscopists,3 4 whereas …

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed medications, but they are associated with a number of serious adverse effects, including hypertension, cardiovascular disease, kidney injury and GI complications. Objective To develop a set of multidisciplinary recommendations for the safe prescription of NSAIDs. Methods Randomised control trials and observational studies published before January 2018 were reviewed, with 329 papers included for the synthesis of evidence-based recommendations. Results Whenever possible, a NSAID should be avoided in patients with treatment-resistant hypertension, high risk of cardiovascular disease and severe chronic kidney disease (CKD). Before treatment with a NSAID is started, blood pressure should be measured, unrecognised CKD should be screened in high risk cases, and unexplained iron-deficiency anaemia should be investigated. For patients with high cardiovascular risk, and if NSAID treatment cannot be avoided, naproxen or celecoxib are preferred. For patients with a moderate risk of peptic ulcer disease, monotherapy with a non-selective NSAID plus a proton pump inhibitor (PPI), or a selective cyclo-oxygenase-2 (COX-2) inhibitor should be used; for those with a high risk of peptic ulcer disease, a selective COX-2 inhibitor plus PPI are needed. For patients with pre-existing hypertension receiving renin-angiotensin system blockers, empirical addition (or increase in the dose) of an antihypertensive agent of a different class should be considered. Blood pressure and renal function should be monitored in most cases. Conclusion NSAIDs are a valuable armamentarium in clinical medicine, but appropriate recognition of high-risk cases, selection of a specific agent, choice of ulcer prophylaxis and monitoring after therapy are necessary to minimise the risk of adverse events.

Underwater endoscopic mucosal resection (UEMR) has become widespread for treating colorectal polyps. However, which observational mode is best suited for determining polyp margins underwater remains unclear. To determine the best mode, we analyzed three imaging modes: white light imaging (WLI), blue laser imaging (BLI) and linked color imaging (LCI).

Anti‐reflux mucosectomy (ARMS) is a newfangled minimally invasive technique, with successful outcomes for the management of gastroesophageal reflux (GER). We present our initial experience (success rate) and safety profile for this procedure.

Epstein–Barr virus-positive mucocutaneous ulcer (EBV-MCU) is a new category of mature B-cell neoplasms. Ulcers occur in the oropharyngeal mucosa, skin, and gastrointestinal tract. The onset of EBV-MCU is suggested to be related to the decreased immunity of the patient, the causes of which include the use of immunosuppressive agents and aging. EBV-MCU may regress spontaneously and it often has a benign course after the dose reduction or discontinuation of immunosuppressive agents or during follow-up. Here, we report the case of a patient who required surgical resection for the intestinal obstruction arising from EBV-MCU. A Japanese elderly male visited our hospital with chief complaints of a palpable mass and dull pain in the left upper quadrant, loss of appetite, and weight loss. Although abdominal computed tomography and total colonoscopy (TCS) revealed a tumor with circumferential ulcer in the transverse colon, histopathological analysis of a biopsy specimen of this lesion showed only nonspecific inflammation. Because the tumor spontaneously regressed during the time he underwent tests to obtain a second opinion from another hospital, TCS was reperformed on the patient. TCS revealed that the tumor decreased in size and the inflammatory changes in the surrounding mucosa tended to improve; however, tightening of the surrounding mucosa due to scarring was observed. Another histopathological analysis of a biopsy specimen showed widespread erosion of the mucosa and the formation of granulation tissue with marked infiltration of various inflammatory cells into the mucosal tissue of the large intestine. Moreover, some of the B-lymphocyte antigen CD20-positive B cells were also positive for EBV-encoded small RNA-1, suggesting the possibility of EBV-MCU. Later, the tumor developed into an intestinal obstruction; thus, the transverse colon was resected. Histopathological analysis of the resected specimen demonstrated scattered Hodgkin and Reed–Sternberg-like multinucleated large B cells in addition to EBER-1-positive cells. The patient was finally diagnosed as having EBV-MCU. This is the first report of a case of EBV-MCU that developed into an intestinal obstruction requiring surgical resection. It is necessary to consider the possibility of EBV-MCU when examining an ulcerative or tumorous lesion in the gastrointestinal tract.

A subset of patients with ulcerative colitis (UC) present with, or progress to, moderate to severe disease activity. These patients are at high-risk for colectomy, hospitalization, corticosteroid-dependence, and serious infections. The risk of life-threatening complications and emergency colectomy is particularly high among those patients hospitalized with acute severe ulcerative colitis (ASUC). Optimal management of outpatients or inpatients with moderate-severe UC often requires the use of immunomodulator and/or biologic therapies including thiopurines, methotrexate, cyclosporine, tacrolimus, tumor necrosis factor (TNF)-α antagonists, vedolizumab, tofacitnib or ustekinumab, either as monotherapy, or in combination (with immunomodulators), to mitigate these risks. Decisions about optimal drug therapy in moderate-severe UC are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Therefore, the American Gastroenterological Association prioritized development of clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the GRADE framework. Focused questions in adult outpatients with moderate-severe UC included: (1) overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to TNF-α antagonists, (2) comparative efficacy and safety of biologic monotherapy vs. combination therapy with immunomodulators, (3) comparative efficacy of top-down (upfront use of biologics and/or immunomodulator therapy) vs. step-up therapy (acceleration to biologic and/or immunomodulator therapy only after failure of 5-aminosalicylates), and (4) role of continuing vs. stopping 5-aminosalicylates in patients being treated with immunomodulator and/or biologic therapy for moderate-severe UC. Focused questions in adults hospitalized with ASUC included: (5) overall and comparative efficacy of pharmacological interventions for inpatients refractory to corticosteroids, in reducing risk of colectomy, (6) optimal dosing regimens for intravenous corticosteroids and infliximab in these patients and (7) role of adjunctive antibiotics in the absence of confirmed infections.

Background and Aims Outbreaks of infections transmitted by duodenoscopes have prompted changes to duodenoscope cleaning protocols. However, little is known about effectiveness of clinical cleaning practices. We present culture data after duodenoscope manufacturer-recommended high-level disinfection (HLD) and quarantine. Methods Our institution adopted a combination of manufacturer-recommended cleaning with the CDC-recommended culture and quarantine in 2015. Duodenoscopes (Olympus models TJF-Q180V, TJF-160, PJF-160) underwent HLD according to the manufacturer’s reprocessing manual protocols after use. Two culture specimens were then obtained using a sterile brush from the distal tip, including elevator mechanism, and by flushing sterile water through the working channel. Duodenoscopes were quarantined until cultures resulted. Positive cultures were defined as >10 colony-forming units (CFUs) of low-concern organisms, or any CFUs of high-concern organisms according to CDC recommendations. If either culture specimen was positive, the process was repeated until cultures were negative. Data were collected from December 2015 to July 2018. Results There were 140 instances of duodenoscope cleaning with 280 specimens. Twenty-eight of 234 (12%) initial culture specimens (18% of cultured duodenoscopes) were positive. Five of 36 (14%) second cultures were positive. Two of 8 (25%) third cultures were positive. Ninety-eight percent of organisms cultured were gram positive. There were 8 instances when both culture methods (brushing and flush) were positive; otherwise only one method was positive. There were 11 instances (8%) of duodenoscope removals from quarantine before final culture results. No patients had infections related to ERCP. Conclusions 18% of duodenoscopes had a positive culture after initial HLD. Only 3% were gram negative bacteria. Repeated HLD was 86% and 75% effective at eliminating initial and repeat positive cultures respectively. Initial HLD per manufacturer recommendations is not always effective at eliminating bacterial contamination. Additional steps are necessary to decrease risks of duodenoscope-transmitted infections.

Adolescents and young adults diagnosed with inflammatory bowel diseases (IBDs) in pediatric care are vulnerable during their transition to adult care. There are 6 core elements of transition from pediatric to adult IBD care. We identified gaps in this transition and make recommendations for clinical practice and research. There have been few studies of transition policy (core element 1) or studies that tracked and monitored patients through the transition (core element 2). Several studies have assessed transition readiness (core element 3), but instruments for assessment were not validated using important outcomes such as disease control, health care use, adherence, quality of life, or continuity of care. There have been no studies of best practices for transition planning (core element 4), including how to best educate patients and facilitate gradual shifts in responsibility. A small number of longitudinal studies have investigated transfer of care (core element 5), but these were conducted outside of the United States; these studies found mixed results in short- and intermediate-term outcomes after transition completion (core element 6). We discuss what is known about the transition from pediatric to adult care for IBD, make recommendations to improve this process, and identify areas for additional research.

Background & Aims The incidence of inflammatory bowel diseases (IBD) is increasing in Latin America. We performed a systematic review to identify clinical and epidemiologic features of IBD in Latin America (including Mexico, Central America, and South America) and the Caribbean. Methods We searched MEDLINE, EMBASE, and SciELO databases for clinical or epidemiologic studies of Crohn’s disease (CD) or ulcerative colitis (UC) from Latin American and Caribbean countries and territories that reported incidence, prevalence, ratio of UC:CD, IBD phenotype, and treatment, through September 12, 2018. Data were extracted from 61 articles for analysis. Results The incidence and prevalence of IBD have been steadily increasing in Latin America and the Caribbean. The incidence of CD in Brazil increased from 0.08 per 100,000 person-years in 1988 to 0.68 per 100,000 person-years in 1991–1995 to 5.5 per 100,000 person-years in 2015. The highest reported prevalence of IBD was in Argentina, in 2007, at 15 and 82 per 100,000 person-years for CD and UC, respectively. The ratio of UC:CD exceeded 1 in all regions throughout Latin America and the Caribbean with the exception of Brazil. Treatment with tumor necrosis factor antagonists increased steadily for patients with CD (43.4% of all patients in Brazil were treated in 2014) but less so for patients with UC (4.5% of all patients were treated in 2014). Surgery for IBD decreased with time. In Chile, surgeries were performed on 57.0% of patients with CD and 18.0% of patients with UC during the period of 1990–2002; these values decreased to 38.0% and 5.0%, respectively, during the period of 2012–2015. In Peru, 6.9% of patients with UC received colectomies in the period of 2001–2003 and 6.2% in 2004–2014. Conclusions In a systematic review, we found the incidence of IBD to be increasing throughout Latin America and the Caribbean. Population-based epidemiology studies are needed to evaluate the increase in IBD in these regions, which differ from other global regions in climate, culture, demographics, diet, healthcare delivery and infrastructure, and socioeconomic status.

Background & Aims In unselected patients with cirrhosis, those with reductions in hepatic venous pressure gradient (HVPG) to below a defined threshold (responders) have a reduced risk of variceal hemorrhage (VH) and death. We performed a meta-analysis to compare this effect in patients with vs without ascites. Methods We collected data from 15 studies of primary or secondary prophylaxis of VH that reported data on VH and death in responders vs nonresponders. We included studies in which data on ascites at baseline and on other relevant outcomes during follow-up evaluation were available. We performed separate meta-analyses for patients with vs without ascites. Results Of the 1113 patients included in the studies, 968 patients (87%) had been treated with nonselective β-blockers. In 993 patients (89%), HVPG response was defined as a decrease of more than 20% from baseline (>10% in 11% of patients) or to less than 12 mm Hg. In the 661 patients without ascites, responders (n = 329; 50%) had significantly lower odds of events (ascites, VH, or encephalopathy) than nonresponders (odds ratio [OR], 0.35; 95% CI, 0.22–0.56). Odds of death or liver transplantation were also significantly lower among responders than nonresponders (OR, 0.50, 95% CI, 0.32–0.78). In the 452 patients with ascites, responders (n = 188; 42%) had significantly lower odds of events (VH, refractory ascites, spontaneous bacterial peritonitis, or hepatorenal syndrome) than nonresponders (OR, 0.27; 95% CI, 0.16–0.43). Overall, odds of death or liver transplantation were lower among responders (OR, 0.47; 95% CI, 0.29–0.75). No heterogeneity was observed among studies. Conclusions In a meta-analysis of clinical trials, we found that patients with cirrhosis with and without ascites who respond to treatment with nonselective β-blockers (based on reductions in HVPG) have a reduced risk of events, death, or liver transplantation.

Background & Aims Eosinophilic esophagitis (EoE) is caused by an immune response to specific food allergens. There are no approved therapies beyond avoidance of the allergen(s) or treatment of inflammation. Epicutaneous immunotherapy (EPIT) reduces features of eosinophilic gastrointestinal disease in mice and pigs. We performed randomized, placebo-controlled study to determine the safety and efficacy of EPIT with Viaskin milk in children with milk-induced EoE. Methods In a double-blind study, 20 children (4–17 years old) with milk-induced EoE were randomly assigned to groups given EPIT with Viaskin milk (n = 15) or placebo (n = 5) for 9 months during a milk-free period, followed by milk-containing diet for 2 months with EPIT. Then, subjects underwent upper endoscopy analysis, biopsies were collected, and maximum esophageal eosinophil counts were determined and was the primary endpoint. After upper endoscopy, patients were given open-label EPIT for 11 months (open-label phase). The subjects were allowed to consume milk if they had maximum values of fewer than 10 eosinophils/high-power field (eos/hpf); otherwise, they remained on a milk-free diet until the last 2 months of the open-label phase. Results In the intent to treat population, there was no significant difference between the Viaskin milk group in mean eos/hpf (50.1 ± 43.97 eos/hpf) vs the placebo group (48.20 ± 56.98 eos/hpf). However, in the per-protocol population (7 patients given Viaskin milk and 2 patients given placebo), patients given Viaskin milk patients had a significantly lower mean eos/hpf count (25.57 ± 31.19) than patients given placebo (95.00 ± 63.64) (p = .038). At the end of the open-label phase, 9 of 19 evaluable subjects had mean values of fewer than 15 eos/hpf (47% response). The number of adverse events did not differ significantly between the Viaskin milk and placebo groups; there was 1 serious adverse event in the placebo group. Conclusions In a pilot study of pediatric patients with EoE given EPIT with Viaskin milk or placebo for 11 months, we found no significant difference between groups for the maximum eosinophil count at the end of the study. However, findings from a per-protocol analysis indicate that Viaskin milk can reduce eos/hpf. At study completion, 47% of patients who continued open-label Viaskin milk for an additional 11 months had mean values of fewer than 15 eos/hpf. ClinicalTrials.gov no: NCT02579876

Background & Aims Gastric cancer is the leading cause of infection-related cancer death and the third-leading cause of cancer death worldwide. The effect of immigration on gastric cancer risk is not well-defined but might be helpful for screening or surveillance endeavors. We performed a systematic review and meta-analysis to define the risk of gastric cancer in immigrants from high-incidence regions to low-incidence regions (including Western Europe, Australia, Brazil, Canada, Israel, and the United States). Methods We searched MEDLINE and EMBASE databases, from January 1980 to January 2019, for studies that identified immigrants from high-incidence regions of gastric cancer, provided clear definitions of immigrant and reference populations, and provided sufficient data to calculate gastric cancer incidence and gastric cancer-related mortality. We performed meta-analyses of standardized incidence ratios (SIR) for first-generation immigrants from high- to low-incidence regions, stratified by immigrant generation, sex, and anatomic and histologic subtype, when data were available. Results We identified 38 cohort studies that met our inclusion criteria. All 13 studies of 21 distinct populations reported significantly increased SIRs for gastric cancer in first-generation foreign-born immigrants (men SIR range, 1.24–4.50 and women SIR range, 1.27–5.05). The pooled SIR for immigrants with all types of gastric cancer was 1.66 (95% CI, 1.52–1.80) for men and 1.83 (95% CI, 1.69–1.98) for women. Nine studies from 2 high-incidence populations (the former Soviet Union and Japan) reported an increased gastric cancer standardized mortality ratio in first-generation immigrants who migrated to regions of low incidence (former Soviet Union immigrants, 1.44–1.91 for men and 1.40–2.56 for women). Conclusions Immigrants from regions with a high incidence of gastric cancer to regions of low incidence maintain a higher risk of gastric cancer and related mortality, based on a comprehensive systematic review and meta-analysis. Assessment of immigrant generation along with other risk factors might help identify high-risk populations for prevention and therapeutic interventions.

Background & Aims The safety of different antithrombotic strategies for patients with 1 or more indication for antithrombotic drugs has not been determined. We investigated the risk and time frame for gastrointestinal bleeding (GIB) in patients prescribed different antithrombotic regimens. We proposed that risk would increase over time and with combination regimens, especially among elderly patients. Methods We performed a retrospective analysis of nationwide claims data from privately insured and Medicare Advantage enrollees who received anticoagulant and/or antiplatelet agents from October 1, 2010, through May 31, 2017. Patients were stratified by their prescriptions (anticoagulant alone, antiplatelet alone, or a combination) and by their primary diagnosis (atrial fibrillation, ischemic heart disease, or venous thromboembolism). The 1-year GIB risk was estimated using parametric time-to-event survival models and expressed as annualized risk and number needed to harm (NNH). Results Our final analysis included 311,211 patients (mean ages, 67 years for monotherapy and 69.8 years for combination antithrombotic therapy). There was no significant difference in the proportion of patients with bleeding after anticoagulant or antiplatelet monotherapy (∼3.5%/year). Combination antithrombotic therapy increased GIB risk compared with anticoagulant (NNH, 29) or antiplatelet (NNH, 31) monotherapy, regardless of the patients’ diagnosis or time point analyzed. Advancing age was associated with increasing 1-year probability of GIB. Patients prescribed combination therapy were at the greatest risk for GIB, especially after the age of 75 years (GIB occurred in 10%–17.5% of patients/y). Conclusions In an analysis of nationwide insurance and Medicare claims data, we found GIB to occur in a higher proportion of patients prescribed combinations of anticoagulant and antiplatelet agents compared with monotherapy. Among all drug exposure categories and cardiovascular conditions, the risk of GIB increased with age, especially among patients older than 75 years.

Background & Aims Functional gastrointestinal disorders are highly prevalent, cause significant suffering, and are costly to society. Pain is a central feature of 2 of the most common functional gastrointestinal disorders: irritable bowel syndrome and functional dyspepsia. Although these disorders have been well studied in adults, their etiology is poorly understood. We sought to identify early life factors associated with the development of abdominal pain in children (age, 2–12 y). Methods We collected data from the All Babies in Southeast Sweden study of 1781 children, born from October 1, 1997, through October 31, 1999, whose families answered questions about abdominal pain and risk factors at birth, 1 year, 2.5 years, 5 years, 8 years, and 10 to 12 years. We used latent growth curve models to evaluate risk factors for development of abdominal pain. The primary outcomes were prevalence of abdominal pain and associated factors. Results The prevalence of abdominal pain increased linearly with age in the study cohort, increasing by approximately 6% per year. Psychosocial variables associated with slope of the growth curve included lower emotional control at age 2 years (P = .005), parental concern for the child at age 2 years (P = .02), and measures of parental stress (P = .004). Nonvaginal birth was associated with a reduced slope of the growth curve (P = .03). Conclusions In a study of children in Sweden, we found early psychosocial environment and mode of delivery at birth was associated with development of childhood abdominal pain. Factors associated with development of the early immune system, identified in previous recall-based research, were not supported by data from this study. These findings have important implications for the prevention of abdominal pain in children and later in life.

Background & Aims Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable mutations in genes that encode MMR proteins—this is called Lynch-like syndrome (LLS). There is no consensus on management of patients with LLS. We collected data from a large series of patients with LLS to identify clinical and pathology features. Methods We collected data from a nationwide-registry of patients with colorectal cancer (CRC) in Spain. We identified patients whose colorectal tumors had loss of MSH2, MSH6, PMS2, or MLH1 (based on immunohistochemistry), without the mutation encoding V600E in BRAF (detected by real-time PCR), and/or no methylation at MLH1 (determined by methylation-specific multiplex ligation-dependent probe amplification), and no pathogenic mutations in MMR genes, BRAF, or EPCAM (determined by DNA sequencing). These patients were considered to have LLS. We collected data on demographic, clinical, and pathology features and family history of neoplasms. The χ2 test was used to analyze the association between qualitative variables, followed by the Fisher exact test and the Student t test or the Mann-Whitney test for quantitative variables. Results We identified 160 patients with LLS; their mean age at diagnosis of CRC was 55 years and 66 patients were female (41%). The Amsterdam I and II criteria for Lynch syndrome were fulfilled by 11% of cases and the revised Bethesda guideline criteria by 65% of cases. Of the patients with LLS, 24% were identified in universal screening. There were no proportional differences in sex, indication for colonoscopy, immunohistochemistry, pathology findings, or personal history of CRC or other Lynch syndrome-related tumors between patients who met the Amsterdam and/or Bethesda criteria for Lynch syndrome and patients identified in universal screening for Lynch syndrome, without a family history of CRC. Conclusions Patients with LLS have homogeneous clinical, demographic, and pathology characteristics, regardless of family history of CRC.

Background & Aims The diagnostic criteria for fecal incontinence (FI) were made more restrictive in the Rome IV revision. We aimed to determine the characteristics of FI patients defined by the Rome IV criteria, assess how FI frequency and amount affect quality of life, identify risk factors, and compare prevalence values among countries. Methods We performed an internet-based survey of 5931 subjects in the United States, Canada, and the United Kingdom, from September to December 2015. Subjects were stratified by country, sex, and age. Responders answered questions about diagnosis, health care use, and risk factors. We performed multivariate linear regression analysis to identify risk factors for FI. Results FI was reported by 957 subjects (16.1%) but only 196 (3.3%) fulfilled the Rome IV criteria. Frequency of FI was less than twice a month for 672/957 subjects (70.2%) and duration was less than 6 months for 285/957 subjects (29.8%). Quality of life was significantly impaired in all subjects with FI compared to subjects with fecal continence. The strongest risk factors for FI were diarrhea, urgency to defecate, and abdominal pain. FI was more prevalent in the United States than in the United Kingdom. Between-country differences were due to less diarrhea and urgency in the United Kingdom. Conclusions Rome IV FI prevalence is lower than previous estimates because the new criteria exclude many individuals with less frequent or short duration FI. These excluded patients have impaired quality of life. It might be appropriate to make a diagnosis of FI for all patients with FI ≥2 times in 3 months and to provide additional information on frequency, duration, and amount of stool lost to assist clinicians in treatment selection.

Background & Aims Increased gut permeability might contribute to the pathogenesis of irritable bowel syndrome or functional abdominal pain (IBS or FAP). We investigated whether siblings and parents of children with IBS or FAP have increased gut permeability. Methods We performed permeability tests (using sucrose, lactulose, mannitol, and sucralose) on 29 siblings and 43 parents of children with IBS or FAP, and 43 children (controls) and 42 parents of controls, from primary and secondary care. Permeability studies were repeated in 7 siblings and 37 parents of children with IBS or FAP and 23 controls and 36 parents of controls following ingestion of 400 mg of ibuprofen. Percent recovery of sucrose was calculated based on analyses of urine collected overnight; the lactulose/mannitol ratio and percent recovery of sucralose were based on analyses of urine samples collected over a 24-hour period. Results When we controlled for age, sex, and family membership, siblings of children with IBS or FAP had increased small bowel permeability (urinary lactulose/mannitol ratio) vs controls (P = .004). There was no difference in gastroduodenal (percent sucrose recovery) or colonic (percent sucralose recovery) permeability between groups. Similarly, parents of children with IBS or FAP also had increased small bowel permeability, compared with parents of controls (P = .015), with no differences in gastric or colonic permeability. After administration of ibuprofen, gastroduodenal and small bowel permeability tended to be greater in IBS or FAP siblings (P = .08) and gastroduodenal permeability tended to be greater in IBS or FAP parents (P = .086). Conclusions Siblings and parents of children with IBS or FAP have increased baseline small intestinal permeability compared with control children and their parents. These results indicate that there are familial influences on gastrointestinal permeability in patients with IBS or FAP.

Objectives Few studies have examined the effects of applying the Rome IV criteria for irritable bowel syndrome (IBS) vs the previous standard, the Rome III criteria. We conducted a cross-sectional survey of individuals who self-identify as having IBS to examine this issue. Methods We collected complete demographic, symptom, mood, and psychological health data from 1375 adults who self-identified as having IBS, but were not recruited from a referral population. We applied the Rome III and the Rome IV criteria simultaneously to examine what proportion met each of these diagnostic criteria for IBS. We measured the level of agreement between the Rome III and Rome IV criteria, and assessed for presence of an alternative functional bowel disorder in individuals who no longer met diagnostic criteria for IBS with the more restrictive Rome IV criteria. Finally, we compared characteristics of individuals who met only Rome III criteria with those who met Rome IV criteria. Results In total, 1080 of 1368 individuals (78.9%) with IBS met the Rome III criteria. In contrast, 811 of 1373 individuals (59.1%) with IBS met the Rome IV criteria. Agreement between the criteria was only moderate (Kappa = 0.50). Among those who no longer had IBS according to the Rome IV criteria, 33 (11.5%) met Rome IV criteria for functional constipation, 118 (41.3%) for functional diarrhea, 68 (23.8%) for functional abdominal bloating or distension, and 67 (23.4%) for an unspecified functional bowel disorder. Individuals with Rome IV-defined IBS had more severe symptoms, and a higher proportion had a mood disorder and evidence of poor psychological health, compared with individuals who only met the Rome III criteria for IBS (P < .001). Conclusions The characteristics of people who believe they have IBS differ between those who meet criteria as defined by Rome IV vs Rome III, including the spectrum of disease severity. Studies are needed to determine how these changes will affect outcomes of clinical trials.

Background & Aims Patients with Crohn’s disease (CD) must make decisions about their treatment. We aimed to quantify patients’ preferences for different treatment outcomes and adverse events. We also evaluated the effects of latent class heterogeneity on these preferences. Methods An online stated-preference survey was completed by 812 individuals with CD in the Crohn’s and Colitis Foundation Partners cohort (IBD Partners). Patients were given information on symptoms and severity of active disease; duration of therapy with corticosteroids; and risks of serious infection, cancer and surgery. Patients were asked to assume that their treatment was not working and to choose an alternative therapy. The primary outcome was remission-time equivalents (RTE) of a given duration of symptom severity or treatment-related risk. Latent class choice models identified groups of patients with dominant treatment-outcome preferences and associated patient characteristics with these groups. Results Latent class analysis demonstrated 3 distinct groups of survey responders whose choices were strongly influenced by avoidance of active symptoms (61%), avoidance of corticosteroid use (25%), or avoidance of risks of cancer, infection or surgery (14%) when choosing a therapy. Class membership was correlated with age, sex, mean short CD activity index score and corticosteroid avoidance. RTEs in each latent class differed significantly from the mean RTEs for the overall sample, although the symptom-avoidant class most closely approximated the overall sample. Conclusions In an online survey of patients with CD, we found substantial heterogeneity in preference for medication efficacy and risk of harm. Physicians and regulators should therefore not assume that all patients have mean-value preferences—this could result in significant differences in health-technology assessment models.

Background & Aims Few data are available to guide the use of anal imaging for patients with Crohn’s disease (CD) who are not suspected of having perianal fistulas. We aimed to evaluate the role of anal imaging supplementary to magnetic resonance enterography (MRE) in these patients. Methods In a prospective study, we added a round of anal MR imaging (MRI), collecting axial images alone, to MRE evaluation of 451 consecutive adults who were diagnosed with or suspected of having CD but not believed to have perianal fistulas. Images were examined for perianal tracts; if present, colorectal surgeons reexamined patients to identify external openings or perianal inflammation or abscess. Patients were followed and data were collected on dedicated treatment for perianal fistulas or abscess. We calculated the diagnostic yield for anal MRI, associated factors, and outcomes of MRI-detected asymptomatic perianal tracts. Results A total of 440 patients (mean age, 29.6±8.9 years) met the inclusion criteria. Anal MRI revealed perianal tracts in 53 patients (12%; 95% CI, 9.3%–15.4%). Surgeons however did not identify any lesions that required treatment. The asymptomatic tracts were mostly single unbranched (83%), inter-sphincteric (72%), or had a linear dark signal at the tract margin (79%). Younger age at MRE, female sex, and CD activity index scores of 220–450 were independently associated with detection of perianal tracts. MRI detection of asymptomatic tracts was independently associated with later development of perianal fistulas or abscess that required treatment: 17.8% cumulative incidence at 37 months and an adjusted hazard ratio of 3.06 (95% CI, 1.01–9.27; P = .048). Conclusions In a prospective study of patients with CD, we found that adding anal MRI evaluation to MRE resulted in early identification of patients at risk for perianal complications.

Background & Aims Imaging patterns from endoscopic ultrasound (EUS)-guided needle-based confocal laser endomicroscopy (nCLE) have been associated with specific pancreatic cystic lesions (PCLs). We compared the accuracy of EUS with nCLE in differentiating mucinous from nonmucinous PCLs with that of measurement of carcinoembryonic antigen (CEA) and cytology analysis. Methods We performed a prospective study of 144 consecutive patients with a suspected PCL (≥20 mm) who underwent EUS with fine-needle aspiration of pancreatic cysts from June 2015 through December 2018 at a single center; 65 patients underwent surgical resection. Surgical samples were analyzed by histology (reference standard). During EUS, the needle with the miniprobe was placed in the cyst, which was analyzed by nCLE. Fluid was aspirated and analyzed for level of CEA and by cytology. We compared the accuracy of nCLE in differentiating mucinous from nonmucinous lesions with that of measurement of CEA and cytology analysis. Results The mean size of dominant cysts was 36.4 ± 15.7 mm and the mean duration of nCLE imaging was 7.3 ± 2.8 min. Among the 65 subjects with surgically resected cysts analyzed histologically, 86.1% had at least 1 worrisome feature based on the 2012 Fukuoka criteria. Measurement of CEA and cytology analysis identified mucinous PCLs with 74% sensitivity, 61% specificity, and 71% accuracy. EUS with nCLE identified mucinous PCLs with 98% sensitivity, 94% specificity, and 97% accuracy. nCLE was more accurate in classifying mucinous vs nonmucinous cysts than the standard method (P < .001). The overall incidence of postprocedure acute pancreatitis was 3.5% (5 of 144); all episodes were mild, based on the revised Atlanta criteria. Conclusions In a prospective study, we found that analysis of cysts by nCLE identified mucinous cysts with greater accuracy than measurement of CEA and cytology analysis. EUS with nCLE can be used to differentiate mucinous from nonmucinous PCLs. ClincialTrials.gov no: NCT02516488.

Background & Aims With several options available for patients with moderate–severe ulcerative colitis (UC), rapidity of symptom resolution could be an important differentiator. We compared the efficacy and speed of onset of action of infliximab vs golimumab induction therapy using patient-level data from phase 3 trials (ACT-1, ACT-2, and PURSUIT-SC). Methods We compared differences in proportions of patients who achieved the composite outcome of a rectal bleeding score=0 and stool frequency score ≤1 (patient-reported outcome 2 remission) at weeks 2 and 6 of treatment with standard-dose infliximab vs golimumab using logistic generalized estimating equation. Overall efficacy for inducing clinical remission (Mayo clinic score <3) was compared using logistic regression. Analyses were adjusted for sex, disease extent, baseline clinical and endoscopic severity, C-reactive protein, albumin, body weight and concomitant medications (immunomosuppressives, corticosteroids, and 5-aminsalicylates). Results Trial populations were similar and no differences were observed among the placebo groups in the studies. A significantly higher proportion patients treated with infliximab than golimumab achieved patient-reported outcome 2 remission at week 2 (35% vs 30%; adjusted odds ratio [OR], 1.71; 95% CI, 1.15–2.55) and at week 6 (50.0% vs 38.9%; adjusted OR, 2.0; 95% CI, 1.40–2.94). Infliximab-treated patients were also significantly more likely to achieve clinical remission than golimumab-treated patients (adjusted OR, 3.01; 95% CI, 1.95–4.70), with consistent findings in patients with moderate or severe UC. Conclusions Based on a patient-level analysis of data from phase 3 trials, infliximab resolves symptoms more rapidly and has greater efficacy for inducing remission than golimumab in patients with moderate-to-severe UC.

Background & Aims Although single-operator cholangioscopy is considered to be the most sensitive method for tissue acquisition in patients with indeterminate bile duct strictures (IBDS), methods are needed to optimize the specimen collection and processing techniques. We aimed to determine the optimal method for specimen processing and identify the number of biopsies required to establish a definitive diagnosis. Methods Patients with IBDS were randomly assigned to groups that underwent specimen processing using the onsite (n = 32) or offsite (n = 30) method. The primary outcome was to compare operating characteristics of onsite vs offsite specimen processing techniques. The secondary outcome was number of biopsies needed to establish definitive diagnosis. A final diagnosis was established at surgery or after a minimum clinical follow-up period of 18 months Results The final diagnosis was benign disease in 33 patients and malignancy in 29 patients. There were no significant differences between the offsite and onsite groups in diagnostic accuracy (90% vs 87.5%; P=.99), sensitivity (76.9% vs 75%; P=.99), specificity (100% vs 100%; P=.99), positive predictive value (100% vs 100%; P=.99), or negative predictive value (85% vs 80%; P=.99). Although diagnoses were established by analysis of a median of 1 biopsy in the onsite cohort (interquartile range, 1–1.5), the diagnostic accuracy was identical (90%) in each group, regardless of whether 3 or 4 biopsies were collected from each patient in the offsite cohort. Conclusions In a prospective comparative study, we found that centers without onsite cytopathology support that analyze 3 single-operator cholangioscopy-guided biopsies of a biliary stricture and process the specimens offsite make the correct diagnosis for 90% of cases. ClinicalTrials.gov, Number: NCT01815619.

Background & Aims Treatment of chronic hepatitis B virus (HBV) infection with entecavir suppresses virus replication and reduces disease progression, but could require life-long therapy. To investigate clinical outcome events and safety associated with long-term treatment with entecavir, we followed up patients treated with entecavir or another standard-of-care HBV nucleos(t)ide analogue for up to 10 years. We assessed long-term outcomes and relationships with virologic response. Methods Patients with chronic HBV infection at 299 centers in Asia, Europe, and North and South America were assigned randomly to groups that received entecavir (n = 6216) or an investigator-selected nonentecavir HBV nucleos(t)ide analogue (n = 6162). Study participants were followed up for up to 10 years in hospital-based or community clinics. Key end points were time to adjudicated clinical outcome events and serious adverse events. In a substudy, we examined relationships between these events and virologic response. Results There were no significant differences between groups in time to event assessments for primary end points including malignant neoplasms, liver-related HBV disease progression, and death. There were no differences between groups in the secondary end points of nonhepatocellular carcinoma malignant neoplasms and hepatocellular carcinoma. In a substudy of 5305 patients in China, virologic response, regardless of treatment group, was associated with a reduced risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.038–0.221) and hepatocellular carcinoma (hazard ratio, 0.03; 95% CI, 0.009–0.113). Twelve patients given entecavir (0.2%) and 50 patients given nonentecavir drugs (0.8%) reported treatment-related serious adverse events. Conclusions In a randomized controlled trial of patients with chronic HBV infection, we associated entecavir therapy with a low rate of adverse events over 10 years of follow-up evaluation. Patients receiving entecavir vs another nucleos(t)ide analogue had comparable rates of liver- and non–liver-related clinical outcome events. Participants in a China cohort who maintained a virologic response, regardless of treatment group, had a reduced risk of HBV-related outcome events including hepatocellular carcinoma. ClinicalTrials.gov identifier no: NCT00388674.

Background & Aims In some individuals with undetectable serum levels of hepatitis B surface antigen (HBsAg), hepatitis B virus (HBV) DNA can still be detected in serum or hepatocytes and HBV replicates at low levels—this is called occult HBV infection (OBI). OBI has been associated with increased risk of hepatocellular carcinoma (HCC). We investigated the incidence of OBI in patients with HCC and other liver diseases. We also investigated whether, in patients with OBI and HCC, HBV DNA has integrated into the DNA of hepatocytes. Methods We collected clinical information and liver tissues from 110 HBsAg-negative patients (90 with HCC and 20 without HCC; median ages at surgical resection and biopsy collection, 64.1 and 48.6 years, respectively) who underwent liver resection or liver biopsy from November 2002 through July 2017 in Hong Kong. HBV DNA and covalently closed circular DNA (cccDNA) were analyzed and quantified by PCR in liver tissues. Integration of HBV DNA into the DNA of liver cells was detected by Alu-PCR. Results Of the 90 HBsAg-negative patients with HCC, 18 had alcoholic liver disease (20%), 14 had non-alcoholic fatty liver disease or steatohepatitis (16%), 2 had primary biliary cholangitis, 2 had recurrent pyogenic cholangitis, 1 had autoimmune hepatitis, and 53 had none of these (59%). Among the 20 patients without HCC, 7 had non-alcoholic fatty liver disease or steatohepatitis, 7 had primary biliary cholangitis, and 6 had autoimmune hepatitis. OBI was detected in 62/90 patients with HCC (69%) and 3/20 patients without HCC (15%) (P < .0001). cccDNA was detectable in liver cells of 29 patients with HCC and OBI (47%) and HBV DNA had integrated into DNA of liver cells of 43 patients with HCC and OBI (69%); cccDNA and integrated HBV DNA were not detected in the 3 patients who had OBI without HCC. There were 29 patients with integration of HBV DNA among 33 patients with undetectable cccDNA in liver tissues (88%) and 14 patients with integration of HBV DNA among the 29 patients with cccDNA in liver tissues (48%) (P = .001). HBV DNA was found to integrate near genes associated with hepatocarcinogenesis, such as those encoding telomerase reverse transcriptase, lysine methyltransferase 2B, and cyclin A2. Among the 43 patients with integration of HBV DNA, 39 (91%) did not have cirrhosis. Conclusions In an analysis of clinical data and liver tissues from 90 HBsAg-negative patients with HCC, we found that almost 70% had OBI, of whom 70% had integration of HBV DNA into liver cell DNA; 90% of these patients did not have cirrhosis. HBV DNA integrated near hepatic oncogenes; these integrations might promote development of liver cancer.

Background & Aims Patients admitted to the hospital for alcoholic hepatitis (AH) are at increased risk of readmission and death. We aimed to identify factors associated with readmission, alcohol relapse, and mortality. Methods We performed a retrospective analysis of consecutive patients admitted with AH to a tertiary care hospital from 1999 through 2016 (test cohort, n = 135). We validated our findings in a prospective analysis of patients in a multi-center AH research consortium from 2013 through 2017 (validation cohort, n = 159). Alcohol relapse was defined as any amount of alcohol consumption within 30 days after hospital discharge. Early alcohol rehabilitation was defined as residential or outpatient addiction treatment or mutual support group participation within 30 days after hospital discharge. Results Thirty-day readmission rates were 30% in both cohorts. Alcohol relapse rates were 37% in the test and 34% in the validation cohort. Following hospital discharge, 27 patients (20%) in the test cohort and 19 patients (16%) in the validation cohort attended early alcohol rehabilitation. There were 53 deaths (39%) in a median follow-up time of 2.8 years and 42 deaths (26%) in a median follow-up time of 1.3 years, respectively. In the test cohort, early alcohol rehabilitation reduced odds for 30-day readmission (adjusted odds ratios [AOR] 0.16; 95% CI, 0.04–0.65; P = .01), 30-day alcohol relapse (AOR, 0.11; 95% CI, 0.02–0.53; P < .001), and death (adjusted hazard ratio [AHR], 0.20; 95% CI, 0.05–0.56; P = .001). In the validation cohort early alcohol rehabilitation reduced odds for 30-day readmission (AOR, 0.30; 95% CI, 0.09–0.98; P = .04), 30-day alcohol relapse (AOR 0.09; 95% CI, 0.01–0.73; P = .02), and death (AHR, 0.20; 95% CI, 0.01–0.94; P = .04). A model combining alcohol rehabilitation and bilirubin identified patients with readmission to the hospital within 30 days with an area under the receiver operating characteristic curve of 0.73. Conclusions In an analysis from two cohorts of patients admitted with AH, early alcohol rehabilitation can reduce risk of hospital readmission, alcohol relapse, and death and should be considered as a quality indicator in AH hospitalization treatment.

Background & Aims Chronic liver disease is a major health burden that produces significant liver-related morbidity and mortality. We aimed to evaluate liver-related outcomes of patients with different causes of chronic liver disease in Australia. Methods We collected data from 10,933 patients with chronic liver disease assessed by Hepascore (a serum fibrosis model) in Western Australia from 2004 through 2015. We obtained records of liver-related death, transplantation, decompensation, and hepatocellular carcinoma from WA Data Linkage Unit databases. Competing risk analysis was used to calculate the cumulative risk of each clinical endpoint, and risks for clinical endpoints were compared among all causes of chronic liver disease. Results In our final cohort for analysis, 5566 patients had hepatitis C virus (HCV) infection, 1989 had HBV infection, 119 were infected with HBV and HCV, 955 had alcohol-associated liver disease, 1597 had non-alcoholic fatty liver disease (NAFLD), 123 had alcohol-associated liver disease and metabolic risk factors, 561 had autoimmune liver disease without overlap syndrome, and 23 autoimmune overlap syndrome. Significant differences among chronic liver diseases were observed in risk of all-cause death (P < .001), liver-related death (P < .001), liver transplantation (P < .001), and decompensation (P < .001) but not hepatocellular carcinoma (P=.095). Patients with alcohol-associated liver disease had the highest 5-year cumulative risk of liver-related death (17.1%) and the second-highest 5-year cumulative risk of decompensation (29.2%). Multivariate analysis found patients with alcohol-associated liver disease had significantly higher risks of liver-related death and decompensation than patients with HCV infection with hazard ratios (HRs) of 2.39 (95% CI, 1.88–3.03) and 3.42 (95% CI, 2.74–4.27), respectively. Patients with NAFLD had a significantly lower risk of liver related death and decompensation than patients with HCV infection, with HRs of 0.67 (95% CI, 0.48–0.95) and 0.70 (95% CI, 0.52–0.94) respectively. Conclusions In an analysis of patients in Western Australia, we found patients with alcohol-associated liver disease to have significantly higher risk of decompensation and liver-related death than patients with HCV infection, whereas patients with NAFLD have significantly lower risks of either outcome.

Background & Aims Endogenous heparinoids or heparin-like effects (HLEs) can cause coagulation failure in patients with cirrhosis and sepsis. We performed a prospective study of the association between HLE and bleeding events, sepsis, and outcomes of patients with severe alcohol-associated hepatitis. Methods Our final analysis comprised 78 patients with severe alcohol-associated hepatitis (44.3 ± 11.7 years; all male; discriminant function >32) who presented without sepsis at a single center in India from August 2015 through August 2016. Blood samples were collected at days 0, 3, and 7 after presentation and assessed by a global coagulation assay; by SONOCLOT (global and heparinase treated); and in assays for factor VIII, von Willebrand factor, protein C, and antithrombin. Patients were followed for sepsis, bleeding and outcome. The primary outcome was association of HLE with survival 28 days after presentation. Results HLEs were observed in 32 patients (41%) at day 0, 27 patients (34.6%) at day 3, and 28 patients (35.9%) patients at day 7. Factors associated with mortality at day 0 were factor VIII activity >160% (hazard ratio [HR], 3.1; 95% CI, 1.4–9.5; P = .026), level of protein C <34% (HR, 0.7; 95% CI, 0.5–0.8; P = .037), antithrombin activity <28% (HR, 0.7; 95% CI, 0.3–1.1; P = .008) and international normalized ratio >2.6 (HR, 2.3; 95% CI, 1.8–9.7; P = .010). In multivariate analyses, only factor VIII activity (HR, 2.3; 95% CI, 1.6–7.8; P = .046), international normalized ratio (1.9; 95% CI, 1.2–4.3; P = .039), level of protein C (HR, 0.9; 95% CI, 0.7–1.1; P = .052) and model for end-stage liver disease score (HR, 3.2; 95% CI, 1.9–10.2; P = .042) were associated with mortality. Episodes of epistaxis, hemorrhoid bleeding, hemoperitoneum, and pulmonary hemorrhage occurred in 10.2%, 12.3%, 3.4%, and 4.5% of patients respectively. The presence of HLE at day 0 increased the risk of sepsis (HR, 2.5; 95% CI, 2.2–4.3; P = .002), bleeding (HR, 1.4; 95% CI, 1.2–5.3; P = .004) and death (HR, 1.2; 95% CI, 1.4–1.7; P = .044). Conclusions In a prospective study of patients with severe alcohol-associated hepatitis, we associated HLE with coagulation abnormalities, risk of sepsis, and mortality. Clinicaltrials.gov NCT02307409.

Background & Aims We compared the efficacy and safety of different first-line (biologic-naïve) and second-line (prior exposure to tumor necrosis factor [TNF] antagonists) agents for treatment of moderate to severely active ulcerative colitis in a systematic review and network meta-analysis. Methods We searched publication databases through September 30, 2019 for randomized trials of adults with moderate to severe ulcerative colitis treated with TNF antagonists, vedolizumab, tofacitinib, or ustekinumab, as first-line or second-line agents, compared with placebo or another active agent. Efficacy outcomes were induction and maintenance of remission and endoscopic improvement; safety outcomes were serious adverse events and infections. We performed fixed-effects network meta-analysis using frequentist approach, and calculated odds ratios (ORs) and 95% CI values. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Results In biologic-naïve patients, infliximab was ranked highest for induction of clinical remission (OR vs placebo, 4.07; 95% CI, 2.67–6.21; SUCRA,0.95) and endoscopic improvement (SUCRA, 0.95) (moderate confidence in estimates [CE]). In patients with prior exposure to TNF antagonists, ustekinumab (SUCRA,0.87) and tofacitinib (SUCRA,0.87) were ranked highest for induction of clinical remission and were superior to vedolizumab (OR vs ustekinumab, 5.99; 95% CI, 1.13–31.76 and OR vs tofacitinib, 6.18; 95% CI, 1.003–8.00; moderate CE) and adalimumab (OR vs ustekinumab, 10.71; 95% CI, 2.01–57.20 and OR vs tofacitinib, 11.05; 95% CI, 1.79–68.41; moderate CE). Vedolizumab had lowest risk of infections (SUCRA, 0.81), followed by ustekinumab (SUCRA, 0.63) in maintenance trials. Conclusions In a systematic review and network meta-analysis, we found infliximab to be ranked highest in biologic-naïve patients, and ustekinumab and tofacitinib were ranked highest in patients with prior exposure to TNF antagonists, for induction of remission and endoscopic improvement in patients with moderate to severe ulcerative colitis. More trials of direct comparisons are needed to inform clinical decision-making with greater confidence.

Background & Aims Alcohol-related liver disease (ALD) causes chronic liver disease. We investigated how information on patients’ drinking history and amount, stage of liver disease, and demographic feature can be used to determine risk of disease progression. Methods We collected data from 2334 heavy drinkers (50 g/day or more) with persistently abnormal results from liver tests who had been admitted to a hepato-gastroenterology unit in France from January 1982 through December 1997; patients with a recorded duration of alcohol abuse were assigned to the development cohort (n=1599; 75% men) or the validation cohort (n=735; 75% men), based on presence of a liver biopsy. We collected data from both cohorts on patient history and disease stage at the time of hospitalization. For the development cohort, severity of the disease was scored by the METAVIR (due to the availability of liver histology reports); in the validation cohort only the presence of liver complications was assessed. We developed a model of ALD progression and occurrence of liver complications (hepatocellular carcinoma and/or liver decompensation) in association with exposure to alcohol, age at the onset of heavy drinking, amount of alcohol intake, sex and body mass index. The model was fitted to the development cohort and then evaluated in the validation cohort. We then tested the ability of the model to predict disease progression for any patient profile (baseline evaluation). Patients with a 5-y weighted risk of liver complications greater than 5% were considered at high risk for disease progression. Results Model results are given for the following patient profiles: men and women, 40 y old, who started drinking at an age of 25 y, drank 150 g/day, and had a body mass index of 22 kg/m2 according to the disease severity at baseline evaluation. For men with baseline F0–F2 fibrosis, the model estimated the probabilities of normal liver, steatosis, or steatohepatitis at baseline to be 31.8%, 61.5% and 6.7%, respectively. The 5-y weighted risk of liver complications was 1.9%, ranging from 0.2% for men with normal liver at baseline evaluation to 10.3% for patients with steatohepatitis at baseline. For women with baseline F0–F2 fibrosis, probabilities of normal liver, steatosis, or steatohepatitis at baseline were 25.1%, 66.5% and 8.4%, respectively; the 5-y weighted risk of liver complications was 3.2%, ranging from 0.5% for women with normal liver at baseline to 14.7% for patients with steatohepatitis at baseline. Based on the model, men with F3–F4 fibrosis at baseline have a 24.5% 5-y weighted risk of complications (ranging from 20.2% to 34.5%) and women have a 30.1% 5-y weighted risk of complications (ranging from 24.7% to 41.0%). Conclusions We developed a Markov model that integrates data on level and duration of alcohol use to identify patients at high risk of liver disease progression. This model might be used to adapt patient care pathways.

Watch a video of this article

The anti-immunological rejection therapy for small-for-size syndrome (SFSS) after live donor liver transplantation (LDLT) play a central role in keeping graft survival. The hepatocyte number and grafts function has undergone real-time changes with the proliferation and apoptosis of the grafts after reperfusion. Lacking an accurate and effective treatment regiments or indicators to guide the use of immunosuppressive drugs in SFS liver transplantation has made immunotherapy after SFS liver transplantation an urgent problem to be solved. Herein, we established small-for-size (SFS) and normal size liver transplantation model in rats to explore the effective indicators in guiding immunotherapy, to find an effective way for overcoming SFSS. Lewis rats (donors) and BN rats (recipients) were used to mimic allograft liver transplantation and treated with tacrolimus. Local graft immune response was analyzed through haematoxylin and eosin and immunohistochemistry. Flow cytometry was used to assess the overall immune status of recipient. The pharmacokinetics mechanism of immunosuppressive drugs was explored through detecting CYP3A2 expression at mRNA level and protein levels. The results showed the local immune reaction of SFS grafts and systemic immune responses of recipient were significantly increased compared with those in normal size grafts and their recipient at four days after liver transplantation. Regression equation was used to regulate the tacrolimus dose which not only controlled tacrolimus serum concentration effectively but alleviated liver damage and improved survival rate. This study showed that AST level and tacrolimus serum concentrations are effective indicators in guiding immunotherapy. Regression equation (TD = − 0.494TC-0.0035AST + 260.487) based on AST and tacrolimus serum concentration can be used as a reference for adjustment of immunotherapy after SFS liver transplantation, which is applicable in clinical practice.

Interleukin-10 (IL10) signalling pathway deficiency results in severe very early onset inflammatory bowel disease (VEOIBD), and enterostomy is often inevitable. However, studies in these surgical populations are lacking. This study aims to determine the enterostomy characteristics, postoperative complications and related risk factors in enterostomy patients. From March 1, 2015, to December 31, 2018, patients with IL10R-mutation who underwent enterostomy were recruited for analysis. We collected data on the patients’ clinical characteristics, enterostomy characteristics, postoperative complications and related risk factors. Twelve patients required emergency enterostomy, and 10 patients underwent elective enterostomy. Twelve patients experienced postoperative complications, including wound infection (27.3%), wound dehiscence (18.2%), reoperation (18.2%), etc. Compared with the pre-enterostomy values, there was a decrease in C-reactive protein (CRP) (P = 0.001), an increase in albumin (P = 0.001) and an improvement in the weight-for-age (P = 0.029) and body mass index (BMI) Z-scores (P = 0.004) after enterostomy. There was a significant difference between the pre-operation and postoperation medicine expenses (P = 0.002). Univariate binary logistic regression analysis revealed a statistically significant influence of CRP (OR: 1.43, 95% CI: 1.07–1.91, P = 0.016) and a tendency towards a significant influence of intestinal perforation, albumin level, BMI Z-score and weighted paediatric Crohn’s disease activity index (wPCDAI). Multivariate logistic regression analysis showed that CRP (OR: 1.40), wPCDAI (OR: 2.88) and perforation (OR: 1.72) showed a tendency to behave as independent risk factors for postoperative complications, but the results were not significant (all P > 0.05). Surgery and enterostomy showed benefits for VEOIBD with IL-10 signalling deficiency. The timing of intervention, potential postoperative complications, economic burden and other related problems should be considered.

With a worldwide prevalence of 15%, chronic constipation is one of the most frequent gastrointestinal diagnoses made in ambulatory medicine clinics and is a common source cause for referrals to gastroenterologists and colorectal surgeons in the United States. Symptoms vary among patients; straining, incomplete evacuation, and a sense of anorectal blockage are just as important as decreased stool frequency. Chronic constipation is either a primary disorder (such as normal transit, slow transit, or defecatory disorders) or a secondary one (due to medications or in rare cases anatomic alterations). Colonic sensorimotor disturbances and pelvic floor dysfunction (such as defecatory disorders) are the most widely recognized pathogenic mechanisms. Guided by efficacy and cost, management of constipation should begin with dietary fiber supplementation and stimulant and/or osmotic laxatives, as appropriate, followed, if necessary, by intestinal secretagogues and/or prokinetic agents. Peripherally acting μ-opiate antagonists are another option for opioid-induced constipation. Anorectal tests to evaluate for defecatory disorders should be performed in patients who do not respond to over-the-counter agents. Colonic transit, followed if necessary with assessment of colonic motility with manometry and/or a barostat, can identify colonic dysmotility. Defecatory disorders often respond to biofeedback therapy. For specific patients, slow-transit constipation may necessitate a colectomy. No studies have compared inexpensive laxatives with newer drugs with different mechanisms. We review the mechanisms, evaluation, and management of chronic constipation. We discuss the importance of meticulous analyses of patients’ histories and physical examination, advantages and disadvantages of diagnostic testing, guidance for individualized treatment, and management of medically refractory patients.

Background & Aims In addition to Notch and Wnt signaling pathways, energy metabolism also regulates intestinal stem cell (ISC) function. Tumor suppressor and kinase STK11 (also called LKB1) regulates stem cells and cell metabolism. We investigated whether loss of LKB1 alters ISC homeostasis in mice. Methods We deleted LKB1 from ISCs in mice using Lgr5-regulated CRE–ERT2 (Lkb1Lgr5-KO mice) and the traced lineages using a CRE-dependent TdTomato reporter. Intestinal tissues were collected and analyzed by immunohistochemical and immunofluorescence analyses. We purified ISCs and intestinal progenitors using flow cytometry and performed RNA sequencing analysis. We measured organoid-forming capacity and ISC percentages using intestinal tissues from Lkb1Lgr5-KO mice. We analyzed human Ls174t cells with knockdown of LKB1 or other proteins by immunoblotting, real-time quantitative PCR, and the Seahorse live-cell metabolic assay. Results Some intestinal crypts from Lkb1Lgr5-KO mice lost ISCs, compared with crypts from control mice. However, most crypts from Lkb1Lgr5-KO mice contained functional ISCs that expressed increased levels of Atoh1 mRNA, acquired a gene expression signature associated with secretory cells, and generated more cells in the secretory lineage, compared with control mice. Knockdown of LKB1 in Ls174t cells induced expression of Atoh1 mRNA and a phenotype of increased mucin production; knockdown of ATOH1 prevented induction of this phenotype. The increased expression of Atoh1 mRNA following LKB1 loss from ISCs or Ls174t cells did not involve Notch or Wnt signaling. Knockdown of pyruvate dehydrogenase kinase 4 (PDK4) or inhibition with dichloroacetate reduced the upregulation of Atoh1 mRNA following LKB1 knockdown in Ls174t cells. Cells with LKB1 knockdown had a reduced rate of oxygen consumption, which was partially restored by PDK4 inhibition with dichloroacetate. ISCs with knockout of LKB1 increased expression of PDK4 and had an altered metabolic profile. Conclusions LKB1 represses transcription of ATOH1, via PDK4, in ISCs, restricting their differentiation into secretory lineages. These findings provide a connection between metabolism and fate determination of ISCs.

Abstract Background/Aims We examined the quality of palliative care received by patients with decompensated cirrhosis using an explicit set of palliative care quality indicators (QIs) for patients with end-stage liver disease (PC-ESLD). Methods We identified patients newly diagnosed with decompensated cirrhosis at a single veterans health center and followed up them for 2 years or until death. We piloted measurement of PC-ESLD QIs in all patients confirmed to have ESLD using a chart abstraction tool. Results Out of 167 patients identified using at least one sampling strategy, 62 were confirmed to meet ESLD criteria with chart abstraction. Ninety-eight percent of veterans in the cohort were male, mean age at diagnosis was 61 years, and 74% were White. The overall QI pass rate was 68% (64% for information care planning QIs and 76% for supportive care QIs). Patients receiving specialty palliative care consultation were more likely to receive information care planning QIs (67% vs. 37%, p = 0.02). The best performing sampling strategy had a sensitivity of 62% and specificity of 60%. Conclusion Measuring the quality of palliative care for patients with ESLD is feasible in the veteran population. Our single-center data suggest that the quality of palliative care is inadequate in the veteran population with ESLD, though patients offered specialty palliative care consultation and those affected by homelessness, drug, and alcohol abuse may receive better care. Our combination of ICD-9 codes can be used to identify a cohort of patients with ESLD, though better sensitivity and specificity may be needed.

Abstract Background The adenoma detection rate (ADR) is a widely accepted quality benchmark for screening colonoscopy but can be burdensome to calculate. Previous studies have shown good correlation between polyp detection rate (PDR) and ADR, but this has not been validated in trainees. Additionally, the correlation between PDR and detection rates for sessile serrated polyps (SSPDR) and advanced neoplasia (ANDR) is not well studied. Aims We investigated the relationship between PDR and ADR, SSPDR, and ANDR in trainees. Methods We examined 1600 outpatient colonoscopies performed by 24 trainees at a VA hospital from 2014 to 2017. Variables collected included patient demographics, year of fellowship, colonoscopy indication, and endoscopic and histologic findings. We calculated the overall ratios of PDR to ADR, SSPDR, and ANDR to assess the correlation between measured and calculated ADR, SSPDR, and ANDR, which is equivalent to the correlation between PDR and measured ADR, SSPDR, and ANDR. Results The overall PDR, ADR, SSPDR, and ANDR were 72%, 52%, 2%, and 14%. PDR (48%) was highest in the left colon, while ADR (32%) and ANDR (7%) were highest in the right colon (p < 0.001 for all). The overall ADR/PDR, SSPDR/PDR, and ANDR/PDR ratios were 0.73, 0.03, and 0.20. Correlation between PDR and ADR was highly positive overall (r = 0.87, p < 0.0001) and stronger in the right (r = 0.91) and transverse (r = 0.94) colon than the left colon (r = 0.80). Correlation between PDR and overall SSPDR and ANDR were not statistically significant. Conclusions PDR can serve as a surrogate measure of ADR to monitor colonoscopy quality in gastroenterology fellowship.

Immune checkpoint inhibitors have revolutionized treatment and overall survival for several different types of cancer. Antibodies to cytotoxic T-lymphocyte-associated protein 4 and to programmed cell death protein 1 and its ligand enhance cytotoxic T-cell survival, thus augmenting antitumor action and consequently inducing immune-related adverse events, of which the most relevant is diarrhea and colitis. This review compiles recent data on pathophysiology, clinical manifestations, and treatment of immune-mediated colitis (IMC). The pathogenesis of IMC is not completely understood, but recent studies have focused on the role of regulatory T cells and interactions with the gut microbiome. While sharing similarities with inflammatory bowel disease, IMC is considered a distinct form of colitis with acute onset and rapid progression leading to potential complications including bowel perforation and death. Prompt recognition and management of IMC is imperative for optimal outcomes. Although prospective clinical trials are lacking to guide therapy, recent guidelines recommend early endoscopic evaluation to establish the diagnosis and prompt initiation of corticosteroids. Response to first-line therapy should be assessed early to determine the need of escalation to biologic agents. With treatment, most patients will experience full resolution of symptoms, and subsequent rechallenge with anti–programmed cell death protein 1 or anti–programmed death-ligand 1 inhibitors can be considered. Correspondence: Emanuelle Bellaguarda, MD. E-mail: emanuelle.bellaguarda@northwestern.edu. Received July 24, 2019 Accepted November 15, 2019 © The American College of Gastroenterology 2020. All Rights Reserved.

No abstract available

Background and aimsMost patients with perianal Crohn’s fistula receive medical treatment with anti-TNF, while the results of anti-TNF treatment have not been directly compared to chronic seton drainage or surgical closure. The aim of this study was to assess if chronic seton drainage for patients with perianal Crohn’s disease fistulas would result in less re-interventions, compared to anti-TNF and compared to surgical closure. MethodsThis randomised trial was performed in 19 European centres. Patients with high perianal Crohn’s fistulas with a single internal opening were randomly assigned to i) chronic seton drainage for 1 year, ii) anti-TNF therapy for 1 year, and iii) surgical closure after 2 months under a short course anti-TNF. The primary outcome was the cumulative number of patients with fistula-related re-intervention(s) at 1.5 year. Patients declining randomisation due to a specific treatment preference were included in a parallel prospective PISA registry cohort. ResultsBetween September 14, 2013 and November 20, 2017, 44 of the 126 planned patients were randomised. The study was stopped by the data safety monitoring board because of futility. Seton treatment was associated with the highest re-intervention rate (10/15, versus 6/15 anti-TNF and 3/14 surgical closure patients, P= 0.02). No substantial differences in perianal disease activity and quality of life between the three treatment groups were observed. Interestingly, in the PISA prospective registry, inferiority of chronic seton treatment was not observed for any outcome measure. ConclusionsThe results imply that chronic seton treatment should not be recommended as the sole treatment for perianal Crohn’s fistulas.The trial is registered with Trialregister.nl number NTR4137.

This review aims to provide a guidance in the decision process when to choose a janus kinase (JAK) inhibitor as medical treatment strategy. The focus will be on ulcerative colitis, since the only yet available JAK inhibitor, tofacitinib, has the approval for ulcerative colitis. The guidance path will include consideration on disease activity, previous treatment, comorbidities, family planning, patients’ preferences, pharmacology as well as concurrent chronic inflammatory diseases or extraintestinal manifestations. The suggested guidance path illustrates our daily difficulties in the decision process of making the best choice for the individual patient. However, as long as predictive biomarkers are lacking, the named criteria can be applied to any other strategy and hence provide support in daily practice.

IntroductionIt is unclear whether vedolizumab therapy can be discontinued in patients with inflammatory bowel disease (IBD) after achieving steroid-free clinical remission. AimTo assess the risk of relapse after vedolizumab therapy was discontinued. Patients and MethodsRetrospective observational study, collecting data from 21 tertiary centres affiliated with the GETAID from January 2017 to April 2019. Consecutive patients with IBD who were in steroid-free clinical remission for at least three months and were treated with vedolizumab for at least six months were included at the time of vedolizumab discontinuation. ResultsNinety-five patients (58 with Crohn’s disease) discontinued vedolizumab after a median duration of therapy of 17.5 [10.6-25.4] months. After a median follow-up period of 11.2 (5.8-17.7) months, 61 (64%) patients experienced disease relapse. The probabilities of relapse-free survival were 83%, 59% and 36% at 6, 12 and 18 months, respectively. According to the multivariate analysis, a CRP level less than 5 mg/L at vedolizumab discontinuation (HR=0.56, 95% CI [0.33-0.95], p=0.03) and discontinuation due to patients’ elective choice (HR=0.41, 95% CI [0.21-0.80], p=0.009) were significantly associated with a lower risk of relapse. Re-treatment with vedolizumab was noted in 24 patients and provided steroid-free clinical remission in 71% and 62.5% at week 14 and after a median follow-up of 11.0 [5.4-13.3] months, respectively, without any infusion reactions. ConclusionIn this retrospective study, two-thirds of patients with IBD treated with vedolizumab experienced relapse within the first year after vedolizumab discontinuation. Re-treatment with vedolizumab was effective in two-thirds of patients.

Background and Aims The visual detection of early esophageal neoplasia (high-grade dysplasia and T1 cancer) in Barrett’s esophagus (BE) with white-light and virtual chromoendoscopy still remains challenging. The aim of this study was to assess whether a convolutional neural artificial intelligence network can aid in the recognition of early esophageal neoplasia in BE. Methods Nine hundred sixteen images from 65 patients were collected of histology-proven early esophageal neoplasia in BE containing high-grade dysplasia or T1 cancer. The area of neoplasia was masked using image annotation software. Nine hundred nineteen control images were collected of BE without high-grade dysplasia. A convolutional neural network (CNN) algorithm was pretrained on ImageNet and then fine-tuned with the goal to provide the correct binary classification of “dysplastic” or “nondysplastic.” We developed an object detection algorithm that drew localization boxes around regions classified as dysplasia. Results The CNN analyzed 458 test images (225 dysplasia/233 nondysplasia) and correctly detected early neoplasia with sensitivity of 96.4%, specificity of 94.2% and accuracy of 95.4%. With regard to the object detection algorithm for all images in the validation set, the system was able to achieve a mean-average-precision (mAP) of 0.7533 at an intersection over union (IOU) of 0.3 Conclusion In this pilot study, our AI model was able to detect early esophageal neoplasia in Barrett’s esophagus images with high accuracy. In addition, the object detection algorithm was able to draw a localization box around the areas of dysplasia with high precision and at a speed that allows for real-time implementation.

Background and Aims Propofol is increasingly being used for sedation in colonoscopy; however, its benefits over midazolam (+/- short-acting opioids) are not well quantified. The objective of this study was to compare safety, satisfaction, and efficiency outcomes of propofol versus midazolam (+/- short-acting opioids) in patients undergoing colonoscopy. Methods We systematically searched MEDLINE, Embase, and the Cochrane library (to July 30, 2018) for randomized controlled trials of colonoscopies performed with propofol versus midazolam (+/- short-acting opioids). We pooled odds ratios for cardiorespiratory outcomes using mixed-effects conditional logistic models. We pooled standardized mean differences (SMD) for patient and endoscopist satisfaction and efficiency outcomes using random-effects models. Results Nine studies of 1,427 patients met inclusion criteria. There were no significant differences in cardiorespiratory outcomes (hypotension, hypoxia, bradycardia) between sedative groups. Patient satisfaction was high in both groups, with most patients reporting willingness to undergo a future colonoscopy with the same sedative regimen. In meta-analysis, patients sedated with propofol had greater satisfaction than those sedated with midazolam (+/- short-acting opioids) (SMD, 0.54; 95% CI, 0.30-0.79); however, there was considerable heterogeneity. Procedure time was similar between groups (SMD, 0.15; 95% CI, 0.04-0.27). Recovery time was shorter in the propofol group (SMD, 0.41; 95% CI, 0.08-0.74). The median difference in recovery time was 3 minutes 6 seconds shorter in patients sedated with propofol. Conclusions Both propofol and midazolam (+/- short-acting opioids) result in high patient satisfaction and appear safe for use in colonoscopy. There are marginal benefits to propofol, including improvements in satisfaction and recovery time.

Background & Aims We assessed the preliminary diagnostic accuracy of a recently developed computer aided detection (CAD) system for detection of Barrett’s neoplasia during live endoscopic procedures. Methods The CAD system was tested during endoscopic procedures of 10 patients with nondysplastic Barrett’s esophagus (NDBE), and 10 patients with confirmed Barrett’s neoplasia. White-light endoscopy images were obtained at every 2-centimeter level of the Barrett’s segment, and immediately analyzed by the CAD system, providing instant feedback to the endoscopist. At every level, 3 images were evaluated by the CAD system. Outcome measures were as follows: (1) diagnostic performance of the CAD system per-level and per-patient, defined as accuracy, sensitivity, and specificity. Ground truth was established by expert assessment and corresponding histopathology; and (2) concordance of 3 sequential CAD predictions per-level. Results Accuracy, sensitivity, and specificity of the CAD system in a per-level analyses were 90%, 91%, and 89%, respectively. In total, 9 out of 10 neoplastic patients were correctly diagnosed. The single lesion not detected by CAD, showed NDBE in the endoscopic resection specimen. In only 1 NDBE patient, the CAD system produced false positive predictions. In 75% of all levels, the CAD system produced 3 concordant predictions. Conclusion This is one of the first studies to evaluate a CAD system for Barrett’s neoplasia during live endoscopic procedures. The system detected neoplasia with high accuracy, with only a small number of false-positive predictions, and with a high concordance rate between separate predictions. The CAD system is thereby ready for testing in larger, multicenter trials.