Rigorous Donor Selection for Fecal Microbiota Transplantation in Active Ulcerative Colitis: Key Lessons From a Randomized Controlled Trial Halted for Futility.

BACKGROUND & AIMS: Rigorous donor preselection on microbiota level, strict anaerobic processing, and repeated fecal microbiota transplantation (FMT) administration were hypothesized to improve FMT induction of remission in ulcerative colitis (UC). METHODS: The RESTORE-UC trial was a multi-centric, double-blind, sham-controlled, randomized trial. Patients with moderate to severe UC (defined by total Mayo 4-10) were randomly allocated to receive 4 anaerobic-prepared allogenic or autologous donor FMTs. Allogenic donor material was selected after a rigorous screening based on microbial cell count, enterotype, and the abundance of specific genera. The primary endpoint was steroid-free clinical remission (total Mayo ≤2, no sub-score >1) at week 8. A pre-planned futility analysis was performed after 66% (n = 72) of intended inclusions (n = 108). Quantitative microbiome profiling (n = 44) was performed at weeks 0 and 8. RESULTS: In total, 72 patients were included, of which 66 received at least 1 FMT (allogenic FMT, n = 30 and autologous FMT, n = 36). At week 8, respectively, 3 and 5 patients reached the primary endpoint of steroid-free clinical remission (P = .72), indicating no treatment difference of at least 5% in favor of allogenic FMT. Hence, the study was stopped due to futility. Microbiome analysis showed numerically more enterotype transitions upon allogenic FMT compared with autologous FMT, and more transitions were observed when patients were treated with a different enterotype than their own at baseline (P = .01). Primary response was associated with lower total Mayo scores, lower bacterial cell counts, and higher Bacteroides 2 prevalence at baseline. CONCLUSION: The RESTORE-UC trial did not meet its primary endpoint of increased steroid-free clinical remission at week 8. Further research should additionally consider patient selection, sterilized sham-control, increased frequency, density, and viability of FMT prior to administration. CLINICALTRIALS: gov, Number: NCT03110289.

International Consensus Recommendations for Safe Use of LAMS for On- and Off-Label Indications Using a Modified Delphi Process.

INTRODUCTION: The study aimed to develop international consensus recommendations on the safe use of lumen-apposing metal stents (LAMSs) for on- and off-label indications. METHODS: Based on the available literature, statements were formulated and grouped into the following categories: general safety measures, peripancreatic fluid collections, endoscopic ultrasound (EUS)-biliary drainage, EUS-gallbladder drainage, EUS-gastroenterostomy, and gastric access temporary for endoscopy. The evidence level of each statement was determined using the Grading of Recommendations Assessment, Development, and Evaluation methodology.International LAMS experts were invited to participate in a modified Delphi process. When no 80% consensus was reached, the statement was modified based on expert feedback. Statements were rejected if no consensus was reached after the third Delphi round. RESULTS: Fifty-six (93.3%) of 60 formulated statements were accepted, of which 35 (58.3%) in the first round. Consensus was reached on the optimal learning path, preprocedural imaging, the need for airway protection and essential safety measures during the procedure, such as the use of Doppler, and measurement of the distance between the gastrointestinal lumen and the target structure. Specific consensus recommendations were generated for the different LAMS indications, covering, among others, careful patient selection, the preferred size of the LAMS, the need for antibiotics, the preferred anatomic location of the LAMS, the need for coaxial pigtail placement, and the appropriate management of LAMS-related adverse events. DISCUSSION: Through a modified international Delphi process, we developed general and indication-specific experience- and evidence-based recommendations on the safe use of LAMS.

Endoscopic Ultrasound-guided Radiofrequency Ablation Versus Surgical Resection for Treatment of Pancreatic Insulinoma.

BACKGROUND & AIMS: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is emerging as a safe and effective treatment for pancreatic neuroendocrine tumors. We aimed to compare EUS-RFA and surgical resection for the treatment of pancreatic insulinoma (PI). METHODS: Patients with sporadic PI who underwent EUS-RFA at 23 centers or surgical resection at 8 high-volume pancreatic surgery institutions between 2014 and 2022 were retrospectively identified and outcomes compared using a propensity-matching analysis. Primary outcome was safety. Secondary outcomes were clinical efficacy, hospital stay, and recurrence rate after EUS-RFA. RESULTS: Using propensity score matching, 89 patients were allocated in each group (1:1), and were evenly distributed in terms of age, sex, Charlson comorbidity index, American Society of Anesthesiologists score, body mass index, distance between lesion and main pancreatic duct, lesion site, size, and grade. Adverse event (AE) rate was 18.0% and 61.8% after EUS-RFA and surgery, respectively (P < .001). No severe AEs were observed in the EUS-RFA group compared with 15.7% after surgery (P < .0001). Clinical efficacy was 100% after surgery and 95.5% after EUS-RFA (P = .160). However, the mean duration of follow-up time was shorter in the EUS-RFA group (median, 23 months; interquartile range, 14-31 months vs 37 months; interquartile range, 17.5-67 months in the surgical group; P < .0001). Hospital stay was significantly longer in the surgical group (11.1 ± 9.7 vs 3.0 ± 2.5 days in the EUS-RFA group; P < .0001). Fifteen lesions (16.9%) recurred after EUS-RFA and underwent a successful repeat EUS-RFA (11 patients) or surgical resection (4 patients). CONCLUSION: EUS-RFA is safer than surgery and highly effective for the treatment of PI. If confirmed in a randomized study, EUS-RFA treatment can become first-line therapy for sporadic PI.

MRI texture analysis of T2-weighted images is preferred over magnetization transfer imaging for readily longitudinal quantification of gut fibrosis.

OBJECTIVES: To investigate the value of magnetization transfer (MT) MRI and texture analysis (TA) of T2-weighted MR images (T2WI) in the assessment of intestinal fibrosis in a mouse model. METHODS: Chronic colitis was induced in mice by cyclic administration of dextran sodium sulphate (DSS) resulting in chronic inflammation and progressive bowel fibrosis. Mice underwent 7-T MR imaging at various time points. Bowel wall MT ratio (MTR) and textural features (skewness, kurtosis, entropy), extracted by a filtration histogram technique, were correlated with histopathology. Performance of both techniques were validated using antifibrotic therapy. Finally, a retrospective study was conducted in five patients with Crohn's disease (CD) who underwent bowel surgery. RESULTS: MTR and texture entropy correlated with histopathological fibrosis (r = .85 and .81, respectively). Entropy was superior to MTR for monitoring bowel fibrosis in the presence of coexisting inflammation (linear regression R2 = .93 versus R2 = .01). Furthermore, texture entropy was able to assess antifibrotic therapy response (placebo mice versus treated mice at endpoint scan; Δmean = 0.128, p < .0001). An increase in entropy was indicative of fibrosis accumulation in human CD strictures (inflammation: 1.29; mixed strictures: 1.4 and 1.48; fibrosis: 1.73 and 1.9). CONCLUSION: MT imaging and TA of T2WI can both noninvasively detect established intestinal fibrosis in a mouse model. However, TA is especially useful for the longitudinal quantification of fibrosis in mixed inflammatory-fibrotic tissue, as well as for antifibrotic treatment response evaluation. This accessible post-processing technique merits further validation as the benefits for clinical practice as well as antifibrotic trial design would be numerous. KEY POINTS: • Magnetization transfer MRI and texture analysis of T2-weighted MR images can detect established bowel fibrosis in an animal model of gut fibrosis. • Texture entropy is able to identify and monitor bowel fibrosis progression in an inflammatory context and can assess the response to antifibrotic treatment. • A proof-of-concept study in five patients with Crohn's disease suggests that texture entropy can detect and grade fibrosis in human intestinal strictures.

EUS-guided versus PTC-guided rendezvous in case of failed ERCP: a case-control study.

BACKGROUND: Endoscopic ultrasound-guided rendezvous (EUS-RV) is a recently added alternative salvage technique to percutaneous transhepatic cholangiography rendezvous (PTC-RV) for achieving biliary cannulation in failed ERCP. Comparative data on these two techniques are lacking. The aim of this study is to evaluate the efficacy and safety of EUS-RV versus PTC-RV in a tertiary referral center. METHODS: A case-control study was conducted in the tertiary referral center, Ghent University Hospital. All consecutive patients that underwent a rendezvous procedure between February 2014 and March 2022 for failed biliary cannulation were included. Patients that underwent PTC-RV (between February 2014 and February 2018) were compared to those who underwent EUS-RV (between March 2018 and March 2022). A sub-analysis was performed for malignant biliary strictures (MBO), benign biliary strictures (BBO) and common bile duct stones (CBDS). The primary endpoints of interest were technical success rate and complication rate. These outcome variables were compared among techniques using Fisher's exact test. Statistical analyses were performed using STATA version 15. RESULTS: A total of 59 consecutive procedures in 57 patients were included for analysis; 20/59 (33.9%) were PTC-RV; the remaining 39/59 (66.1%) procedures were EUS-RV. Two patients in the PTC-RV group underwent two procedures. Of the PTC-RV procedures, 18/20 (90.0%) were technically successful, as compared to 28/39 EUS-RV procedures (71.8%) (P = 0.184; Fig. 1). Adverse events were reported in 7/20 PTC-RV procedures (35.0%) and in 13/39 EUS-RV procedures (33.3%) (P = 1.000). In 5/20 PTC-RV procedures (25.0%) and 4/39 EUS-RV procedures (10.3%), the adverse event was considered major (defined as AGREE classification of 3 or more; P = 0.249). CONCLUSIONS: EUS-RV has an acceptable success rate and is not associated with an increased risk of adverse events as compared to PTC-RV.

Outcome of primary ERCP versus primary PTC for biliary drainage in malignant hilar biliary strictures: a systematic review and meta-analysis.

BACKGROUND: Patients with malignant hilar biliary strictures can suffer from obstructive jaundice. Controversy remains on the optimal approach to obtain preoperative or palliative biliary drainage in these patients. A systematic review and meta-analysis was conducted to compare the two modalities most commonly used in this scenario: endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC). METHODS: MEDLINE via PubMed was searched for relevant articles published from 2005 to April 2019. Following outcome measures were used to compare ERCP and PTC: therapeutic success rate, cholangitis, pancreatitis, bleeding, tube dislocation, reintervention rate, mortality such as 30d mortality and in-hospital death, median survival time, drainage patency, duration until decompression and hospital stay. Risk of bias assessment for the retrospective studies was conducted by NOS. RoB 2 was used for RCT. A meta-analysis was performed by using Review Manager 5.3. The certainty of evidence was appraised using GRADE. RESULTS: Eleven articles of which one RCT and ten retrospective cohort studies fulfilled the inclusion criteria for data-analysis (1417 patients; 784 ERCP, 633 PTC). The combined odds ratio (OR) for therapeutic succes was 3.5 times higher in the PTC group (95% CI 2.05-5.97; high certainty). In terms of cholangitis, ERCP carried a 1.7-fold risk as compared to PTC (95% CI 0.92-3.08; moderate certainty). Patients who underwent ERCP were 11.50 times more likely to undergo a reintervention (95% CI 3.51-37.70; moderate certainty). ERCP was comparable to PTC in terms of pancreatitis (low certainty), bleeding (high certainty) and tube dislocation rate (moderate certainty). Mortality tended to be numerically higher in the PTC group but low patient numbers, selection bias and study heterogeneity did not allow uniform comparative analysis. CONCLUSIONS: In patients with malignant hilar biliary strictures, PTC is associated with a better therapeutic success rate, less cholangitis and lower reintervention rate as compared to ERCP.

Multicenter cohort study of patients with buried bumper syndrome treated endoscopically with a novel, dedicated device.

BACKGROUND AND AIMS: Buried bumper syndrome (BBS) is a rare adverse event of percutaneous endoscopic gastrostomy (PEG) placement in which the internal bumper migrates through the stomal tract to become embedded within the gastric wall. Excessive tension between the internal and external bumpers, causing ischemic necrosis of the gastric wall, is believed to be the main etiologic factor. Several techniques for endoscopic management of BBS have been described using off-label devices. The Flamingo set is a novel, sphincterotome-like device specifically designed for BBS management. We aimed to evaluate the effectiveness of the Flamingo device in a large, homogeneous cohort of patients with BBS. METHODS: A guidewire was inserted through the external access of the PEG tube into the gastric lumen. The Flamingo device was then introduced into the stomach over the guidewire. This dedicated tool can be flexed by 180 degrees, exposing a sphincterotome-like cutting wire, which is used to incise the overgrown tissue until the PEG bumper is exposed. A retrospective, international, multicenter cohort study was conducted on 54 patients between December 2016 and February 2019. RESULTS: The buried bumper was successfully removed in 53 of 55 procedures (96.4%). The median time for the endoscopic removal of the buried bumper was 22 minutes (range, 5-60). Periprocedural endoscopic adverse events occurred in 7 procedures (12.7%) and were successfully managed endoscopically. A median follow-up of 150 days (range, 33-593) was performed in 29 patients (52.7%), during which no significant adverse events occurred. CONCLUSIONS: Through our experience, we found this dedicated novel device to be safe, quick, and effective for minimally invasive, endoscopic management of BBS.

Lumen-apposing metal stents for approved and off-label indications: a single-centre experience.

BACKGROUND AND STUDY AIMS: Lumen-apposing stents (LAMS) are approved to treat peripancreatic collections and for gallbladder and bile duct drainage. Over the last years, LAMS have also been used for off-label indications including gastrojejunostomy, gastro-gastrostomy and drainage of postsurgical collections. We aimed to analyze indications, technical/clinical success rates and complications of all LAMS placed over the last 2 years. PATIENTS AND METHODS: Data from 61 consecutive LAMS (Hot Axios, Boston Scientific) in 57 patients were analyzed. Technical success was defined as successful deployment of the LAMS in the desired position. Clinical success was defined as follows: for pancreatic collections: resolution without the need for non-endoscopic interventions; for choledochoduodenostomy: ≥ 50% drop in baseline serum bilirubin within 2 weeks AND patient can receive chemotherapy if indicated; for gastrojejunostomy: resolution of gastric outlet obstruction and successful re-initiation of oral intake; for gastro-gastrostomy: successful endoscopic access to the excluded stomach; for gallbladder or postsurgical collection drainage: resolution of sepsis. RESULTS: Indications were drainage of peripancreatic collections in 24 cases (39.3%), choledochoduodenostomy in 13 (21.3%), gastrojejunostomy in 6 (9.8%), gastro-gastrostomy in 13 (21.3%), gallbladder drainage in 1 (1.6%) and postsurgical collection drainage in 4 (6.6%). Overall technical and clinical success rates were high (57/61; 93.4% and 54/61; 88.5%, respectively). Clinical success rate for non-approved indications was 95.6% (22/23 cases). Complications occurred in 13 patients (21.3%, 4 serious). CONCLUSIONS: LAMS are increasingly used in interventional endoscopy. In our cohort, more than one third of LAMS are placed for off-label indications, with a high success rate and acceptable complication rate.

Development and Validation of a Magnetic Resonance Index for Assessing Fistulas in Patients With Crohn's Disease.

BACKGROUND & AIMS: There is no validated magnetic resonance imaging (MRI) index for assessment of perianal fistulas in patients with Crohn's disease (CD). We developed and internally validated a new instrument. METHODS: We used paired baseline and week-24 MRI scans from 160 participants in a randomized placebo-controlled trial of stem cell therapy for patients with perianal fistulizing CD. Four radiologists scored disease activity using index items identified during previous studies and exploratory items. Reliability was assessed using intraclass correlation coefficients. We developed an index using backward elimination linear regression analysis, in which potential independent variables were items having intraclass correlation coefficients of at least 0.4 and the dependent variable was perianal fistulizing disease activity, measured on a 100-mm visual analogue scale. The final model was internally validated using the .632 bootstrap method to correct model optimism and quantify calibration accuracy. We evaluated responsiveness of the index by assessing longitudinal validity and estimating standardized effect sizes. RESULTS: We developed the magnetic resonance novel index for fistula imaging in CD (MAGNIFI-CD) using 6 items. The optimism-corrected R2 of the model was 0.71, which was comparable to R2 for the original sample (0.74). The calibration slope for the model was 0.98. Compared with the original and modified versions of the Van Assche Index, the MAGNIFI-CD had improved operating characteristics. Estimates of intraclass correlation coefficients for MAGNIFI-CD, the modified Van Assche Index, and Van Assche Index were 0.85 (95% confidence interval [CI], 0.77-0.90), 0.81 (95% CI, 0.74-0.86), and 0.81 (95% CI, 0.71-0.86) for intra-rater reliability, and 0.74 (95% CI, 0.63-0.80), 0.67 (95% CI, 0.55-0.75) and 0.68 (95% CI, 0.56-0.77) for inter-rater reliability. Corresponding standardized effect size estimates were 1.02 (95% CI, 0.65-1.39), 0.84 (95% CI, 0.48-1.21), and 0.68 (95% CI, 0.33-1.03). CONCLUSIONS: We developed an index called the MAGNIFI-CD, which is based on 6 items. It assesses MRI data and determines perianal fistulizing CD activity with improved operating characteristics compared to previous indices. This index may be used as an outcome measure in clinical trials comparing treatment effects in patients with perianal fistulizing CD. Although the performance of the MAGNIFI-CD indicates its stability and reasonable external validity, external validation is needed.

Vedolizumab Induces Endoscopic and Histologic Remission in Patients With Crohn's Disease.

BACKGROUND & AIMS: We evaluated the ability of vedolizumab to induce endoscopic and histologic remission in patients with Crohn's disease (CD). METHODS: We performed a prospective study of 110 patients with active CD, based on CD activity index (CDAI) scores >220 and mucosal ulcerations, who received open-label vedolizumab (300 mg) infusions at weeks 0, 2, and 6, and every 8 weeks thereafter through week 52 at tertiary centers in Europe. Patients received an additional infusion at week 10 if their CDAI score had not decreased by 70 points. Patients underwent ileocolonoscopy with collection of biopsies at baseline and weeks 26 and 52; a local and central reader determined simple endoscopic index for CD (SES-CD) scores. Histologic features were assessed by a blinded pathologist at week 26. Serum concentrations of vedolizumab were measured at serial time points. The primary outcome was endoscopic and histologic remission in patients with active CD treated with vedolizumab for 52 weeks. RESULTS: At weeks 26 and 52, 36 patients (29%) and 34 patients (31%), respectively, were in corticosteroid-free clinical remission (CDAI score <150), respectively. Based on intent-to-treat analysis, endoscopic remission (SES-CD score <4) was achieved by 36 patients (33%) and 40 patients (36%) at weeks 26 and 52. Endoscopic responses (decrease in SES-CD score ≥50%) occurred in 44 patients (40%) at week 26 and 5 patients (45%) at week 52. Serum concentrations of vedolizumab were higher at weeks 2, 10, and 22 in patients with lower SES-CD scores. Histologic remission at week 26 was observed in 43 (64%) of 67 patients based on Geboes Score and 37 (66%) of 56 patients based on Robarts Histopathology Index scores in analyses of paired biopsies with inflammation at baseline. Serum concentrations of vedolizumab above 10 mg/L at week 22 were associated with endoscopic remission at week 26. CONCLUSIONS: In a prospective trial, we found that approximately one-third of patients with CD achieve endoscopic remission after 52 weeks of treatment with vedolizumab and two-thirds achieve histologic remission at week 26. Higher serum concentrations of vedolizumab were associated with better outcomes. EUDRACT no: 2014-005376-29.

A novel device for the endoscopic management of buried bumper syndrome.

BACKGROUND: Buried bumper syndrome (BBS) is a complication of percutaneous endoscopic gastrostomy (PEG) in which the internal bumper is overgrown by the gastric mucosa. Apart from loss of patency of the PEG tube, the buried bumper may evoke symptoms such as abdominal pain or peritubular leakage. While the management of an incompletely buried bumper is fairly straightforward, this is not the case for a completely buried bumper. Different approaches to remove completely buried bumpers have been described, including endoscopic knife- or papillotome-based techniques. However, these devices are used off-label and the procedures can be laborious. METHODS: The Flamingo device has recently been introduced as the first tool specifically designed to remove a completely buried bumper. RESULTS: We describe the technique and our first experience in five patients with a completely (n = 4) or almost completely (n = 1) buried bumper. Fast and save removal of the buried bumper was obtained in all patients. CONCLUSION: We believe that this device has the potential to become the standard first-line tool for the management of completely buried bumpers.

Endoscopic management of biliary leaks: a systematic review with meta-analysis.

BACKGROUND: The first-line approach to the treatment of biliary leaks is endoscopic retrograde cholangiopancreatography. A variety of techniques can be used, including sphincterotomy, stenting, a combination of both techniques, or nasobiliary drainage. We performed a systematic review with meta-analysis to define the optimal strategy. METHODS: We searched MEDLINE/PubMed, EMBASE, CENTRAL, Scopus, Google Scholar, and Web of Science until January 2018 for randomized clinical trials, case-control studies, and prospective cohort studies. Data on procedure, success, and complication rate were extracted. Risk of bias was assessed. A network meta-analysis was performed to compare sphincterotomy alone vs. stenting alone vs. combination treatment. Stenting was further stratified into leak-bridging and short stenting. RESULTS: 11 studies out of 5085 references were included. Compared with sphincterotomy alone, the combination of sphincterotomy with leak-bridging stenting had the highest success rate (risk ratio [RR] 1.15, 95 % confidence interval [CI] 0.97 - 1.50), followed by leak-bridging stenting alone (RR 1.10, 95 %CI 0.84 - 1.44). For nonbridgeable leaks, stenting alone had a higher success rate than sphincterotomy alone (RR 1.07, 95 %CI 0.72 - 1.40). The combination of short stents with sphincterotomy had no added benefit (RR 0.94, 95 %CI 0.49 - 1.29). Overall quality of the included studies was considered to be moderate. CONCLUSIONS: We recommend sphincterotomy with stenting if the biliary leak can be bridged. If not, stenting alone with a short stent may be preferred in order to avoid sphincterotomy-related complications. More and larger studies are needed to confirm these findings.

Feasibility study using iodine quantification on dual-energy CT enterography to distinguish normal small bowel from active inflammatory Crohn's disease.

BACKGROUND: Assessment of Crohn's disease (CD) activity is important to identify patients with active inflammation for therapy management. Quantitative analysis can provide objective measurement of disease presence. PURPOSE: To evaluate the feasibility of quantitative analysis of contrast-enhanced dual-energy computed tomography (DECT) data in detection of small bowel inflammation in patients with CD with an emphasis on iodine quantification. MATERIAL AND METHODS: DECT enterography was prospectively performed in 20 patients with active CD and in 20 healthy individuals, as the control group. Iodine overlay images were created. Wall thickness, attenuation, absolute iodine density, relative iodine density, and fat fraction were measured in the terminal ileum of all patients by two radiologists. Intraclass correlation coefficients were calculated to assess inter-rater agreement. Parameters were compared between patient groups using mixed model analysis. Receiver operating characteristic (ROC) analysis was performed. RESULTS: Both absolute and relative iodine density were significantly higher in active disease than in normal small bowel (all P < 0.001). In contrast, measurement of fat fraction was not significantly different in affected terminal ileal loops compared to normal terminal ileum ( P = 0.075). ROC analysis demonstrated a similar excellent diagnostic accuracy of wall thickness, attenuation, and absolute and relative iodine density with area under the ROC curve (AUC) values in the range of 0.96 for attenuation to 1 for relative iodine density. CONCLUSION: DECT with iodine quantification can be used in distinguishing normal small bowel from active inflammatory CD. Further research should investigate the value of iodine quantification in grading CD activity and in monitoring therapeutic response.

Disease activity indices in coeliac disease: systematic review and recommendations for clinical trials.

OBJECTIVE: Although several pharmacological agents have emerged as potential adjunctive therapies to a gluten-free diet for coeliac disease, there is currently no widely accepted measure of disease activity used in clinical trials. We conducted a systematic review of coeliac disease activity indices to evaluate their operating properties and potential as outcome measures in registration trials. DESIGN: MEDLINE, EMBASE and the Cochrane central library were searched from 1966 to 2015 for eligible studies in adult and/or paediatric patients with coeliac disease that included coeliac disease activity markers in their outcome measures. The operating characteristics of histological indices, patient-reported outcomes (PROs) and endoscopic indices were evaluated for content and construct validity, reliability, responsiveness and feasibility using guidelines proposed by the US Food and Drug Administration (FDA). RESULTS: Of 19 123 citations, 286 studies were eligible, including 24 randomised-controlled trials. Three of five PROs identified met most key evaluative criteria but only the Celiac Disease Symptom Diary (CDSD) and the Celiac Disease Patient-Reported Outcome (CeD PRO) have been approved by the FDA. All histological and endoscopic scores identified lacked content validity. Quantitative morphometric histological analysis had better reliability and responsiveness compared with qualitative scales. Endoscopic indices were infrequently used, and only one index demonstrated responsiveness to effective therapy. CONCLUSIONS: Current best evidence suggests that the CDSD and the CeD PRO are appropriate for use in the definition of primary end points in coeliac disease registration trials. Morphometric histology should be included as a key secondary or co-primary end point. Further work is needed to optimise end point configuration to inform efficient drug development.

Treatment of Intestinal Fibrosis in Experimental Inflammatory Bowel Disease by the Pleiotropic Actions of a Local Rho Kinase Inhibitor.

BACKGROUND: Intestinal fibrosis resulting in (sub)obstruction is a common complication of Crohn's disease (CD). Rho kinases (ROCKs) play multiple roles in TGFß-induced myofibroblast activation that could be therapeutic targets. Because systemic ROCK inhibition causes cardiovascular side effects, we evaluated the effects of a locally acting ROCK inhibitor (AMA0825) on intestinal fibrosis. METHODS: Fibrosis was assessed in mouse models using dextran sulfate sodium (DSS) and adoptive T-cell transfer. The in vitro and ex vivo effects of AMA0825 were studied in different cell types and in CD biopsy cultures. RESULTS: ROCK is expressed in fibroblastic, epithelial, endothelial, and muscle cells of the human intestinal tract and is activated in inflamed and fibrotic tissue. Prophylactic treatment with AMA0825 inhibited myofibroblast accumulation, expression of pro-fibrotic factors, and accumulation of fibrotic tissue without affecting clinical disease activity and histologic inflammation in 2 models of fibrosis. ROCK inhibition reversed established fibrosis in a chronic DSS model and impeded ex vivo pro-fibrotic protein secretion from stenotic CD biopsies. AMA0825 reduced TGFß1-induced activation of myocardin-related transcription factor (MRTF) and p38 mitogen-activated protein kinase (MAPK), down-regulating matrix metalloproteinases, collagen, and IL6 secretion from fibroblasts. In these cells, ROCK inhibition potentiated autophagy, which was required for the observed reduction in collagen and IL6 production. AMA0825 did not affect pro-inflammatory cytokine secretion from other ROCK-positive cell types, corroborating the selective in vivo effect on fibrosis. CONCLUSIONS: Local ROCK inhibition prevents and reverses intestinal fibrosis by diminishing MRTF and p38 MAPK activation and increasing autophagy in fibroblasts. Overall, our results show that local ROCK inhibition is promising for counteracting fibrosis as an add-on therapy for CD.

Haematopoietic prolyl hydroxylase-1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis.

Prolyl hydroxylase domain-containing proteins (PHDs) regulate the adaptation of cells to hypoxia. Pan-hydroxylase inhibition is protective in experimental colitis, in which PHD1 plays a prominent role. However, it is currently unknown how PHD1 targeting regulates this protection and which cell type(s) are involved. Here, we demonstrated that Phd1 deletion in endothelial and haematopoietic cells (Phd1f/f Tie2:cre) protected mice from dextran sulphate sodium (DSS)-induced colitis, with reduced epithelial erosions, immune cell infiltration, and colonic microvascular dysfunction, whereas the response of Phd2f/+ Tie2:cre and Phd3f/f Tie2:cre mice to DSS was similar to that of their littermate controls. Using bone marrow chimeras and cell-specific cre mice, we demonstrated that ablation of Phd1 in haematopoietic cells but not in endothelial cells was both necessary and sufficient to inhibit experimental colitis. This effect relied, at least in part, on skewing of Phd1-deficient bone marrow-derived macrophages towards an anti-inflammatory M2 phenotype. These cells showed an attenuated nuclear factor-κB-dependent response to lipopolysaccharide (LPS), which in turn diminished endothelial chemokine expression. In addition, Phd1 deficiency in dendritic cells significantly reduced interleukin-1ß production in response to LPS. Taken together, our results further support the development of selective PHD1 inhibitors for ulcerative colitis, and identify haematopoietic cells as their primary target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Bleeding Lesion of the Small Bowel: an Extensive Update Leaving No Stone Unturned.

PURPOSE OF REVIEW: Gastrointestinal bleeding originating from the small bowel (SB) poses a challenge to the treating gastroenterologist. Once diagnosed, management is not a walk in the park either. This review intends to summarize the current state-of-the-art evidence in a complete way with special attention for vascular and ulcerative lesions, to provide the reader with a clinical guide and flow chart towards SB bleeding. RECENT FINDINGS: Absence of SB bleeding lesions on CE does not directly yield better prognosis; although having a lower rebleeding rate the first 2 years, rebleeding in the long term is high. Push enteroscopy can play an early role in patients with SB bleeding if suspicion of angioectasia is high, since these lesions tend to be located in the proximal SB. Endoscopic management of angioectasia is, however, difficult and shows poor results. Capsule endoscopy (CE) or device-assisted enteroscopy (DAE) remain the diagnostic mainstay in SB bleeding, choosing one over the other based upon patient characteristics and expected lesions.

Tauroursodeoxycholic acid protects bile acid homeostasis under inflammatory conditions and dampens Crohn's disease-like ileitis.

Bile acids regulate the expression of intestinal bile acid transporters and are natural ligands for nuclear receptors controlling inflammation. Accumulating evidence suggests that signaling through these receptors is impaired in inflammatory bowel disease. We investigated whether tauroursodeoxycholic acid (TUDCA), a secondary bile acid with cytoprotective properties, regulates ileal nuclear receptor and bile acid transporter expression and assessed its therapeutic potential in an experimental model of Crohn's disease (CD). Gene expression of the nuclear receptors farnesoid X receptor, pregnane X receptor and vitamin D receptor and the bile acid transporters apical sodium-dependent bile acid transporter and organic solute transporter α and ß was analyzed in Caco-2 cell monolayers exposed to tumor necrosis factor (TNF)α, in ileal tissue of TNFΔARE/WT mice and in inflamed ileal biopsies from CD patients by quantitative real-time polymerase chain reaction. TNFΔARE/WT mice and wild-type littermates were treated with TUDCA or placebo for 11 weeks and ileal histopathology and expression of the aforementioned genes were determined. Exposing Caco-2 cell monolayers to TNFα impaired the mRNA expression of nuclear receptors and bile acid transporters, whereas co-incubation with TUDCA antagonized their downregulation. TNFΔARE/WT mice displayed altered ileal bile acid homeostasis that mimicked the situation in human CD ileitis. Administration of TUDCA attenuated ileitis and alleviated the downregulation of nuclear receptors and bile acid transporters in these mice. These results show that TUDCA protects bile acid homeostasis under inflammatory conditions and suppresses CD-like ileitis. Together with previous observations showing similar efficacy in experimental colitis, we conclude that TUDCA could be a promising therapeutic agent for inflammatory bowel disease, warranting a clinical trial.

Systematic Review: Disease Activity Indices in Eosinophilic Esophagitis.

OBJECTIVES: There is no clear consensus regarding the most appropriate measure(s) of eosinophilic esophagitis (EoE) disease activity. We aimed to identify all scoring indices used for the measurement of disease activity in EoE, appraise their operating properties, and discuss their value as outcome measures. METHODS: MEDLINE, EMBASE, and CENTRAL (The Cochrane library) were searched from inception to 11 May 2016. Randomized controlled trials (RCTs), cohort, case-control, and cross-sectional studies that reported outcomes to measure EoE disease activity or response to treatment were eligible. Operating properties of histologic, endoscopic, and patient reported/symptomatic and health-related quality of life measures were critically appraised according to guidelines proposed by the United States Food and Drug Administration. RESULTS: Of 4,373 citations, 130 studies were eligible, of which 20 were RCTs. Although no index met all evaluative criteria, we found that: (1) the EoE histologic scoring system (EoEHSS) is the most valid histologic measure; (2) the Endoscopic Reference Score (EREFS) is the most reliable and responsive endoscopy measure; and (3) the Eosinophilic Esophagitis Activity Index (EEsAI) or the Dysphagia Symptoms Questionnaire (DSQ) had superior construct validity and responsiveness in adults. The Pediatric Quality of Life Inventory EoE was the most valid pediatric symptomatic measure. CONCLUSIONS: Current evidence supports the use of the EoEHSS and EREFS as measures of histologic and endoscopic EoE disease activity, respectively, and the EEsAI, DSQ, or Pediatric Quality of Life Inventory EoE as measures of adult and pediatric symptoms. Additional research is needed to optimize endpoint configuration to facilitate development of new therapies.

T84 monolayers are superior to Caco-2 as a model system of colonocytes.

Colonic adenocarcinoma-derived Caco-2 and T84 epithelial cell lines are frequently used as in vitro model systems of functional epithelial barriers. Both are utilised interchangeably despite evidence that differentiated Caco-2 cells are more reminiscent of small intestinal enterocytes than of colonocytes, whereas differentiated T84 cells are less well characterised. The aim of this study was, therefore, to further characterise and compare differentiated Caco-2 and T84 cells. The objectives were to (1) compare the brush border morphology, (2) measure the expression of enterocyte- and colonocyte-specific genes and (3) compare their response to butyrate, which is dependent on the monocarboxylate transporter 1 (MCT1), an apical protein expressed primarily in colonocytes. T84 microvilli were significantly shorter than those of Caco-2 cells, which is a characteristic difference between small intestinal enterocytes and colonocytes. Also, enterocyte-associated brush border enzymes expressed in differentiated Caco-2 cells were not increased during T84 maturation, whereas colonic markers such as MCT1 were more abundant in differentiated T84 cells compared to differentiated Caco-2 cells. Consequently, T84 cells displayed a dose-responsive improvement of barrier function towards butyrate, which was absent in Caco-2 cells. On the other hand, differences in epithelial toll-like receptor expression between Caco-2 and T84 monolayers did not result in a corresponding differential functional response. We conclude that differentiated Caco-2 and T84 cells have distinct morphological, biochemical and functional characteristics, suggesting that T84 cells do not acquire the biochemical signature of mature small intestinal enterocytes like Caco-2 cells, but retain much of their original colonic characteristics throughout differentiation. These findings can help investigators select the appropriate intestinal epithelial cell line for specific in vitro research purposes.