Patient selection for urgent endoscopic retrograde cholangio-pancreatography by endoscopic ultrasound in predicted severe acute biliary pancreatitis (APEC-2): a multicentre prospective study.

OBJECTIVE: Routine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings. DESIGN: A multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013-2017) applying the same study design. RESULTS: Overall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17-23) after hospital presentation and at a median of 29 hours (IQR 23-41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92). CONCLUSION: In patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group. TRIAL REGISTRATION NUMBER: ISRCTN15545919.

Overuse and Misuse of Antibiotics and the Clinical Consequence in Necrotizing Pancreatitis: An Observational Multicenter Study.

OBJECTIVE: The use and impact of antibiotics and the impact of causative pathogens on clinical outcomes in a large real-world cohort covering the entire clinical spectrum of necrotizing pancreatitis remain unknown. SUMMARY BACKGROUND DATA: International guidelines recommend broad-spectrum antibiotics in patients with suspected infected necrotizing pancreatitis. This recommendation is not based on high-level evidence and clinical effects are unknown. MATERIALS AND METHODS: This study is a post-hoc analysis of a nationwide prospective cohort of 401 patients with necrotizing pancreatitis in 15 Dutch centers (2010-2019). Across the patient population from the time of admission to 6 months postadmission, multivariable regression analyses were used to analyze (1) microbiological cultures and (2) antibiotic use. RESULTS: Antibiotics were started in 321/401 patients (80%) administered at a median of 5 days (P25-P75: 1-13) after admission. The median duration of antibiotics was 27 days (P25-P75: 15-48). In 221/321 patients (69%) infection was not proven by cultures at the time of initiation of antibiotics. Empirical antibiotics for infected necrosis provided insufficient coverage in 64/128 patients (50%) with a pancreatic culture. Prolonged antibiotic therapy was associated with Enterococcus infection (OR 1.08 [95% CI 1.03-1.16], P =0.01). Enterococcus infection was associated with new/persistent organ failure (OR 3.08 [95% CI 1.35-7.29], P <0.01) and mortality (OR 5.78 [95% CI 1.46-38.73], P =0.03). Yeast was found in 30/147 cultures (20%). DISCUSSION: In this nationwide study of patients with necrotizing pancreatitis, the vast majority received antibiotics, typically administered early in the disease course and without a proven infection. Empirical antibiotics were inappropriate based on pancreatic cultures in half the patients. Future clinical research and practice must consider antibiotic selective pressure due to prolonged therapy and coverage of Enterococcus and yeast. Improved guidelines on antimicrobial diagnostics and therapy could reduce inappropriate antibiotic use and improve clinical outcomes.

Short-term and Long-term Outcomes of a Disruption and Disconnection of the Pancreatic Duct in Necrotizing Pancreatitis: A Multicenter Cohort Study in 896 Patients.

INTRODUCTION: Necrotizing pancreatitis may result in a disrupted or disconnected pancreatic duct (DPD) with the potential for long-lasting negative impact on a patient's clinical outcome. There is a lack of detailed data on the full clinical spectrum of DPD, which is critical for the development of better diagnostic and treatment strategies. METHODS: We performed a long-term post hoc analysis of a prospectively collected nationwide cohort of 896 patients with necrotizing pancreatitis (2005-2015). The median follow-up after hospital admission was 75 months (P25-P75: 41-151). Clinical outcomes of patients with and without DPD were compared using regression analyses, adjusted for potential confounders. Predictive features for DPD were explored. RESULTS: DPD was confirmed in 243 (27%) of the 896 patients and resulted in worse clinical outcomes during both the patient's initial admission and follow-up. During hospital admission, DPD was associated with an increased rate of new-onset intensive care unit admission (adjusted odds ratio [aOR] 2.52; 95% confidence interval [CI] 1.62-3.93), new-onset organ failure (aOR 2.26; 95% CI 1.45-3.55), infected necrosis (aOR 4.63; 95% CI 2.87-7.64), and pancreatic interventions (aOR 7.55; 95% CI 4.23-13.96). During long-term follow-up, DPD increased the risk of pancreatic intervention (aOR 9.71; 95% CI 5.37-18.30), recurrent pancreatitis (aOR 2.08; 95% CI 1.32-3.29), chronic pancreatitis (aOR 2.73; 95% CI 1.47-5.15), and endocrine pancreatic insufficiency (aOR 1.63; 95% CI 1.05-2.53). Central or subtotal pancreatic necrosis on computed tomography (OR 9.49; 95% CI 6.31-14.29) and a high level of serum C-reactive protein in the first 48 hours after admission (per 10-point increase, OR 1.02; 95% CI 1.00-1.03) were identified as independent predictors for developing DPD. DISCUSSION: At least 1 of every 4 patients with necrotizing pancreatitis experience DPD, which is associated with detrimental, short-term and long-term interventions, and complications. Central and subtotal pancreatic necrosis and high levels of serum C-reactive protein in the first 48 hours are independent predictors for DPD.

Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomised controlled trial.

BACKGROUND: It remains unclear whether urgent endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy improves the outcome of patients with gallstone pancreatitis without concomitant cholangitis. We did a randomised trial to compare urgent ERCP with sphincterotomy versus conservative treatment in patients with predicted severe acute gallstone pancreatitis. METHODS: In this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, patients with predicted severe (Acute Physiology and Chronic Health Evaluation II score ≥8, Imrie score ≥3, or C-reactive protein concentration >150 mg/L) gallstone pancreatitis without cholangitis were assessed for eligibility in 26 hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module with randomly varying block sizes to urgent ERCP with sphincterotomy (within 24 h after hospital presentation) or conservative treatment. The primary endpoint was a composite of mortality or major complications (new-onset persistent organ failure, cholangitis, bacteraemia, pneumonia, pancreatic necrosis, or pancreatic insufficiency) within 6 months of randomisation. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN97372133. FINDINGS: Between Feb 28, 2013, and March 1, 2017, 232 patients were randomly assigned to urgent ERCP with sphincterotomy (n=118) or conservative treatment (n=114). One patient from each group was excluded from the final analysis because of cholangitis (urgent ERCP group) and chronic pancreatitis (conservative treatment group) at admission. The primary endpoint occurred in 45 (38%) of 117 patients in the urgent ERCP group and in 50 (44%) of 113 patients in the conservative treatment group (risk ratio [RR] 0·87, 95% CI 0·64-1·18; p=0·37). No relevant differences in the individual components of the primary endpoint were recorded between groups, apart from the occurrence of cholangitis (two [2%] of 117 in the urgent ERCP group vs 11 [10%] of 113 in the conservative treatment group; RR 0·18, 95% CI 0·04-0·78; p=0·010). Adverse events were reported in 87 (74%) of 118 patients in the urgent ERCP group versus 91 (80%) of 114 patients in the conservative treatment group. INTERPRETATION: In patients with predicted severe gallstone pancreatitis but without cholangitis, urgent ERCP with sphincterotomy did not reduce the composite endpoint of major complications or mortality, compared with conservative treatment. Our findings support a conservative strategy in patients with predicted severe acute gallstone pancreatitis with an ERCP indicated only in patients with cholangitis or persistent cholestasis. FUNDING: The Netherlands Organization for Health Research and Development, Fonds NutsOhra, and the Dutch Patient Organization for Pancreatic Diseases.

Risk factors and clinical outcomes of endoscopic dilation in benign esophageal strictures: a long-term follow-up study.

BACKGROUND AND AIMS: Endoscopic dilation (ED) is still the mainstay of therapeutic management of benign esophageal strictures (BESs). This study aimed to establish risk factors for refractory BESs and assess long-term clinical outcomes of ED. METHODS: We performed a retrospective study in 891 patients who underwent ED from 2003 to 2018 for BESs. We searched electronic medical records in 6 tertiary care centers in the Netherlands for data on clinical outcome of ED. Median follow-up was 39 months. The primary endpoint was risk factors for refractory BESs, defined as factors associated with an increased number of ED sessions during follow-up. Secondary endpoints were time from first to last ED session and adverse events. RESULTS: Dilation up to 13 to 15 mm was associated with a higher number of ED sessions than dilation up to 16 to 18 mm (5.0 vs 4.1; hazard ratio [HR], 1.4; P = .001). Compared with peptic strictures, anastomotic (4.9 vs 3.6; HR, 2.1; P < .001), radiation (5.0 vs 3.6; HR, 3.0; P < .001), caustic (7.2 vs 3.6; HR, 2.7; P < .001), and postendotherapy (3.9 vs 3.6; HR, 1.8; P = .005) strictures were associated with a higher number of ED sessions. After 1 year of follow-up, the proportions of patients who remained free of ED was 75% in anastomotic, 71% in radiation, 70% in peptic, 83% in postendotherapy, and 62% in caustic strictures. Esophageal perforation occurred in 23 ED sessions (.4%) in 22 patients (2.4%). CONCLUSIONS: More than 60% of patients with BESs remain free of ED after 1 year of follow-up. Because dilation up to 16 to 18 mm diameter was associated with fewer ED sessions during follow-up, we suggest that clinicians should consider dilation up to at least 16 mm to reduce the number of ED sessions in these patients.

Impact of multidisciplinary tumor board discussion on palliation of patients with esophageal or gastro-esophageal junction cancer: a population-based study.

Background: The Dutch guidelines for esophageal and gastro-esophageal junction (GEJ) cancer recommend discussion of patients by a multidisciplinary tumor board (MDT). Despite this recommendation, one previous study in the Netherlands suggested that therapeutic guidance was missing for palliative care of patients with esophageal cancer. The aim of the current study was therefore to assess the impact of an MDT discussion on initial palliative treatment and outcome of patients with esophageal or GEJ cancer.Material and methods: The population-based Netherlands Cancer Registry was used to identify patients treated for esophageal or GEJ cancer with palliative intent between 2010 and 2017 in 7 hospitals. We compared patients discussed by the MDT with patients not discussed by the MDT in a multivariate analysis. Primary outcome was type of initial palliative treatment. Secondary outcome was overall survival.Results: A total of 389/948 (41%) patients with esophageal or GEJ cancer were discussed by the MDT before initial palliative treatment. MDT discussion compared to non-MDT discussion was associated with more patients treated with palliative intent external beam radiotherapy (38% vs. 21%, OR 2.7 [95% CI 1.8-3.9]) and systemic therapy (30% vs. 23%, OR 1.6 [95% CI 1.0-2.5]), and fewer patients treated with stent placement (4% vs. 12%, OR 0.3 [95% CI 0.1-0.6]) and best supportive care alone (12% vs. 33%, OR 0.2 [95% CI 0.1-0.3]). MDT discussion was also associated with improved survival (169 days vs. 107 days, HR 1.3 [95% CI 1.1-1.6]).Conclusion: Our study shows that MDT discussion of patients with esophageal or GEJ cancer resulted in more patients treated with initial palliative radiotherapy and chemotherapy compared with patients not discussed by the MDT. Moreover, MDT discussion may have a positive effect on survival, highlighting the importance of MDT meetings at all stages of treatment.

Common single nucleotide polymorphisms in transient receptor potential melastatin type 6 increase the risk for proton pump inhibitor-induced hypomagnesemia: a case-control study.

OBJECTIVE: Proton pump inhibitors (PPIs) are effective drugs for the treatment of gastric acid-related disorders. Serious adverse events are rare for PPIs, but recent data suggest that PPIs cause hypomagnesemia. The aim of this study was to estimate the frequency of PPI-induced hypomagnesemia and to define the risk factors for its development. MATERIALS AND METHODS: A total of 133 chronic users of PPIs were enrolled and patients were distinguished on the basis of their serum Mg concentrations. Common single nucleotide polymorphisms (SNPs) in the candidate gene, transient receptor potential melastatin type 6 (TRPM6), were screened. RESULTS: Seventeen out of 133 patients had PPI-induced hypomagnesemia. The duration of PPI use was longer in those with hypomagnesemia (7.7 vs. 5.2 years). Two common SNPs in TRPM6 (rs3750425 and rs2274924) increased the risk for PPI-induced hypomagnesemia by 5.8-fold. CONCLUSION: We found hypomagnesemia in 13% of PPI users. SNPs in TRPM6 drive the risk of developing hypomagnesemia during chronic PPI use.

Dietary supplement use is not associated with recurrence of colorectal adenomas: a prospective cohort study.

Diet and lifestyle influence colorectal adenoma recurrence. The role of dietary supplement use in colorectal adenoma recurrence remains controversial. In this prospective cohort study, we examined the association between dietary supplement use, total colorectal adenoma recurrence and advanced adenoma recurrence. Colorectal adenoma cases (n = 565) from a former case-control study, recruited between 1995 and 2002, were prospectively followed until 2008. Adenomas with a diameter of ≥1 cm and/or (tubulo)villous histology and/or with high grade dysplasia and/or ≥3 adenomas detected at the same colonic examination were considered advanced adenomas. Hazard ratios (HRs) and 95% confidence intervals (CIs) for dietary supplement users (use of any supplement during the past year) compared to nonusers and colorectal adenoma recurrence were calculated using stratified Cox proportional hazard models for counting processes and were adjusted for age, sex, educational level and number of colonoscopies during follow-up. Robust sandwich covariance estimation was used to adjust for the within subject correlation. A number of 165 out of 565 adenoma patients had at least one colorectal adenoma recurrence during a median person-time of 5.4 years and of these, 37 patients had at least one advanced adenoma. One-third of the total study population (n = 203) used a dietary supplement. Compared to no use, dietary supplement use was neither statistically significantly associated with total colorectal adenoma recurrence (HR = 1.03; 95% CI 0.79-1.34) nor with recurrent advanced adenomas (HR = 1.59; 95% CI 0.88-2.87). This prospective cohort study did not suggest an association between dietary supplement use and colorectal adenoma recurrence.

Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk.

Barrett's esophagus, with gastroesophageal reflux disease and obesity as risk factors, predisposes to esophageal adenocarcinoma (EAC). Recently a British genome wide association study identified two Barrett's esophagus susceptibility loci mapping within the major histocompatibility complex (MHC; rs9257809) and closely to the Forkhead-F1 (FOXF1; rs9936833) coding gene. An interesting issue is whether polymorphisms associated with Barrett's esophagus, are also implicated in esophageal carcinoma (EC), and more specifically EAC genesis. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from surveillance programs. Our hypothesis: Barrett associated MHC and FOXF1 variants modify EC risk in Caucasians. In a Dutch case-control study, 431 patients with EC and 605 healthy controls were included. Polymorphisms at chromosomes 6p21 (MHC) and 16q24 (FOXF1) were determined by means of real-time polymerase chain reaction (RT-PCR). Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals. The FOXF1 rs9936833 variant C allele was associated with an increased EAC susceptibility; OR, [95% CI]; 1.21, [0.99-1.47]. A sex-stratified analysis revealed a similar association in males; 1.24 [1.00-1.55]. The variant MHC rs9257809 G allele as well as the MHC heterozygous AG genotype significantly increased ESCC risk; 1.76 [1.16-2.66] and 1.74 [1.08-2.80], respectively. Sex-stratification showed that the variant G allele was especially present in female patients; 2.32 [1.04-5.20]. In conclusion, this study provides evidence that MHC rs9257809 and FOXF1 rs9936833 variants, associated with Barrett's esophagus, also increase ESCC and EAC susceptibility in Caucasians. FOX proteins are transcription factors involved in organogenesis of the GI tract, while MHC haplotypes are strongly associated with smoking behavior, a crucial risk factor for ESCC. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from (Barrett) surveillance programs.

Polymorphisms in alcohol-metabolizing enzymes and esophageal carcinoma susceptibility: a Dutch Caucasian case-control study.

Esophageal cancer (EC), mainly consisting of squamous cell carcinoma (ESCC) in the Eastern world and adenocarcinoma (EAC) in the Western world, is strongly associated with dietary factors such as alcohol use. We aimed to clarify the modifying role in EC etiology in Caucasians of functional genotypes in alcohol-metabolizing enzymes. In all, 351 Caucasian patients with EC and 430 matched controls were included and polymorphisms in CYP2E1, ADH and near ALDH2 genes were determined. In contrast to the results on ESCC in mainly Asian studies, we found that functional genotypes of alcohol-metabolizing enzymes were not significantly associated with EAC or ESCC in an European population.

No role for glutathione S-transferase genotypes in Caucasian esophageal squamous cell or adenocarcinoma etiology: an European case-control study.

BACKGROUND: Identifying and monitoring high-risk patients can aid the prevention of esophageal cancer (EC). The interaction of environmental risk factor exposure and genetic susceptibility may contribute to the etiology of EC. Biotransformation enzymes such as Glutathione S-Transferases (GSTs ) detoxify mutagenic and genotoxic compounds and therefore control the rate of detoxification of carcinogens. Functional polymorphisms in the genes coding for GSTs alter their enzyme activity in vitro, and were reported to modify EC risk in Asians. We hypothesized that altered enzyme activity GST genotypes influence the susceptibility for esophageal adeno- (EAC) and squamous cell carcinoma (ESCC) in Caucasians. METHODS: We performed a case-control study including 440 Caucasian patients with EC and 592 healthy Caucasian controls matched for age and sex. Functional polymorphisms were selected and genotypes were determined in GST classes Alpha, Mu, Theta and Pi by means of polymerase chain reaction. Genotypes were classified into predicted high, intermediate and low enzyme activity categories based on in vitro activity data. The distribution of the activity genotypes were compared between patients with EAC or ESCC, and controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated by logistic regression analyses. Gene-gene interactions were tested and for comparison purposes, the predicted low and intermediate activity genotypes were combined. Genotypes with similar risks for EAC or ESCC were combined and analyzed for multiplicative effects. RESULTS: Our analyses includes 327 patients with EAC and 106 patients with ESCC. Low or intermediate activity enzyme genotypes for GSTM1, GSTA1, GSTP1 I105V and A114V as well as for GSTT1, did not significantly modify the risk for ESCC or EAC in our Dutch population. CONCLUSION: Functional genotypes in GST genes are not involved in EAC or ESCC susceptibility in Caucasians, in contrast to results on ESCC from Asia or Africa.

The additive value of CA19.9 monitoring in a pancreatic cyst surveillance program.

BACKGROUND: Surveillance of pancreatic cysts focuses on the detection of (mostly morphologic) features warranting surgery. European guidelines consider elevated CA19.9 as a relative indication for surgery. We aimed to evaluate the role of CA19.9 monitoring for early detection and management in a cyst surveillance population. METHODS: The PACYFIC-registry is a prospective collaboration that investigates the yield of pancreatic cyst surveillance performed at the discretion of the treating physician. We included participants for whom at least one serum CA19.9 value was determined by a minimum follow-up of 12 months. RESULTS: Of 1865 PACYFIC participants, 685 met the inclusion criteria for this study (mean age 67 years, SD 10; 61% female). During a median follow-up of 25 months (IQR 24, 1966 visits), 29 participants developed high-grade dysplasia (HGD) or pancreatic cancer. At baseline, CA19.9 ranged from 1 to 591 kU/L (median 10 kU/L [IQR 14]), and was elevated (≥37 kU/L) in 64 participants (9%). During 191 of 1966 visits (10%), an elevated CA19.9 was detected, and these visits more often led to an intensified follow-up (42%) than those without an elevated CA19.9 (27%; p < 0.001). An elevated CA19.9 was the sole reason for surgery in five participants with benign disease (10%). The baseline CA19.9 value was (as continuous or dichotomous variable at the 37 kU/L threshold) not independently associated with HGD or pancreatic cancer development, whilst a CA19.9 of ≥ 133 kU/L was (HR 3.8, 95% CI 1.1-13, p = 0.03). CONCLUSIONS: In this pancreatic cyst surveillance cohort, CA19.9 monitoring caused substantial harm by shortening surveillance intervals (and performance of unnecessary surgery). The current CA19.9 cutoff was not predictive of HGD and pancreatic cancer, whereas a higher cutoff may decrease false-positive values. The role of CA19.9 monitoring should be critically appraised prior to implementation in surveillance programs and guidelines.

Validation and update of a prediction model for risk of relapse after cessation of anti-TNF treatment in Crohn's disease.

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy is effective for the treatment of Crohn's disease. Cessation may be considered in patients with a low risk of relapse. We aimed to externally validate and update our previously developed prediction model to estimate the risk of relapse after cessation of anti-TNF therapy. METHODS: We performed a retrospective cohort study in 17 Dutch hospitals. Crohn's disease patients in clinical, biochemical or endoscopic remission were included after anti-TNF cessation. Primary outcome was a relapse necessitating treatment. Discrimination and calibration of the previously developed model were assessed. After external validation, the model was updated. The performance of the updated prediction model was assessed in internal-external validation and by using decision curve analysis. RESULTS: 486 patients were included with a median follow-up of 1.7 years. Relapse rates were 35 and 54% after 1 and 2 years. At external validation, the discriminative ability of the prediction model was equal to that found at the development of the model [c-statistic 0.58 (95% confidence interval (CI) 0.54-0.62)], though the model was not well-calibrated on our cohort [calibration slope: 0.52 (0.28-0.76)]. After an update, a c-statistic of 0.60 (0.58-0.63) and calibration slope of 0.89 (0.69-1.09) were reported in internal-external validation. CONCLUSION: Our previously developed and updated prediction model for the risk of relapse after cessation of anti-TNF in Crohn's disease shows reasonable performance. The use of the model may support clinical decision-making to optimize patient selection in whom anti-TNF can be withdrawn. Clinical validation is ongoing in a prospective randomized trial.

The risk of inflammatory bowel disease-related colorectal carcinoma is limited: results from a nationwide nested case-control study.

OBJECTIVES: The risk for inflammatory bowel disease (IBD)-related colorectal cancer (CRC) remains a matter of debate. Initial reports mainly originate from tertiary referral centers, and conflict with more recent studies. Overall, epidemiology of IBD-related CRC is relevant to strengthen the basis of surveillance guidelines. We performed a nationwide nested case-control study to assess the risk for IBD-related CRC and associated prognostic factors in general hospitals. METHODS: IBD patients diagnosed with CRC between January 1990 and July 2006 in 78 Dutch general hospitals were identified as cases, using a nationwide automated pathology database. Control IBD patients without CRC were randomly selected. Clinical data were collected from detailed chart review. Poisson regression analysis was used for univariable and multivariable analyses. RESULTS: A total of 173 cases were identified through pathology and chart review and compared with 393 controls. The incidence rate of IBD-related CRC was 0.04%. Risk factors for IBD-related CRC were older age, concomitant primary sclerosing cholangitis (PSC, relative ratio (RR) per year duration 1.05; 95% confidence interval (CI) 1.01-1.10), pseudopolyps (RR 1.92; 95% CI 1.28-2.88), and duration of IBD (RR per year 1.04; 95% CI 1.02-1.05). Using immunosuppressive therapy (odds ratio (OR) 0.3; 95% CI 0.16-0.56, P<0.001) or anti-tumor necrosis factor (TNF) (OR 0.09; 95% CI 0.01-0.68, P<0.02) was protective. CONCLUSIONS: We found a limited risk for developing IBD-related CRC in The Netherlands. Age, duration of PSC and IBD, concomitant pseudopolyps, and use immunosuppressives or anti-TNF were strong prognostic factors in general hospitals.

Web-Based Educational Intervention for Patients With Uninvestigated Dyspepsia Referred for Upper Gastrointestinal Tract Endoscopy: A Randomized Clinical Trial.

Importance: Diagnostic yield of upper gastrointestinal (GI) tract endoscopy for uninvestigated dyspepsia is low, and its clinical implications are limited. There is an unmet need for better strategies to reduce the volume of upper GI tract endoscopic procedures for dyspepsia. Objective: To study the effectiveness of a web-based educational intervention as a tool to reduce upper GI tract endoscopy in uninvestigated dyspepsia. Design, Setting, and Participants: This open-label, multicenter, randomized clinical trial enrolled participants between November 1, 2017, and March 31, 2019, with follow-up 52 weeks after randomization, at 4 teaching hospitals in the Netherlands. Participants included patients with uninvestigated dyspeptic symptoms who were referred for upper GI tract endoscopy by their general health care clinician without prior consultation of a gastroenterologist. A total of 119 patients, aged 18 to 69 years, were included. Patients were excluded if any of the following red flag symptoms were present: (indirect) signs of upper GI tract hemorrhage (hematemesis, melena, hematochezia, or anemia), unintentional weight loss of 5% or higher of normal body weight during a period of 6 to 12 months, persistent vomiting, dysphagia, or jaundice. Interventions: Patients were randomly assigned (1:1) to education (intervention) or upper GI tract endoscopy (control). Education consisted of a self-managed web-based educational intervention, containing information on gastric function, dyspepsia, and upper GI tract endoscopy. Main Outcomes and Measures: Difference in the proportion of upper GI tract endoscopy procedures between those who received access to the web-based educational intervention and those who did not at 12 weeks and 52 weeks after randomization, analyzed in the intention-to-treat population. Secondary outcomes included quality of life (Nepean Dyspepsia Index) and symptom severity (Patient Assessment of Gastrointestinal Disorders Symptom Severity Index) measured at baseline and 12 weeks. Results: Of 119 patients included (median age, 48 years [interquartile range, 37-56 years]; 48 men [40%]), 62 were randomized to web-based education (intervention) and 57 to upper GI tract endoscopy (control). Significantly fewer patients compared with controls underwent upper GI tract endoscopy after using the web-based educational intervention: 24 (39%) vs 47 (82%) (relative risk, 0.46; 95% CI, 0.33-0.64; P < .001). Symptom severity and quality of life improved equivalently in both groups. One additional patient in the intervention group required upper GI tract endoscopy during follow-up. Conclusions and Relevance: Findings of this study indicate that web-based patient education is an effective tool to decrease the need for upper GI tract endoscopy in uninvestigated dyspepsia. Trial Registration: ClinicalTrials.gov Identifier: NCT03205319.

Outcome of Reverse Switching From CT-P13 to Originator Infliximab in Patients With Inflammatory Bowel Disease.

BACKGROUND: Patients suffering from inflammatory bowel diseases (IBD) and treated with originator infliximab are increasingly being switched to biosimilars. Some patients, however, are "reverse switched" to treatment with the originator. Here we assess the prevalence of reverse switching, including its indication and outcomes. METHODS: In this retrospective multicenter cohort study, data on patients with IBD from 9 hospitals in the Netherlands were collected. All adult patients with IBD were included if they previously had been switched from originator infliximab to the biosimilar CT-P13 and had a follow-up time of at least 52 weeks after the initial switch. The reasons for reverse switching were categorized into worsening gastrointestinal symptoms, adverse effects, or loss of response to CT-P13. Drug persistence was analyzed through survival analyses. RESULTS: A total of 758 patients with IBD were identified. Reverse switching was observed in 75 patients (9.9%). Patients with reverse switching were predominantly female (70.7%). Gastrointestinal symptoms (25.5%) and dermatological symptoms (21.8%) were the most commonly reported reasons for reverse switching. In 9 patients (12.0%), loss of response to CT-P13 was the reason for reverse switching. Improvement of reported symptoms was seen in 73.3% of patients after reverse switching and 7 out of 9 patients (77.8%) with loss of response regained response. Infliximab persistence was equal between patients who were reverse-switched and those who were maintained on CT-P13. CONCLUSIONS: Reverse switching occurred in 9.9% of patients, predominantly for biosimilar-attributed adverse effects. Switching back to originator infliximab seems effective in patients who experience adverse effects, worsening gastrointestinal symptoms, or loss of response after switching from originator infliximab to CT-P13.

Clip placement to prevent delayed bleeding after colonic endoscopic mucosal resection (CLIPPER): study protocol for a randomized controlled trial.

BACKGROUND: Endoscopic mucosal resection (EMR) for large colorectal polyps is in most cases the preferred treatment to prevent progression to colorectal carcinoma. The most common complication after EMR is delayed bleeding, occurring in 7% overall and in approximately 10% of polyps ≥ 2 cm in the proximal colon. Previous research has suggested that prophylactic clipping of the mucosal defect after EMR may reduce the incidence of delayed bleeding in polyps with a high bleeding risk. METHODS: The CLIPPER trial is a multicenter, parallel-group, single blinded, randomized controlled superiority study. A total of 356 patients undergoing EMR for large (≥ 2 cm) non-pedunculated polyps in the proximal colon will be included and randomized to the clip group or the control group. Prophylactic clipping will be performed in the intervention group to close the resection defect after the EMR with a distance of < 1 cm between the clips. Primary outcome is delayed bleeding within 30 days after EMR. Secondary outcomes are recurrent or residual polyps and clip artifacts during surveillance colonoscopy after 6 months, as well as cost-effectiveness of prophylactic clipping and severity of delayed bleeding. DISCUSSION: The CLIPPER trial is a pragmatic study performed in the Netherlands and is powered to determine the real-time efficacy and cost-effectiveness of prophylactic clipping after EMR of proximal colon polyps ≥ 2 cm in the Netherlands. This study will also generate new data on the achievability of complete closure and the effects of clip placement on scar surveillance after EMR, in order to further promote the debate on the role of prophylactic clipping in everyday clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03309683 . Registered on 13 October 2017. Start recruitment: 05 March 2018. Planned completion of recruitment: 31 August 2021.

Aggressive fluid hydration plus non-steroidal anti-inflammatory drugs versus non-steroidal anti-inflammatory drugs alone for post-endoscopic retrograde cholangiopancreatography pancreatitis (FLUYT): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Prophylactic rectal administration of non-steroidal anti-inflammatory drugs (NSAIDs) is considered as standard of care to reduce the risk of post-ERCP pancreatitis. It has been suggested that aggressive hydration might further reduce this risk. Guidelines already recommend aggressive hydration in patients who are unable to receive rectal NSAIDs, although it is laborious and time consuming. We aimed to evaluate the added value of aggressive hydration in patients receiving prophylactic rectal NSAIDs. METHODS: FLUYT, a multicentre, open-label, randomised, controlled trial done across 22 Dutch hospitals, included patients aged between 18 and 85 years with moderate to high risk of post-ERCP pancreatitis. Patients were randomly assigned (1:1) by a web-based module with varying block sizes to a combination of aggressive hydration and rectal NSAIDs (100 mg diclofenac or indomethacin; aggressive hydration group) or rectal NSAIDs (100 mg diclofenac or indomethacin) alone (control group). Randomisation was stratified according to treatment centre. Aggressive hydration comprised 20 mL/kg intravenous Ringer's lactate solution within 60 min from the start of ERCP, followed by 3 mL/kg per h for 8 h. The control group received normal intravenous saline with a maximum of 1·5 mL/kg per h and 3 L per 24 h. The primary endpoint was post-ERCP pancreatitis and was analysed on a modified intention-to-treat basis (including all patients who underwent randomisation and an ERCP and for whom data regarding the primary outcome were available). The trial is registered with the ISRCTN registry, ISRCTN13659155. FINDINGS: Between June 5, 2015, and June 6, 2019, 826 patients were randomly assigned, of whom 388 in the aggressive hydration group and 425 in the control group were included in the modified intention-to-treat analysis. Post-ERCP pancreatitis occurred in 30 (8%) patients in the aggressive hydration group and in 39 (9%) patients in the control group (relative risk 0·84, 95% CI 0·53-1·33, p=0·53). There were no differences in serious adverse events, including hydration-related complications (relative risk 0·99, 95% CI 0·59-1·64; p=1·00), ERCP-related complications (0·90, 0·62-1·31; p=0·62), intensive care unit admission (0·37, 0·07-1·80; p=0·22), and 30-day mortality (0·95, 0·50-1·83; p=1·00). INTERPRETATION: Aggressive periprocedural hydration did not reduce the incidence of post-ERCP pancreatitis in patients with moderate to high risk of developing this complication who routinely received prophylactic rectal NSAIDs. Therefore, the burden of laborious and time-consuming aggressive periprocedural hydration to further reduce the risk of post-ERCP pancreatitis is not justified. FUNDING: Netherlands Organisation for Health Research and Development and Radboud University Medical Center.

Clinical Outcomes of Covid-19 in Patients With Inflammatory Bowel Disease: A Nationwide Cohort Study.

BACKGROUND AND AIMS: The COVID-19 risk and disease course in inflammatory bowel disease [IBD] patients remains uncertain. Therefore, we aimed to assess the clinical presentation, disease course, and outcomes of COVID-19 in IBD patients. Second, we determined COVID-19 incidences in IBD patients and compared this with the general population. METHODS: We conducted a multicentre, nationwide IBD cohort study in The Netherlands and identified patients with COVID-19. First, we assessed the COVID-19 disease course and outcomes. Second, we compared COVID-19 incidences between our IBD study cohort and the general Dutch population. RESULTS: We established an IBD cohort of 34 763 patients. COVID-19 was diagnosed in 100/34 763 patients [0.29%]; 20/100 of these patients [20%] had severe COVID-19 defined as admission to the intensive care unit, mechanical ventilation, and/or death. Hospitalisation occurred in 59/100 [59.0%] patients and 13/100 [13.0%] died. All patients who died had comorbidities and all but one were ≥65 years old. In line, we identified ≥1 comorbidity as an independent risk factor for hospitalisation (odds ratio [OR] 4.20, 95% confidence interval [CI] 1.58-11.17,; p = 0.004). Incidences of COVID-19 between the IBD study cohort and the general population were comparable (287.6 [95% CI 236.6-349.7] versus 333.0 [95% CI 329.3-336.7] per 100000 patients, respectively; p = 0.15). CONCLUSIONS: Of 100 cases with IBD and COVID-19, 20% developed severe COVID-19, 59% were hospitalised and 13% died. A comparable COVID-19 risk was found between the IBD cohort [100/34 763 = 0.29%] and the general Dutch population. The presence of ≥1 comorbidities was an independent risk factor for hospitalisation due to COVID-19.