BACKGROUND:Pancreatitis significantly alters the microbial composition of the oral and intestinal compartments, causing dysbiosis that may contribute to disease mechanisms and potentially serve as a basis for diagnosis or treatment. OBJECTIVE:To determine whether the oral or gut microbial signature can classify chronic pancreatitis (CP). METHODS:Stool samples (n=707) were collected from participants in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED). Samples were distributed among 200 healthy (HC), 310 CP, 49 acute pancreatitis (AP), and 148 recurrent acute pancreatitis (RAP). In addition, saliva samples were collected for a subset of participants (n=156). Whole genome sequencing was performed to assess microbiome composition. Machine learning algorithms were utilized to identify a signature with microbial features predictive of CP. RESULTS:Gut alpha diversity was significantly decreased in AP, RAP, and CP compared with HC, with CP exhibiting the lowest diversity. In contrast, oral microbial diversity showed no significant variation across groups. Beta diversity analysis revealed distinct gut microbiome compositions between HC and pancreatitis subtypes, with CP showing the most pronounced differences. Random forest models using gut microbial species demonstrated robust predictive performance for CP using a minimum of 10 species (Area under the curve-AUC: 0.834; accuracy: 0.774). Despite similarities in gut microbiome composition across pancreatitis subtypes, a unique gut microbial signature for CP was identified highlighting the microbiome's potential in CP diagnosis. CONCLUSION:Our study reveals a gut microbial signature predictive of CP using machine learning models in a large US multi-institutional cohort.

Importance:Pancreas divisum is implicated as an obstructive cause for acute pancreatitis. Observational data suggest endoscopic retrograde cholangiopancreatography (ERCP) with minor papillotomy reduces the risk of pancreatitis episodes. Even though this endoscopic procedure is widely used in practice, clinical trials are lacking. Objective:To determine whether ERCP with minor papillotomy reduces the risk of acute pancreatitis among adults with unexplained acute recurrent pancreatitis and pancreas divisum. Design, Setting, and Participants:This multicenter, sham-controlled, double-blind randomized clinical trial enrolled adults with 2 or more episodes of acute pancreatitis and pancreas divisum. Adults with other etiologies for acute pancreatitis or concomitant chronic calcific pancreatitis were excluded. The trial was conducted between September 1, 2018, and August 30, 2024, at 21 referral centers in the US and Canada. Last follow-up occurred on February 15, 2025. Intervention:Participants were randomized in a 1:1 ratio to ERCP with minor papillotomy or sham ERCP. Main Outcomes and Measures:The primary outcome was development of acute pancreatitis more than 30 days after randomization as a time-to-event outcome. The secondary outcomes included acute pancreatitis episode frequency and development of chronic calcific pancreatitis, diabetes, and exocrine pancreatic dysfunction. Results:A total of 148 participants were randomized (mean age, 54 [SD, 19.5] years; 68.2% female; 95.3% non-Hispanic or Latino and 87.2% White; mean lifetime acute pancreatitis episodes, 3 [SD, 2]; mean duct diameter, 2.2 [SD, 1.3] mm) and followed up for a median of 34 months (IQR, 21.7-45.7 months). Of the 75 participants in the ERCP with minor papillotomy group, 26 (34.7%) developed acute pancreatitis compared with 32 of 73 participants (43.8%) in the sham ERCP group (adjusted hazard ratio, 0.83 [95% CI, 0.49 to 1.41]). The incidence rate ratio for acute recurrent pancreatitis episode frequency was 0.25 (95% CI, 0.18 to 0.34) in the ERCP with minor papillotomy group vs 0.30 (95% CI, 0.23 to 0.41) in the sham ERCP group. There were no between-group differences in frequency and incidence of chronic calcific pancreatitis (4.0% in the ERCP with minor papillotomy group vs 2.7% in the sham ERCP group; risk difference [RD], 0.01 [95% CI, -0.05 to 0.07]), diabetes (15.8% vs 12.8%, respectively; RD, 0.03 [95% CI, -0.13 to 0.19]), and exocrine pancreatic dysfunction (7.7% vs 17.2%; RD, -0.10 [95% CI, -0.27 to 0.08]). The adverse event of acute pancreatitis within 30 days of randomization occurred more frequently in the ERCP with minor papillotomy group (14.7%) vs the sham ERCP group (8.2%) (RD, 0.06 [95% CI, -0.04 to 0.17]). Conclusions and Relevance:Among patients with unexplained acute recurrent pancreatitis and pancreas divisum, ERCP with minor papillotomy does not reduce the risk of another episode of acute pancreatitis or related sequelae. Trial Registration:ClinicalTrials.gov Identifier: NCT03609944.

OBJECTIVE Hyperglycemia during acute pancreatitis (HDAP) likely reflects both stress hormone responses and pancreatic islet injury, distinguishing it from typical stress-induced hyperglycemia. The aim of this study was to determine the prevalence of HDAP and its prognostic significance for early-onset diabetes following acute pancreatitis (AP). RESEARCH DESIGN AND METHODS Diabetes Related to Acute Pancreatitis and Its Mechanisms (DREAM) is a prospective multicenter study examining the development of diabetes following AP. This analysis included 395 participants without prior diabetes with an AP episode, focusing on their glucose levels during the event. Two definitions of HDAP were examined: peak glucose >140 mg/dL (HDAP140) and >200 mg/dL (HDAP200). Outpatient glycemic status after recovery (median: 111 days post-AP) was evaluated using fasting glucose, oral glucose tolerance test, and HbA(1c). RESULTS HDAP140 and HDAP200 were present in 37.5% and 7.1% of participants, respectively. Age, race, etiology, and AP severity were significant predictors of HDAP140. Among participants with HDAP140, 14.8% developed early-onset diabetes after AP recovery vs. 1.2% in those without (P = 0.0001). In those with HDAP200, 42.9% developed early-onset diabetes vs. 3.5% in those without (P = 0.0001). The absence of HDAP140 and HDAP200 was associated with negative predictive values of 99% and 97%, respectively, for diabetes. CONCLUSIONS HDAP can be common in individuals without diabetes and is associated with early-onset diabetes following AP. Individuals without HDAP have a low risk of diabetes short term, while those with HDAP200 are at high risk. Monitoring glycemia during AP can identify individuals best suited for early targeted postdischarge care.

The adult chronic pancreatitis (CP) working group, formed at the inception of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC), has developed a robust framework and infrastructure to conduct clinical, translational, and mechanistic studies of CP. At its core is PRO spective Evaluation of C hronic Pancreatitis for E pid E miologic and Translational Stu D ies (PROCEED), the first longitudinal cohort study of CP in US adults, launched in 2017. PROCEED has developed a well-annotated clinical data set of over 2000 deeply-phenotyped participants, a biorepository and an imaging repository. Investigators have published promising data on blood-based and imaging-based biomarkers of CP diagnosis and pain, which are awaiting validation. Clinical observations include classification of patients into mechanism-based pain phenotypes using responses to PROMIS questionnaires, prevalence and predictors of opioid use, prevalence of psychological comorbidity, and osteopathy in CP patients. Pilot clinical trials have evaluated the effect of oral indomethacin on pancreatic fluid prostaglandin E2 levels and Internet-based cognitive behavioral therapy (CBT) for chronic pain. Results of pilot trials have led to an ongoing definitive randomized clinical trial for CBT. The rich environment and resources have facilitated mentorship and academic development of many early-stage investigators. Investigators outside of the consortium have opportunities for collaboration. In the next 5 years, the working group plans to further strengthen the research platform, complete primary and key secondary analyses of PROCEED and ancillary studies, continue efforts to develop biomarkers for diagnosis and prognosis of CP, and complete ongoing clinical trials to address unanswered questions in the field.

OBJECTIVES:Smoking is a key risk factor for pancreatitis, contributing to pathogenesis and disease progression. Data regarding second-hand smoking, or passive smoking (PS) exposure, are lacking. We therefore aimed to assess the impact of PS exposure across the pancreatitis spectrum. METHODS:We analyzed baseline data from the PROCEED study, a multicenter study in the United States including patients with acute (AP), recurrent acute (RAP), and chronic (CP) pancreatitis. Participants detailed their individual smoking history and PS exposure, which was compared between AP, RAP, and CP subgroups. Participant factors and clinical characteristics were compared by level of individual and PS exposure. RESULTS:Among 1369 participants (190 AP, 498 RAP, 681 CP), 346 (25.3%) were current and 409 (29.9%) were former smokers. The CP subgroup had the highest proportion of current smokers (36.7% CP vs 15.1% RAP, 11.1% AP, P < 0.001). PS exposure was also significantly higher in the CP subgroup (68.6% CP vs 58.2% RAP, 55.3% AP, P < 0.001). A minority (16.3%) with CP reported no smoking exposure (by self or passive) while nearly half smoked ≥20 pack-years. The mean PS duration was significantly higher in CP participants (21.8 y) compared with those with AP (17.8 y) or RAP (18.9 y) ( P < 0.0166). CONCLUSIONS:In this multicenter study, we affirmed an association with smoking use and intensity with CP-related complications. For the first time, we report a high prevalence of prior exposure to passive smoking in all pancreatitis subtypes, which requires further study to understand the impact on disease outcomes.

Bile leak (BL) remains one of the major adverse events of hepatobiliary surgeries. We evaluated ERCP outcomes for postoperative BL (PBL) cholecystectomy (C-BL), hepatectomy (H-BL), and liver transplantation (LT-BL) and identified predictors of persistent leak after initial ERCP. This study includes consecutive patients who underwent ERCP for PBL at a single high-volume center (2011–2021). Leaks were graded as low-grade BL (LG-BL) or high-grade BL (HG-BL). Initial success was defined as cholangiographic and clinical resolution of BL following a single therapeutic ERCP session at the first follow-up ERCP. Final success was defined as cholangiographic and clinical resolution of the BL at the last follow-up assessment, irrespective of the number of therapeutic ERCP sessions required. 417 patients with PBLs were included: 348 (83.5

Endoscopic ultrasound-directed transgastric ERCP (EDGE) is increasingly used for pancreaticobiliary access in patients with Roux-en-Y gastric bypass (RYGB). However, concerns persist regarding long-term fistula persistence and weight regain after lumen-apposing metal stent (LAMS) removal. Long-term outcome data remain limited. We performed a retrospective study of a prospectively maintained database at a tertiary academic center including RYGB patients who underwent EDGE between June 2018 and November 2024. Outcomes included fistula persistence or recurrence after LAMS removal, weight change during LAMS indwell and long-term follow-up, technical success, and adverse events. Fistula status was assessed by imaging and/or endoscopy when available. Adverse events were graded using the AGREE classification, a validated adverse events grading system. Seventy-three patients underwent EDGE. ERCP technical success was achieved in 93

QuestionDoes endoscopic retrograde cholangiopancreatography (ERCP) with minor papillotomy reduce the risk of acute pancreatitis in patients with unexplained acute recurrent pancreatitis and pancreas divisum anatomy?FindingsIn this randomized trial including 148 individuals with unexplained acute recurrent pancreatitis and pancreas divisum followed up for a median of 34 months, ERCP with minor papillotomy did not significantly reduce the rate of acute pancreatitis during follow-up (34.7% vs 43.8% for sham ERCP; adjusted hazard ratio, 0.83 [95% CI, 0.49-1.41]). There was no between-group difference in acute pancreatitis episode frequency and development of chronic calcific pancreatitis, diabetes, or exocrine pancreatic dysfunction.MeaningAmong patients with unexplained acute recurrent pancreatitis and pancreas divisum, ERCP with minor papillotomy does not reduce the risk of another episode of acute pancreatitis or related sequelae. ImportancePancreas divisum is implicated as an obstructive cause for acute pancreatitis. Observational data suggest endoscopic retrograde cholangiopancreatography (ERCP) with minor papillotomy reduces the risk of pancreatitis episodes. Even though this endoscopic procedure is widely used in practice, clinical trials are lacking.ObjectiveTo determine whether ERCP with minor papillotomy reduces the risk of acute pancreatitis among adults with unexplained acute recurrent pancreatitis and pancreas divisum.Design, Setting, and ParticipantsThis multicenter, sham-controlled, double-blind randomized clinical trial enrolled adults with 2 or more episodes of acute pancreatitis and pancreas divisum. Adults with other etiologies for acute pancreatitis or concomitant chronic calcific pancreatitis were excluded. The trial was conducted between September 1, 2018, and August 30, 2024, at 21 referral centers in the US and Canada. Last follow-up occurred on February 15, 2025.InterventionParticipants were randomized in a 1:1 ratio to ERCP with minor papillotomy or sham ERCP.Main Outcomes and MeasuresThe primary outcome was development of acute pancreatitis more than 30 days after randomization as a time-to-event outcome. The secondary outcomes included acute pancreatitis episode frequency and development of chronic calcific pancreatitis, diabetes, and exocrine pancreatic dysfunction.ResultsA total of 148 participants were randomized (mean age, 54 [SD, 19.5] years; 68.2% female; 95.3% non-Hispanic or Latino and 87.2% White; mean lifetime acute pancreatitis episodes, 3 [SD, 2]; mean duct diameter, 2.2 [SD, 1.3] mm) and followed up for a median of 34 months (IQR, 21.7-45.7 months). Of the 75 participants in the ERCP with minor papillotomy group, 26 (34.7%) developed acute pancreatitis compared with 32 of 73 participants (43.8%) in the sham ERCP group (adjusted hazard ratio, 0.83 [95% CI, 0.49 to 1.41]). The incidence rate ratio for acute recurrent pancreatitis episode frequency was 0.25 (95% CI, 0.18 to 0.34) in the ERCP with minor papillotomy group vs 0.30 (95% CI, 0.23 to 0.41) in the sham ERCP group. There were no between-group differences in frequency and incidence of chronic calcific pancreatitis (4.0% in the ERCP with minor papillotomy group vs 2.7% in the sham ERCP group; risk difference [RD], 0.01 [95% CI, -0.05 to 0.07]), diabetes (15.8% vs 12.8%, respectively; RD, 0.03 [95% CI, -0.13 to 0.19]), and exocrine pancreatic dysfunction (7.7% vs 17.2%; RD, -0.10 [95% CI, -0.27 to 0.08]). The adverse event of acute pancreatitis within 30 days of randomization occurred more frequently in the ERCP with minor papillotomy group (14.7%) vs the sham ERCP group (8.2%) (RD, 0.06 [95% CI, -0.04 to 0.17]).Conclusions and RelevanceAmong patients with unexplained acute recurrent pancreatitis and pancreas divisum, ERCP with minor papillotomy does not reduce the risk of another episode of acute pancreatitis or related sequelae.Trial RegistrationClinicalTrials.gov Identifier: NCT03609944 This randomized clinical trial compares the use of endoscopic retrograde cholangiopancreatography (ERCP) with minor papillotomy vs a sham ERCP procedure for the treatment of patients with idiopathic acute pancreatitis with pancreas divisum.

OBJECTIVES:Participant retention is essential in prospective studies to minimize bias and maintain validity. This study aimed to estimate retention rates and identify factors influencing attrition in a multicenter cohort (PROCEED) of US adults with acute/recurrent acute pancreatitis (AP/RAP) and chronic pancreatitis (CP). METHODS:Participants from the PROCEED study with AP/RAP or CP eligible for follow-up within the designated visit window were included. Retention was defined as completing at least one follow-up visit during the observation period. Retention was analyzed by follow-up mode (in-person and/or medical record review) and disease type (AP/RAP and CP). Retention factors were assessed using univariate analyses (Wilcoxon rank-sum for continuous variables, χ 2 /Fisher's exact for categorical) and multivariable logistic regression. Missing data were adjusted using multiple imputations in statistical modeling. RESULTS:Among 1279 participants (AP/RAP: n=632, median age 47, 48.9% female; CP: n=647, median age 54, 46.5% female), we observed high cumulative and annualized retention rates, with improved retention when incorporating medical record reviews. In multivariable regression analyses, older age was statistically significantly associated with in-person retention in the AP/RAP group ( P =0.0001), while a higher self-reported physical health (assessed with PROMIS Global Health Physical Health T-score) was a key predictor of retention in CP ( P =0.034). CONCLUSIONS:Integrating medical records review substantially enhanced retention rates, enabling robust analyses of pancreatitis outcomes and disease progression. Older age and better self-reported physical health were key predictors of retention, highlighting the need for targeted strategies to enhance engagement among younger participants and those with poorer health in long-term studies.

Dietary patterns have been associated with altered risk of diabetes mellitus (DM) in the general population. These patterns can estimate habitual intake of food groups associated with decreased or increased (e.g., greater intake of red meats) risk of DM. This analysis aimed to examine the underexplored associations of four dietary patterns in patients presenting with an acute pancreatitis (AP) diagnosis based on the presence of pre-existing DM. Study participants were selected from the Diabetes RElated to Acute Pancreatitis and its Mechanisms (DREAM) study, an ongoing, multicenter study of adults (18–75 years) with AP in the US. This is a cross-sectional analysis of baseline data collected using the VioScreen computer-administered Food Frequency Questionnaire. We examined four dietary patterns: the Alternate Mediterranean Diet (AMED), the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND), the Healthy Eating Index-2020 (HEI-2020), and the Alternate Healthy Eating Index-2010 (AHEI-2010). Multivariable logistic regression was used to estimate the odds ratios (ORs) and 95

BACKGROUND:Laparoscopic subtotal cholecystectomy (STC) is an established approach for difficult cholecystectomy (CCY) and a well-recognized strategy to mitigate complications such as bile duct injury. The incidence of post-CCY bile leak is higher after STC than after total CCY (TC). Endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy and bile duct stent placement is the standard, effective therapy for bile leaks after CCY. With the increasing adoption of STC as a strategy for complex CCY, a comprehensive understanding of ERCP's effectiveness for a bile leak after STC is imperative. We performed a comparative analysis of patient characteristics, periprocedure details, and clinical outcomes in patients who underwent ERCP for bile leak after STC vs TC. METHODS:Data from patients referred for ERCP at Indiana University Health Hospital between 2011 and 2021 were collected within a retrospective database. Patients with Strasberg Type A bile leaks and/or leak from the gallbladder remnant were included in the analysis. Patients with bile leaks with etiologies other than CCY (eg, hepatectomy or trauma) or additional CCY-related complications (eg, common bile duct injury) were excluded. Operative reports, ERCP cholangiogram findings, and post-CCY cross-sectional imaging were reviewed to verify TC or STC status. High-grade bile leaks were defined as evidence of contrast extravasation before opacification of the intrahepatic ducts on retrograde cholangiogram. Outcomes evaluated included resolution of the bile leak at the first postintervention follow-up ERCP (via biliary sphincterotomy or stent insertion), the total number of ERCP procedures required for resolution, and the overall success of ERCP for leak resolution. RESULTS:Among patients with bile leak, 301 met study criteria. Patients who underwent STC were older, had a higher body mass index, and were more often male. Patients who underwent STC more frequently had a drain in place at the time of the first ERCP (P <.001) and less often had a biloma (P =.009). Patients who underwent STC were more frequently treated with the placement of self-expanding metal biliary stents (SEMS) (P =.001) and had a longer stent dwell time after the index ERCP (41 vs 35 days; P =.02). The overall success rate for leak resolution was high with ERCP (98%). Although there was a trend toward a higher rate of leak resolution at the first follow-up ERCP among TC patients (P =.07), the total number of ERCP procedures and the overall success of ERCP in managing post-CCY bile leak did not differ between the 2 groups. CONCLUSION:ERCP remains an effective strategy for the management of bile leak after CCY, including in patients experiencing bile leak as a complication of STC. In our cohort, strategies such as SEMS placement and extended stent dwell time were more frequently employed in patients who underwent STC at the discretion of the endoscopist. Despite this, no differences in ERCP procedure burden or rates of bile leak resolution were observed between TC and STC patients.

Purpose Validate the semiquantitative (SQ)-MRI score for chronic pancreatitis (CP) diagnosis in an independent, multicenter cohort. Methods We analyzed MRIs performed at baseline in 337 participants with acute (AP) or recurrent AP (RAP) and 67 with non-calcific chronic pancreatitis (NCCP) enrolled in the PROCEED study from 6/2017 to 3/2023. MRIs were performed at multiple clinical centers using site-specific clinical protocols and a variety of MRI vendors to evaluate the SQ-MRI score in a real-world setting. The SQ-MRI score was calculated using the T1 signal intensity ratio of the pancreas to the spleen (T1 score), arteriovenous enhancement ratio (AVR), and pancreatic body diameter (PBD). We adjusted for confounding by participant characteristics via propensity score weighting. Results Median AVR was higher in AP/RAP (1.18, IQR: 0.97–1.44) than in the NCCP group (1.03, IQR: 0.78–1.22, p = 0.007). Pancreatic body diameters were larger in AP/RAP than in the NCCP group − 7–14 mm (10% vs 25%), 14–20 mm (40% vs 54%), and > 20 mm (50% vs 21%), respectively ( p < 0.01). Median T1 score was higher in AP/RAP (1.18, IQR: 0.96–1.40) than in the NCCP group (1.04, IQR: 0.86–1.32, p = 0.10). Median SQ-MRI score in the AP/RAP group was significantly lower, 1.91 (IQR: 0.97, 2.95), than in the NCCP group, 2.74 (IQR: 2.04–4.03) ( p < 0.001). The propensity score-adjusted AUC for SQ-MRI to distinguish AP/RAP from NCCP was 0.64, which was higher than for individual parameters. Conclusion We have validated the SQ-MRI score in a multicenter cohort using an independent, real-world MRI dataset.