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Introduction: The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort., Methods: We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP., Results: There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3-5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier., Conclusions: Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention., Competing Interests: Declaration of competing interest V.K.S. is a consultant for AbbVie, Vertex, and Ariel Precision Medicine; scientific advisory board member and equity holder in Kyttaro; and receives grant support from AbbVie. D.C.W is co-founder and Chief Scientific Officer of Ariel Precision Medicine and may have equity., (Copyright © 2022. Published by Elsevier B.V.)

Background: Mortality in infected pancreatic necrosis (IPN) is dynamic over the course of the disease, with type and timing of interventions as well as persistent organ failure being key determinants. The timing of infection onset and how it pertains to mortality is not well defined., Objectives: To determine the association between mortality and the development of early IPN., Methods: International multicenter retrospective cohort study of patients with IPN, confirmed by a positive microbial culture from (peri) pancreatic collections. The association between timing of infection onset, timing of interventions and mortality were assessed using Cox regression analyses., Results: A total of 743 patients from 19 centers across 3 continents with culture-confirmed IPN from 2000 to 2016 were evaluated, mortality rate was 20.9% (155/734). Early infection was associated with a higher mortality, when early infection occurred within the first 4 weeks from presentation with acute pancreatitis. After adjusting for comorbidity, advanced age, organ failure, enteral nutrition and parenteral nutrition, early infection (≤4 weeks) and early open surgery (≤4 weeks) were associated with increased mortality [HR: 2.45 (95% CI: 1.63-3.67), p < 0.001 and HR: 4.88 (95% CI: 1.70-13.98), p = 0.003, respectively]. There was no association between late open surgery, early or late minimally invasive surgery, early or late percutaneous drainage with mortality (p > 0.05)., Conclusion: Early infection was associated with increased mortality, independent of interventions. Early surgery remains a strong predictor of excess mortality., Competing Interests: Declaration of competing interest Mouen Khashab is a consultant for Boston Scientific, Olympus and Medtronic. Robert A. Moran is a consultant for Cook medical. Vikesh K Singh is a consultant to Abbvie and Theraly, advisory board participant for Cook Medical, and receives grant funding from Orgenesis. Tyler Stevens is a consultant for Boston Scientific. All other authors have no conflicts of interest to disclose., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Total pancreatectomy with islet autotransplantation (TPIAT) is a viable option for treating debilitating recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) in adults and children. No data is currently available regarding variation in approach to operation., Methods: We evaluated surgical techniques, islet isolation and infusion approaches, and outcomes and complications, comparing children (n = 84) with adults (n = 195) enrolled between January 2017 and April 2020 by 11 centers in the United States in the Prospective Observational Study of TPIAT (POST), which was launched in 2017 to collect standard history and outcomes data from patients undergoing TPIAT for RAP or CP., Results: Children more commonly underwent splenectomy (100% versus 91%, p = 0.002), pylorus preservation (93% versus 67%; p < 0.0001), Roux-en-Y duodenojejunostomy reconstruction (92% versus 35%; p < 0.0001), and enteral feeding tube placement (93% versus 63%; p < 0.0001). Median islet equivalents/kg transplanted was higher in children (4577; IQR 2816-6517) than adults (2909; IQR 1555-4479; p < 0.0001), with COBE purification less common in children (4% versus 15%; p = 0.0068). Median length of hospital stay was higher in children (15 days; IQR 14-22 versus 11 days; IQR 8-14; p < 0.0001), but 30-day readmissions were lower in children (13% versus 26%, p = 0.018). Rate of portal vein thrombosis was significantly lower in children than in adults (2% versus 10%, p = 0.028). There were no mortalities in the first 90 days post-TPIAT., Conclusions: Pancreatectomy techniques differ between children and adults, with islet yields higher in children. The rates of portal vein thrombosis and early readmission are lower in children., Competing Interests: Declaration of competing interest MDB discloses the following: research support from Viacyte and Dexcom; advisory role (DSMB) for Insulet. LFL discloses the following: research support from Abbvie, consultant for Abbvie, speaker for Abbvie and Nestle. SJS discloses funding from Gilead and UpToDate. VKS is a consultant for Abbvie and Nestle, and he receives research support from Orgenesis and Theraly., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objectives: Chronic pancreatitis (CP) is associated with debilitating refractory pain. Distinct subtypes of CP pain have been previously characterized based on severity (none, mild-moderate, severe) and temporal (none, intermittent, constant) nature of pain, but no mechanism-based tools are available to guide pain management. This exploratory study was designed to determine if potential pain biomarkers could be detected in patient serum and whether they associate with specific pain patterns., Methods: Cytokines, chemokines, and peptides associated with nociception and pain were measured in legacy serum samples from CP patients (N = 99) enrolled in the North American Pancreatitis Studies. The unsupervised hierarchical cluster analysis was applied to cluster CP patients based on their biomarker profile. Classification and regression tree was used to assess whether these biomarkers can predict pain outcomes., Results: The hierarchical cluster analysis revealed a subset of patients with predominantly constant, mild-moderate pain exhibited elevated interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP1) whereas patients with higher interleukin-4 (IL-4), interleukin-8 (IL-8) and calcitonin gene related peptide (CGRP) were more likely to have severe pain. Interestingly, analyses of each individual biomarker revealed that patients with constant pain had reduced circulating TNFα and fractalkine. Patients with severe pain exhibited a significant reduction in TNFα as well as trends towards lower levels of IL-6 and substance P., Discussion: The observations from this study indicate that unique pain experiences within the chronic pancreatitis population can be associated with distinct biochemical signatures. These data indicate that further hypothesis-driven analyses combining biochemical measurements and detailed pain phenotyping could be used to develop precision approaches for pain management in patients with chronic pancreatitis., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Objectives: We performed a randomized, double-blind, placebo-controlled trial to determine if using Secretin intra-operatively to identify leaks and subsequently target operative intervention would decrease the frequency of clinically significant post-operative pancreatic fistula formation., Methods: Patients undergoing pancreaticoduodenectomy or distal pancreatectomy were randomized to receive intra-operative Secretin or placebo intra-operatively following the completed pancreaticojejunostomy or closure of the cut remnant stump. If a potential leak was identified, targeted therapy with directed suture placement was performed., Results: 170 patients were randomized; 83 receiving placebo and 87 receiving Secretin. The rate of clinically significant fistula formation was 3% (3/87) in the Secretin group and 6% (5/83) in the placebo group (p = 0.489). The rate of biochemical leak was 29% (25/87) in the Secretin group and 19% (16/83) in the placebo group (p = 0.157). There were no Grade C post-operative fistula in either group. Of the 9% of patients in the Secretin group who had a targeted intra-operative intervention, none developed a clinically significant fistula. Adverse events were similar between groups., Conclusions: Compared to placebo, intra-operative Secretin administration was not associated with an overall reduction in clinically significant pancreatic fistula formation. However, patients with an intra-operative leak identified by Secretin may benefit from intervention (clinicaltrials.gov: NCT02160808)., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Many patients undergoing total pancreatectomy with islet autotransplant (TPIAT) for severe, refractory chronic pancreatitis or recurrent acute pancreatitis have a history of endoscopic retrograde cholangiopancreatography (ERCP). Using data from the multicenter POST (Prospective Observational Study of TPIAT) cohort, we aimed to determine clinical characteristics associated with ERCP and the effect of ERCP on islet yield., Methods: Using data from 230 participants (11 centers), demographics, pancreatitis history, and imaging features were tested for association with ERCP procedures. Logistic and linear regression were used to assess association of islet yield measures with having any pre-operative ERCPs and with the number of ERCPs, adjusting for confounders., Results: 175 (76%) underwent ERCPs [median number of ERCPs (IQR) 2 (1-4). ERCP was more common in those with obstructed pancreatic duct (p = 0.0009), pancreas divisum (p = 0.0009), prior pancreatic surgery (p = 0.005), and longer disease duration (p = 0.004). A greater number of ERCPs was associated with disease duration (p < 0.0001), obstructed pancreatic duct (p = 0.006), and prior pancreatic surgery (p = 0.006) and increased risk for positive islet culture (p < 0.0001). Mean total IEQ/kg with vs. without prior ERCP were 4145 (95% CI 3621-4669) vs. 3476 (95% CI 2521-4431) respectively (p = 0.23). Adjusting for confounders, islet yield was not significantly associated with prior ERCP, number of ERCPs, biliary or pancreatic sphincterotomy or stent placement., Conclusions: ERCP did not appear to adversely impact islet yield. When indicated, ERCP need not be withheld to optimize islet yield but the risk-benefit ratio of ERCP should be considered given its potential harms, including risk for excessive delay in TPIAT., Competing Interests: Declaration of competing interest M. Bellin discloses research funding from Viacyte and Dexcom, and medical advisory role (DSMB) for Insulet., (Copyright © 2020. Published by Elsevier B.V.)

Background: We have previously reported that physicians under-recognize smoking as a chronic pancreatitis (CP) risk factor. We hypothesized that availability of empiric data will influence physician recognition of this relationship., Methods: We analyzed data from 508 CP patients prospectively enrolled in the North American Pancreatitis Study-2 Continuation and Validation (NAPS2-CV) or NAPS2-Ancillary (AS) studies (2008-2014) from 26 US centers who self-reported ever-smoking. Information on smoking status, physician-defined etiology and identification of smoking as a CP risk factor was obtained from structured patient and physician questionnaires. We compared how often physician identified smoking as a CP risk factor in NAPS2-CV/NAPS2-AS studies with NAPS2-original study (2000-2006)., Results: Enrolling physician identified smoking as a risk factor in significantly (all p < 0.001) greater proportion of patients in NAPS2-CV/AS studies when compared with NAPS2-original study among ever (80.7 vs. 45.3%), current (91.3 vs. 53%), past (60.3 vs. 30.2%) smokers, in those who smoked ≤1 pack/day (79.3 vs. 39.5%) or ≥1 packs/day (83 vs. 49.8%). In multivariable analyses, the enrolling physician was 3.32-8.49 times more likely to cite smoking as a CP risk factor in the NAPS2-CV/NAPS2-AS studies based on smoking status and amount after controlling for age, sex, race and alcohol etiology. The effect was independent of enrolling site in a sub-analysis limited to sites participating in both phases of enrollment., Conclusions: Availability of empiric data likely enhanced physician recognition of the association between smoking and CP. Wide-spread dissemination of this information could potentially curtail smoking rates in subjects with and those at risk of CP., (Copyright © 2019. Published by Elsevier B.V.)

Background: Multiple pathogenic genetic variants are associated with pancreatitis in patients of European (EA) and Asian ancestries, but studies on patients of African ancestry (AA) are lacking. We evaluated the prevalence of known genetic variations in African-American subjects in the US., Methods: We studied prospectively enrolled controls (n = 238) and patients with chronic (CP) (n = 232) or recurrent acute pancreatitis (RAP) (n = 45) in the NAPS2 studies from 2000-2014 of self-identified AA. Demographic and phenotypic information was obtained from structured questionnaires. Ancestry and admixture were evaluated by principal component analysis (PCA). Genotyping was performed for pathogenic genetic variants in PRSS1, SPINK1, CFTR and CTRC. Prevalence of disease-associated variants in NAPS2 subjects of AA and EA was compared., Results: When compared with CP subjects of EA (n = 862), prevalence of established pathogenic genetic variants was infrequent in AA patients with CP, overall (29 vs. 8.19%, OR 4.60, 95% CI 2.74-7.74, p < 0.001), and after stratification by alcohol etiology (p < 0.001). On PCA, AA cases were more heterogeneous but distinct from EA subjects; no difference was observed between AA subjects with and without CP-associated variants. Of 19 A A patients with CP who had pathogenic genetic variants, 2 had variants in PRSS1 (R122H, R122C), 4 in SPINK1 (all N34S heterozygotes), 12 in CFTR (2 CFTR sev , 9 CFTR BD , 1 compound heterozygote with CFTR sev and CFTR BD ), and 1 in CTRC (R254W)., Conclusion: Pathogenic genetic variants reported in EA patients are significantly less common in AA patients. Further studies are needed to determine the complex risk factors for AA subjects with pancreatitis., (Copyright © 2018. Published by Elsevier B.V.)

Background/aims: Smoking is an established risk factor for chronic pancreatitis (CP). We sought to identify how often and in which CP patients physicians consider smoking to be a risk factor., Methods: We analyzed data on CP patients and controls prospectively enrolled from 19 US centers in the North American Pancreatitis Study-2. We noted each subject's self-reported smoking status and quantified the amount and duration of smoking. We noted whether the enrolling physician (gastroenterologist with specific interest in pancreatology) classified alcohol as the etiology for CP and selected smoking as a risk factor., Results: Among 382/535 (71.4%) CP patients who were self-reported ever smokers, physicians cited smoking as a risk factor in only 173/382 (45.3%). Physicians cited smoking as a risk factor more often among current smokers, when classifying alcohol as CP etiology, and with higher amount and duration of smoking. We observed a wide variability in physician decision to cite smoking as a risk factor. Multivariable regression analysis however confirmed that the association of CP with smoking was independent of physician decision to cite smoking as a risk factor., Conclusions: Physicians often underrecognize smoking as a CP risk factor. Efforts are needed to raise awareness of the association between smoking and CP. and IAP., (Copyright © 2011 S. Karger AG, Basel.)

Background/aims: We evaluated the impact of the initial intravenous fluid resuscitation rate within the first 24 h of presentation to the emergency room on important outcomes in severe acute pancreatitis., Methods: Patients presenting directly with a diagnosis of severe acute pancreatitis were identified retrospectively. Patients were divided into two groups - those who received >or=33% ('early resuscitation') and <33% ('late resuscitation') of their cumulative 72-hour intravenous fluid volume within the first 24 h of presentation. The primary clinical outcomes were in-hospital mortality, development of persistent organ failure, and duration of hospitalization., Results: 17 patients were identified in the 'early resuscitation' group and 28 in the 'late resuscitation' group and there were no baseline differences in clinical characteristics between groups. Patients in the 'late resuscitation' group experienced greater mortality than those in the 'early resuscitation' group (18 vs. 0%, p < 0.04) and demonstrated a trend toward greater rates of persistent organ failure (43 vs. 35%, p = 0.31). There was no difference in the total amount of fluid given during the first 72 h., Conclusions: Patients with severe acute pancreatitis who do not receive at least one third of their initial 72-hour cumulative intravenous fluid volume during the first 24 h are at risk for greater mortality than those who are initially resuscitated more aggressively., (Copyright 2010 S. Karger AG, Basel.)

Background/aims: The endoscopic ultrasound (EUS) diagnosis of chronic pancreatitis (CP) relies on the presence of up to nine distinct pancreatic parenchymal and ductal abnormalities, without considering other factors such as age, duration of disease or clinical symptoms. Our goal was to examine the impact of patient symptoms on EUS findings in patients with CP., Methods: All patients with previously suspected CP who had symptomatic disease referred to our medical center for pancreatic EUS were identified. Patients were stratified into two groups based on their clinical symptoms--pain only and steatorrhea +/- pain. Groups were compared using two-tailed comparative testing., Results: 53 patients (group 1) with pain only and 27 patients with steatorrhea +/- pain (group 2) were identified. Patients in group 1 were younger and more likely female. Compared to group 1 (pain only), group 2 (steatorrhea +/- pain) had more total (5.37 vs. 3.28, p < 0.01) and ductal abnormalities (2.56 vs. 0.83, p < 0.01), although the number of parenchymal abnormalities between groups 1 and 2 (2.45 vs. 2.88, p = 0.07) was not different., Conclusion: The presence of steatorrhea +/- pain in patients with CP undergoing pancreatic EUS examination is associated with more total and ductal abnormalities. Stratification based on underlying patient symptoms may be valuable as an adjunct to endosonographic findings in making or excluding the diagnosis of CP., (Copyright 2009 S. Karger AG, Basel.)

Background/aims: The role of age as an important independent risk factor in severe acute pancreatitis is debated. We evaluated clinical outcomes, including in-hospital mortality and long-term disease stigmata, in elderly patients admitted with severe acute pancreatitis., Methods: We performed a retrospective case-control study in which cases were 56 elderly patients > or =70 years old and controls were 56 younger patients <70 years old. All patients were admitted to the Mayo Medical Center between 1992 and 2007 with severe acute pancreatitis, as defined by the Atlanta classification. The groups were matched for body mass index, medical comorbidities and etiology of pancreatitis. Both hospitalization and subsequent follow-up data were collected., Results: With the exception of age, the baseline characteristics of the two groups were similar. In-hospital mortality in the elderly was 3-fold greater than in controls (21.4 vs. 7.1%, p = 0.028), although length of stay was similar between the groups (26.9 vs. 31.0 days, p = 0.460). The development of organ failure, but not necrosis, was more frequent in the elderly group (64.3 vs. 48.2%, p = 0.043). There was no in-hospital mortality among patients without organ failure. The subsequent development of diabetes, recurrence of acute pancreatitis and incidence of post-hospitalization mortality was similar between groups., Conclusion: Age > or =70 years is an independent risk factor for mortality in patients admitted with severe acute pancreatitis. and IAP., (Copyright 2008 S. Karger AG, Basel.)

Background: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are complex syndromes associated with numerous etiologies, clinical variables and complications. We developed the North American Pancreatitis Study 2 (NAPS2) to be sufficiently powered to understand the complex environmental, metabolic and genetic mechanisms underlying RAP and CP., Methods: Between August 2000 and September 2006, a consortium of 20 expert academic and private sites prospectively ascertained 1,000 human subjects with RAP or CP, plus 695 controls (spouse, family, friend or unrelated). Standardized questionnaires were completed by both the physicians and study subjects and blood was drawn for genomic DNA and biomarker studies. All data were double-entered into a database and systematically reviewed to minimize errors and include missing data., Results: A total of 1,000 subjects (460 RAP, 540 CP) and 695 controls who completed consent forms and questionnaires and donated blood samples comprised the final dataset. Data were organized according to diagnosis, supporting documentation, etiological classification, clinical signs and symptoms (including pain patterns and duration, and quality of life), past medical history, family history, environmental exposures (including alcohol and tobacco use), medication use and therapeutic interventions. Upon achieving the target enrollment, data were organized and classified to facilitate future analysis. The approaches, rationale and datasets are described, along with final demographic results., Conclusion: The NAPS2 consortium has successfully completed a prospective ascertainment of 1,000 subjects with RAP and CP from the USA. These data will be useful in elucidating the environmental, metabolic and genetic conditions, and to investigate the complex interactions that underlie RAP and CP., (Copyright 2008 S. Karger AG, Basel.)