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Objectives: To develop a bounding-box-based 3D convolutional neural network (CNN) for user-guided volumetric pancreas ductal adenocarcinoma (PDA) segmentation., Methods: Reference segmentations were obtained on CTs (2006-2020) of treatment-naïve PDA. Images were algorithmically cropped using a tumor-centered bounding box for training a 3D nnUNet-based-CNN. Three radiologists independently segmented tumors on test subset, which were combined with reference segmentations using STAPLE to derive composite segmentations. Generalizability was evaluated on Cancer Imaging Archive (TCIA) (n = 41) and Medical Segmentation Decathlon (MSD) (n = 152) datasets., Results: Total 1151 patients [667 males; age:65.3 ± 10.2 years; T1:34, T2:477, T3:237, T4:403; mean (range) tumor diameter:4.34 (1.1-12.6)-cm] were randomly divided between training/validation (n = 921) and test subsets (n = 230; 75% from other institutions). Model had a high DSC (mean ± SD) against reference segmentations (0.84 ± 0.06), which was comparable to its DSC against composite segmentations (0.84 ± 0.11, p = 0.52). Model-predicted versus reference tumor volumes were comparable (mean ± SD) (29.1 ± 42.2-cc versus 27.1 ± 32.9-cc, p = 0.69, CCC = 0.93). Inter-reader variability was high (mean DSC 0.69 ± 0.16), especially for smaller and isodense tumors. Conversely, model's high performance was comparable between tumor stages, volumes and densities (p > 0.05). Model was resilient to different tumor locations, status of pancreatic/biliary ducts, pancreatic atrophy, CT vendors and slice thicknesses, as well as to the epicenter and dimensions of the bounding-box (p > 0.05). Performance was generalizable on MSD (DSC:0.82 ± 0.06) and TCIA datasets (DSC:0.84 ± 0.08)., Conclusion: A computationally efficient bounding box-based AI model developed on a large and diverse dataset shows high accuracy, generalizability, and robustness to clinically encountered variations for user-guided volumetric PDA segmentation including for small and isodense tumors., Clinical Relevance: AI-driven bounding box-based user-guided PDA segmentation offers a discovery tool for image-based multi-omics models for applications such as risk-stratification, treatment response assessment, and prognostication, which are urgently needed to customize treatment strategies to the unique biological profile of each patient's tumor., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Digestive capacity of the gastrointestinal tract, largely but not wholly, depends on exocrine pancreatic function to achieve near complete digestion and absorption of ingested food. Coefficient of fat absorption (CFA), the proportion of ingested fat absorbed (normal >93%), reflects digestive capacity. Exocrine pancreatic insufficiency (EPI) is the state of insufficient digestive capacity (CFA <93%) caused by severe loss of pancreatic exocrine function despite variable compensation by upregulation of extra-pancreatic lipolysis. Fecal elastase 1 (FE1) level is the most widely used, though imperfect, non-invasive test of pancreatic enzyme output. Decline in pancreas enzyme output, or pancreatic exocrine dysfunction (EPD), has a variable correlation with measurable decline in CFA. EPI results in steatorrhea, weight loss and nutrient deficiency, which are mitigated by pancreatic enzyme replacement therapy (PERT). We propose a staging system for EPD, based on measurement of fecal elastase (FE1) and, if necessary, CFA and serum fat-soluble vitamin levels. In Stage I (Mild) EPD, FE1 is 100-200 mcg/gm; if steatorrhea is present, non-pancreatic causes are likely. In Stage II (Moderate) EPD), FE1 is < 100 mcg/gm without clinical and/or laboratory evidence of steatorrhea. In Stage III, there are marked reductions in FE1 and CFA, but vitamin levels remain normal (Severe EPD or EPI without nutritional deficiency). In Stage IV all parameters are abnormal (Severe EPD or EPI with nutritional deficiency). EPD stages I and II are pancreas sufficient and PERT may not be the best or first approach in management of early-stage disease; it needs further study to determine clinical utility. The term EPI refers strictly to EPD Stages III and IV which should be treated with PERT, with Stage IV requiring micronutrient supplementation as well., (Copyright © 2021. Published by Elsevier B.V.)

Background & Aims: Increased intrapancreatic fat is associated with pancreatic diseases; however, there are no established objective diagnostic criteria for fatty pancreas. On non-contrast computed tomography (CT), adipose tissue shows negative Hounsfield Unit (HU) attenuations (-150 to -30 HU). Using whole organ segmentation on non-contrast CT, we aimed to describe whole gland pancreatic attenuation and establish 5th and 10th percentile thresholds across a spectrum of age and sex. Subsequently, we aimed to evaluate the association between low pancreatic HU and risk of pancreatic ductal adenocarcinoma (PDAC)., Methods: The whole pancreas was segmented in 19,456 images from 469 non-contrast CT scans. A convolutional neural network was trained to assist pancreas segmentation. Mean pancreatic HU, volume, and body composition metrics were calculated. The lower 5th and 10th percentile for mean pancreatic HU were identified, examining the association with age and sex. Pre-diagnostic CT scans from patients who later developed PDAC were compared to cancer-free controls., Results: Less than 5th percentile mean pancreatic HU was significantly associated with increase in BMI (OR 1.07; 1.03-1.11), visceral fat (OR 1.37; 1.15-1.64), total abdominal fat (OR 1.12; 1.03-1.22), and diabetes mellitus type 1 (OR 6.76; 1.68-27.28). Compared to controls, pre-diagnostic scans in PDAC cases had lower mean whole gland pancreatic HU (-0.2 vs 7.8, p = 0.026)., Conclusion: In this study, we report age and sex-specific distribution of pancreatic whole-gland CT attenuation. Compared to controls, mean whole gland pancreatic HU is significantly lower in the pre-diagnostic phase of PDAC., Competing Interests: Declaration of competing interest statement and disclosures As co-inventor on licensed technologies, S.M. could share potential future royalties to Mayo Clinic from Exact Sciences in accordance with institutional policy and oversight. V.C. provides consulting for Interpace Diagnostics and is a shareholder of Nevakar Corporation. S.V. contributes to UpToDate chapters. The other authors of this manuscript have no conflict of interest to declare., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Quality gaps in medical imaging datasets lead to profound errors in experiments. Our objective was to characterize such quality gaps in public pancreas imaging datasets (PPIDs), to evaluate their impact on previously published studies, and to provide post-hoc labels and segmentations as a value-add for these PPIDs., Methods: We scored the available PPIDs on the medical imaging data readiness (MIDaR) scale, and evaluated for associated metadata, image quality, acquisition phase, etiology of pancreas lesion, sources of confounders, and biases. Studies utilizing these PPIDs were evaluated for awareness of and any impact of quality gaps on their results. Volumetric pancreatic adenocarcinoma (PDA) segmentations were performed for non-annotated CTs by a junior radiologist (R1) and reviewed by a senior radiologist (R3)., Results: We found three PPIDs with 560 CTs and six MRIs. NIH dataset of normal pancreas CTs (PCT) (n = 80 CTs) had optimal image quality and met MIDaR A criteria but parts of pancreas have been excluded in the provided segmentations. TCIA-PDA (n = 60 CTs; 6 MRIs) and MSD(n = 420 CTs) datasets categorized to MIDaR B due to incomplete annotations, limited metadata, and insufficient documentation. Substantial proportion of CTs from TCIA-PDA and MSD datasets were found unsuitable for AI due to biliary stents [TCIA-PDA:10 (17%); MSD:112 (27%)] or other factors (non-portal venous phase, suboptimal image quality, non-PDA etiology, or post-treatment status) [TCIA-PDA:5 (8.5%); MSD:156 (37.1%)]. These quality gaps were not accounted for in any of the 25 studies that have used these PPIDs (NIH-PCT:20; MSD:1; both: 4). PDA segmentations were done by R1 in 91 eligible CTs (TCIA-PDA:42; MSD:49). Of these, corrections were made by R3 in 16 CTs (18%) (TCIA-PDA:4; MSD:12) [mean (standard deviation) Dice: 0.72(0.21) and 0.63(0.23) respectively]., Conclusion: Substantial quality gaps, sources of bias, and high proportion of CTs unsuitable for AI characterize the available limited PPIDs. Published studies on these PPIDs do not account for these quality gaps. We complement these PPIDs through post-hoc labels and segmentations for public release on the TCIA portal. Collaborative efforts leading to large, well-curated PPIDs supported by adequate documentation are critically needed to translate the promise of AI to clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Chronic pancreatitis is a known risk factor of pancreatic cancer (PDAC). A similar association has been suggested but not demonstrated for autoimmune pancreatitis (AIP)., Objective: The aim of our study was to identify and analyse all published cases of AIP and PDAC co-occurrence, focusing on the interval between the diagnoses and the cancer site within the pancreas., Methods: Relevant studies were identified through automatic searches of the MEDLINE, EMBASE, Scopus, and Web of Science databases, and supplemented by manual checks of reference lists in all retrieved articles. Missing/unpublished data were obtained from the authors of relevant publications in the form of pre-prepared questionnaires., Results: A total of 45 cases of PDAC in AIP patients were identified, of which 12 were excluded from the analysis due to suspicions of duplicity or lack of sufficient data. Thirty-one patients (94%) had type 1 AIP. Synchronous occurrence of PDAC and AIP was reported in 11 patients (33%), metachronous in 22 patients (67%). In the metachronous group, the median period between diagnoses was 66.5 months (2-186) and a majority of cancers (86%) occurred more than two years after AIP diagnosis. In most patients (70%), the cancer originated in the part of the pancreas affected by AIP., Conclusions: In the literature, there are reports on numerous cases of PDAC in AIP patients. PDAC is more frequent in AIP type 1 patients, typically metachronous in character, and generally found in the part of the pancreas affected by AIP., (Copyright © 2021 IAP and EPC. All rights reserved.)

Objectives: Despite substantial morbidity and mortality associated with acute pancreatitis (AP), only one small randomized controlled drug trial (RCT) is available in the past few decades from the United States. Hence, we conducted a single-center, double-blind, placebo-controlled RCT of pentoxifylline in AP., Methods: A total of 9 doses of oral pentoxifylline 400 mg or placebo tablet, three times daily, was administered within 72 h of diagnosis, using randomization blocks by pharmacy. Primary outcome was a composite outcome including any of the following: death, peripancreatic and/or pancreatic necrosis, infected pancreatic necrosis, persistent organ failure, persistent systemic inflammatory response syndrome, hospital stay longer than 4 days, need for intensive care, and need for intervention for necrosis., Results: Between July 7, 2015, and April 4, 2017, we identified 685 patients with AP, 233 met eligibility criteria and 176 were approached for the study. Of these, 91 (51.7%) declined and finally 45 in pentoxifylline group and 38 in placebo group (83 total) were compared. There were no significant differences in primary outcome (27 [60.0%] vs 15 [39.5%]; P = .06). Pentoxifylline group was not associated with any benefit, but withlonger stay (42% vs. 21%; P = .04) and higher readmission rates (16 %vs 3%; P = .047)., Conclusions: We could not demonstrate superiority of pentoxifylline over placebo. Smaller sample size and inclusion of all types of severity might be the reasons for lack of efficacy. The challenges observed in the present study indicate that, in order to conduct a successful drug trial in AP, a multi center collaboration is essential., Competing Interests: Declaration of ompeting interest There are no conflicts of interest to report for any authors., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: The frequency, nature and timeline of changes on thin-slice (≤3 mm) multi-detector computerized tomography (CT) scans in the pre-diagnostic phase of pancreatic ductal adenocarcinoma (PDAC) are unknown. It is unclear if identifying imaging changes in this phase will improve PDAC survival beyond lead time., Methods: From a cohort of 128 subjects (Cohort A) with CT scans done 3-36 months before diagnosis of PDAC we developed a CTgram defining CT Stages (CTS) I through IV in the radiological progression of pre-diagnostic PDAC. We constructed Cohort B of PDAC resected at CTS I and II and compared survival in CTS I and II in Cohort A (n = 22 each; control natural history cohort) vs Cohort B (n = 33 and 72, respectively; early interception cohort)., Results: CTs were abnormal in 16% and 85% at 24-36 and 3-6 months respectively, before PDAC diagnosis. The PDAC CTgram stages, findings and median lead times (months) to clinical diagnosis were: CTS I: Abrupt duct cut-off/duct dilatation (-12.8); CTS II: Low density mass confined to pancreas (-9.5), CTS III: Peri-pancreatic infiltration (-5.8), CTS IV: Distant metastases (only at diagnosis). PDAC survival was better in cohort B than in cohort A despite inclusion of lead time in Cohort A: CTS I (36 vs 17.2 months, p = 0.03), CTS II (35.2 vs 15.3 months, p = 0.04)., Conclusion: Starting 12-18 months before PDAC diagnosis, progressive and increasingly frequent changes occur on CT scans. Resection of PDAC at the time of pre-diagnostic CT changes is likely to provide survival benefit beyond lead time., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objectives: In this study, we aim to assess the diagnostic utility of elevated serum IgG4 (sIgG4) concentration alone and in combination with peripheral eosinophilia (PE) for IgG4-related disease (IgG4-RD)., Methods: From the Mayo Clinic, Rochester electronic medical record database we identified 409 patients with above normal levels of sIgG4 (reference range 121-140 mg/dL) who had sIgG4 measured to differentiate IgG4-RD from another disease., Results: Among 409 patients with any elevation in sIgG4 levels, 129 (31.5%) had a definite diagnosis of IgG4-RD. The prevalence of PE increased with increasing sIgG4 levels and was more likely to be seen in subjects with IgG4-RD vs. non-IgG4-RD at ≥1X (n = 35/120, 29.2% vs. n = 23/258, 8.9%; p < 0.001), ≥2X (n = 23/64, 35.9% vs. n = 5/54,9.3%; p = 0.001) and ≥3X (n = 18/42, 42.9% vs. n = 0/9, 0%; p = 0.015) of sIgG4 upper limit of normal (ULN), respectively. After adjusting for gender and age, sIgG4 levels ≥ 2X ULN with PE as a predictor, had a higher positive predictive value in predicting IgG4-RD (72.2% vs. 65.9%) with an Area Under the Receiver Operatic Characteristic Curve (AUC) of 0.776, compared to sIgG4 ≥ 2X ULN without PE predictor (AUC = 0.74), p = 0.016. PE, sIgG4≥2X ULN, male gender, and age independently predicted the disease with odds ratio of 4.89 (95% CI:2.51-9.54), 3.78 (95% CI:2.27-6.28), 2.78 (95% CI:1.55-4.97), and 1.03 (95% CI:1.02-1.05), respectively., Conclusion: Even in subjects in whom IgG4-RD is suspected, only a minority (∼30%) with elevated sIgG4 levels have IgG4-RD. sIgG4 by itself is more specific at higher levels, though never diagnostic. PE increases with increasing sIgG4 and adds diagnostic value at higher sIgG4 levels., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Pre-operative staging of pancreatic adenocarcinoma guides clinical decision making. Limited data indicate that metastasis to celiac ganglia (CG) correlates with poor prognosis. We investigated feasibility and safety of endoscopic ultrasound fine needle aspiration (EUS-FNA) detection of CG metastasis and its impact upon tumor stage, resectability, and survival in pancreatic ductal adenocarcinoma (PDAC)., Patients: We reviewed our prospectively maintained EUS and cytopathology databases to identify patients with FNA proven CG metastasis in patients with PDAC from 2004 to 2017. Clinical demographics, EUS, CT, MRI, cytopathology, cancer stage, and resectability data were analyzed. Survival of PDAC patients with CG metastasis was compared to the expected survival of PDAC patients of similar stage as reported by the United States National Cancer Database., Results: Twenty-one patients with PDAC [median age 73 (IQR63-78); 14 (67%) female)], had CG metastasis confirmed by cytopathologic assessment. CG metastasis resulted in tumor upstaging relative to other EUS findings and cross sectional imaging findings in 12 (57%) and 15 (71%) patients, and converted cancers from resectable to unresectable relative to EUS and cross sectional imaging in 7 (37%) and 7 (37%) patients, respectively. In patients with PDAC, the survival of patients with CG metastasis was not significantly different from the overall survival (hazard ratio 0.71; 95% confidence interval 0.44, 1.13; p = 0.15)., Conclusions: EUS-FNA may safely identify CG metastases. While CG metastasis upstaged and altered the resectability status among this cohort of patients with PDAC, the survival data with regard to PDAC suggest that this may be misguided., Competing Interests: Declaration of competing interest All authors having nothing to disclose., (Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: The sentinel acute pancreatitis event (SAPE) hypothesis for pathogenesis of chronic pancreatitis (CP) postulates that acute pancreatitis (AP), especially recurrent AP (RAP), precedes development of CP. However, in a recent population-based study, 52/89 (58.4%) of CP had no prior episodes of AP. In a large clinic-based CP cohort, we aimed to determine the incidence and timing of prior AP in patients diagnosed with CP., Methods: We retrospectively identified 499 consecutive patients with classic CP diagnosed at our institution from January 2013 through December 2015. We abstracted their demographic and clinical data, especially regarding prior AP., Results: We identified 3 cohorts: 1) CP with no AP (n = 231 [46.3%]), 2) AP before CP (n = 250 [50.1%]), and 3) AP after CP (n = 18 [3.6%]). At CP diagnosis, 249 patients (49.9%) had no prior AP. Compared with the "CP preceded by AP" cohort, the "CP without AP"' cohort was older (59.2 ± 13.9 vs 48.6 ± 15.7 years; P < .001), had a higher prevalence of diabetes mellitus (30.3% vs 12.4%; P < .001), reported less pain (52.8% vs 87.6%; P < .001), and had a lower rate of endoscopic interventions (16.0% vs 39.2%; P < .001). In the "CP preceded by AP" cohort, 117 (46.8%) had a single episode of AP and 133 (53.2%) had RAP., Conclusion: Nearly half the patients with classic CP did not have prior AP. Only a quarter of patients had CP that could potentially have evolved from prior RAP. Development of CP may be attributable to an altogether different pathogenesis (a non-SAPE pathway) for a considerable proportion of patients., (Copyright © 2019 IAP and EPC. All rights reserved.)

Background: Chronic pancreatitis (CP) is a progressive inflammatory disorder currently diagnosed by morphologic features. In contrast, an accurate diagnosis of Early CP is not possible using imaging criteria alone. If this were possible and early treatment instituted, the later, irreversible features and complications of CP could possibly be prevented., Method: An international working group supported by four major pancreas societies (IAP, APA, JPS, and EPC) and a PancreasFest working group sought to develop a consensus definition and diagnostic criteria for Early CP. Ten statements (S1-10) concerning Early CP were used to gauge consensus on the Early CP concept using anonymous voting with a 9 point Likert scale. Consensus required an alpha ≥0.80., Results: No consensus statement could be developed for a definition of Early-CP or diagnostic criteria. There was consensus on 5 statements: (S2) The word "Early" in early chronic pancreatitis is used to describe disease state, not disease duration. (S4) Early CP defines a stage of CP with preserved pancreatic function and potentially reversible features. (S8) Genetic variants are important risk factors for Early CP and can add specificity to the likely etiology, but they are neither necessary nor sufficient to make a diagnosis. (S9) Environmental risk factors can provide evidence to support the diagnosis of Early CP, but are neither necessary nor sufficient to make a diagnosis. (S10) The differential diagnosis for Early CP includes other disorders with morphological and functional features that overlap with CP., Conclusions: Morphology based diagnosis of Early CP is not possible without additional information. New approaches to the accurate diagnosis of Early CP will require a mechanistic definition that considers risk factors, biomarkers, clinical context and new models of disease. Such a definition will require prospective validation., (Copyright © 2018. Published by Elsevier B.V.)

Background: Based on reports from tertiary care centers, chronic pancreatitis (CP) is considered to be a painful and debilitating disease frequently requiring invasive interventions. Our primary aim was to assess the natural course of CP in a population-based cohort using endoscopic and surgical interventions as surrogates for disease aggressiveness., Methods: We identified all patients (n = 89, alcoholic [ACP = 46], non-alcoholic [NACP] = 43) with newly diagnosed definite CP from Olmsted County, Minnesota between 1977 and 2006. Patients were followed until death or censoring. Medical records were reviewed at time of diagnosis and during each follow-up. Both lifetime proportions and cumulative incidence since the initial manifestation of CP were estimated and compared. Survival was estimated with Kaplan-Meier methodology., Results: Median age at CP diagnosis was 56 years (IQR, 48-67) and 56% were male. During median follow-up of 10 years, 68 (76%) experienced pancreatic pain, but only 27 (30%) needed any invasive therapeutic intervention: 23% had endotherapy and 11% had pancreatic surgery. During the clinical course, when compared with NACP, ACP patients had significantly more (all p < 0.05) pain (87 vs. 65%), recurrent acute pancreatitis (44 vs. 23%), pseudocysts (41 vs. 16%), cumulative incidence of exocrine insufficiency (60 vs. 21%), and annual hospitalizations after CP diagnosis (0.79 vs. 0.25). The cumulative risk of diabetes, calcifications, surgery and overall survival was similar in ACP and NACP., Conclusions: Our study suggests that CP at a population level may have a milder course than that reported from tertiary centers. We confirm that ACP has a more severe phenotype than NACP., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Acute pancreatitis (AP) in patients with fulminant viral hepatitis is well recognized and its mortality depends on the severity of hepatitis rather than pancreatitis. Acute pancreatitis associated with non-fulminant acute hepatitis A (AHA) has been rarely described, and is considered to have a benign course with good response to conservative management., Objective: To perform a systematic review of the frequency and prognosis of AP associated with fulminant or non-fulminant AHA., Rationale: An increasing number of reports describe AP associated with AHA. Some life-threatening complications related to AP may occur, and death has been reported. In addition, it is possible that early diagnosis of these cases may help in reducing the morbidity and mortality., Data Sources: Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Scopus, Google Scholar, and reference lists of relevant articles., Study Selection: All available studies discussing AP associated with fulminant or non-fulminant AHA., Data Extraction and Assessment: Two blinded independent observers extracted and assessed the frequency of AP associated with AHA based on large studies including all cases of AHA observed during a prolonged period of time, diagnosis of AHA based on anti-HAV IgM, diagnosis of fulminant hepatitis (FH) based on the American Association for the study of Liver Diseases (AASLD) position paper, diagnosis of AP based on the American College of Gastroenterology (ACG) guidelines, diagnosis of AP associated with AHA based on Makharia's association, and diagnosis of AP severity based on the Revision of the Atlanta Classification (RAC). We have developed a tool for risk of bias assessment of case reports and case-series and applied it to the included studies., Results: The frequency of reported AP associated with AHA is 0-0.1%. Thirty-eight publications with a total of 54 patients meeting the inclusion criteria have been published. Twenty-two studies had a low risk for bias, 10 had moderate risk and 6 had high risk. Patients originated from all continents but most of them were from Asia. The median age at diagnosis was 16 years (range: 2-81) with a male to female ratio of 2. The median interval between the onset of jaundice and onset of AP pain was 4 days (range: 0-30). AP was severe in 9% of patients. The median hospital stay for AP was 8 days (range: 3-35). Most cases occur in patients without FH (94%). Mortality was reported in 2 patients (3.7%)., Conclusion: Acute pancreatitis associated with AHA is rare with an estimated frequency of 0-0.1%. Fifty-four documented cases, mostly in Asian patients, have been reported. The median age of patients is 16 years with a M/F ratio of 2. Acute pancreatitis occurs less than one week after the onset of jaundice and mostly in patients without FH. Acute pancreatitis in this setting is severe in 9% of patients with a mortality rate similar to all other causes of AP., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The International Consensus Diagnostic Criteria (ICDC) for AIP has proposed two distinctive type of AIP, type 1 and type 2, and enabled us first to differentiate two types of AIP each other. By initial steroid treatment for induction of remission, remission can be successfully induced in almost all subjects with type 1 and type 2 AIP. As relapse rate in type 1 AIP is significantly higher than in type 2 AIP, there has been ongoing debate on how to treat effectively relapse of type 1 AIP., Methods: By a modified Delphi approach, a panel of international experts has proposed an international consensus on the treatment of AIP after intense discussion and deliberation during an international consensus symposium of the International Association of Pancreatology (IAP) 2016., Results: Individual statements for nine clinical questions with recommendation levels and the therapeutic strategy have been proposed., Conclusion: The recommendations are based on the available evidence, and eastern and western experts' opinions to find standard treatment of AIP worldwide. These recommendations can be tailored according to the local expertise and context in the management of individual patients., (Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objective: Autoimmune pancreatitis (AIP) responds dramatically to corticosteroids treatment. We reviewed our experience to determine the safety and effectiveness of treating obstructive jaundice in definitive AIP with corticosteroids alone without biliary stenting., Methods: From our AIP database, we retrospectively identified type 1 AIP subjects whose jaundice was treated with corticosteroids alone without biliary stenting. Their medical records were reviewed and clinical data were evaluated to determine the outcomes., Results: Fifteen AIP subjects (87% male, mean age 68.4 years) were treated with corticosteroids at initial presentation (n = 8), first (n = 5) or subsequent (n = 2) relapse. Mean values (upper limit of normal, ULN) of liver tests prior to corticosteroids were aspartate aminotransferase (AST) 203.5u/l (4 × ULN), alanine aminotransferase (ALT) 325.8u/l (6 × ULN), alkaline phosphatase (ALP) 567.4u/l (5 × ULN), and total bilirubin (TB) 5.9 mg/dl (5.9 × ULN). At first follow-up (mean 4 days) the decrease was 54.9% for AST, 51.6% for ALT, 33% for ALP and 47.2% for TB (all p < 0.05). After 15-45 days, all patients had normal AST, 3/15 had ALT > 1.5 × ULN, 1/15 had ALP > 1.5 × ULN, 1/15 had TB > 1.5 × ULN. No patient required biliary stent placement, or developed cholangitis or other infectious complications during steroid treatment., Conclusion: Under the supervision of an experienced pancreatologist and with close monitoring of patients, obstructive jaundice secondary to definitive AIP can be safely and effectively managed with corticosteroids alone, without the need for biliary stenting., (Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Introduction: Pancreatic polypeptide (PP) is a hormone secreted by islet cells of the ventral pancreas. It has been proposed that a blunted PP response to a mixed meal can distinguish diabetes mellitus (DM) secondary to pancreatic disease from other types of DM. We performed a proof of concept study to determine if PP response to a mixed meal discriminates DM secondary to pancreatic cancer (PaCDM) from type 2 DM (T2DM)., Methods: We studied 18 subjects with new onset DM (PaCDM (n = 9) and T2DM (n = 9); matched for age and gender). Serum PP levels were measured at 0, 30, and 60 min following a mixed meal. Increases in PP levels from baseline were compared using the Wilcoxon test., Results: In PaCDM the PP increase following a mixed meal was less than T2DM at 30 min (median 60.0%, IQR, 33.0-119.8 vs. 134.5%, IQR, 117.5-265.9; p = 0.03), but statistically similar at 60 min (median 55.8%, interquartile range (IQR) 23.7-121.5 vs. 100.0%, IQR, 47.7-202.5; p = 0.17). In PaCDM subjects, the PP increase over baseline was smaller in those with a tumor located in the pancreatic head (n = 6) compared to the body/tail (n = 3) at 30 min (41.3% vs. 158.7%, p = 0.02) and at 60 min (37.4% vs. 167.4%,p = 0.04)., Conclusions: Subjects with PaCDM have a blunted PP response to a mixed meal compared to T2DM. However, the blunted PP response is only observed in those PaC subjects with a tumor located in the head of the pancreas. Confirmation in larger studies may suggest this could be used to aid screening for sporadic PaC., (Copyright © 2015 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Description: Diabetes and glucose intolerance are common complications of chronic pancreatitis, yet clinical guidance on their detection, classification, and management is lacking., Methods: A working group reviewed the medical problems, diagnostic methods, and treatment options for chronic pancreatitis-associated diabetes for a consensus meeting at PancreasFest 2012., Results: Guidance Statement 1.1: Diabetes mellitus is common in chronic pancreatitis. While any patient with chronic pancreatitis should be monitored for development of diabetes, those with long-standing duration of disease, prior partial pancreatectomy, and early onset of calcific disease may be at higher risk. Those patients developing diabetes mellitus are likely to have co-existing pancreatic exocrine insufficiency. Guidance Statement 1.2: Diabetes occurring secondary to chronic pancreatitis should be recognized as pancreatogenic diabetes (type 3c diabetes). Guidance Statement 2.1: The initial evaluation should include fasting glucose and HbA1c. These tests should be repeated annually. Impairment in either fasting glucose or HbA1c requires further evaluation. Guidance Statement 2.2: Impairment in either fasting glucose or HbA1c should be further evaluated by a standard 75 g oral glucose tolerance test. Guidance Statement 2.3: An absent pancreatic polypeptide response to mixed-nutrient ingestion is a specific indicator of type 3c diabetes. Guidance Statement 2.4: Assessment of pancreatic endocrine reserve, and importantly that of functional beta-cell mass, should be performed as part of the evaluation and follow-up for total pancreatectomy with islet autotransplantation (TPIAT). Guidance Statement 3: Patients with pancreatic diabetes shall be treated with specifically tailored medical nutrition and pharmacologic therapies., Conclusions: Physicians should evaluate and treat glucose intolerance in patients with pancreatitis., (Copyright © 2013 IAP and EPC. All rights reserved.)

Background: Autoimmune pancreatitis (AIP) has been classified into type 1 and type 2 subtypes. Serum immunoglobulin G4 (IgG4) elevation characterizes type 1 AIP. Type 2 AIP and a subset of type 1 AIP are seronegative, i.e., have normal serum IgG4 levels., Aim: We compared the profiles of the three subsets of AIP to identify the unique characteristics of seronegative type 1 AIP and type 2 AIP., Methods: We compared the clinical profiles of 69 seropositive type 1 AIP patients, 21 seronegative type 1 AIP patients and 22 type 2 AIP patients., Results: Among type 1 AIP, seronegative group had similar clinical profiles when compared to seropositive group except that they were more likely to undergo surgical resection than seropositive patients (p = 0.001). Seronegative type I AIP patients were older (61.9 ± 13.7 vs 45.3 ± 17.4; p = 0.004), and differed in the occurrence of other organ involvement (OOI) (71.4% vs 0%; p < 0.001) and disease relapse (33.3% vs 0%; p = 0.005) when compared with type 2 AIP. All seronegative type 1 AIP patients had at least one of the following -OOI, disease relapse, and age >50 years while none of the type 2 AIP had OOI or disease relapse., Conclusions: Seronegative and seropositive type 1 AIP patients have similar clinical profiles, which are distinct from that of type 2 AIP. Among the seronegative AIP group, patients are more likely to have type 1 AIP rather than type 2 AIP if they are older than 50 years or have OOI or disease relapse., (Copyright © 2012 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Onset of diabetes mellitus (DM) is often first noted by primary care physicians. New-onset DM (duration <36 months before PaC diagnosis) can be a harbinger of pancreatic cancer (PaC). However, its clinical significance remains unclear., Methods: To determine the prevalence, onset, and delay in diagnosis of DM in PaC patients in the primary care setting, we retrospectively reviewed the records of consecutive patients followed in Mayo Clinic's primary care clinics (at least one visit in the preceding 2 years) from 1995 to 2009 who were eventually diagnosed with PaC. Onset of DM was the first date the fasting blood glucose was ≥126 mg/dl., Results: Of the 111 PaC patients (59 male, median age 74 years), 52 (47%) had DM of whom 30 (58%) had new-onset DM. Among the 30 with new-onset DM, 24 (80%) were asymptomatic (no cancer-specific symptoms), at DM onset. In these 24 patients, median duration of DM prior to PaC diagnosis was 6.5 (0.5-35) months, and median delay between onset and physician diagnosis of DM was 2.5 (0.25-14) months, which decreased from 8.8 (3.5-14) months in patients with DM onset between 1995 and 1999 to 0 (0-2) months, in patients with DM onset between 2004 and 2009. However, the proportion of patients with undiagnosed DM (~33%) remained unchanged., Conclusions: Diabetes is very common (~50%) in PaC. In over a fifth of PaC, the onset of DM occurs when the cancer is asymptomatic, providing a potential window-of-opportunity to diagnose early PaC. However, nearly a third of new-onset DM in PaC remains undiagnosed., (Copyright © 2012 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background/aims: Recent data demonstrate the presence of two autoimmune pancreatitis (AIP) subtypes. All existing endoscopic ultrasonography-guided trucut biopsy (EUS-TCB) data pertain to type 1 disease. Our aim is to determine if EUS-TCB samples are sufficient for diagnosing type 2 AIP., Methods: This is a retrospective case series conducted in an academic tertiary care center. Patients included those with type 2 AIP (n = 5), retrospectively identified from a database of all patients with AIP, diagnosed by HISORt criteria (n = 125). The primary outcome measure was the diagnostic capability of EUS-TCB for type 2 AIP., Results: 5 patients (4 male, 1 female; mean age 39.6 years) who underwent EUS-TCB were diagnosed with type 2 AIP. The serum IgG(4) level was elevated in 1 of the 4 patients tested. CT/MRI revealed diffuse pancreas enlargement (n = 3), a pancreas head mass (n = 1), and a normal pancreas (n = 1). Prior to EUS, AIP was not specifically suspected, but part of a broad differential (n = 3) or not suspected at all (n = 2). Fine-needle aspiration was negative for neoplasia and AIP. The TCB histology was definitive (n = 4) or suggestive (n = 1) for type 2 AIP. No complications developed., Conclusions: EUS-TCB may be safe and may provide sufficient material to definitively diagnose type 2 AIP. and IAP., (Copyright © 2011 S. Karger AG, Basel.)

Autoimmune pancreatitis (AIP) has been extensively reported from Japan, Europe and the USA. While the descriptions of AIP from Japan have predominantly been based on the presence of a distinct clinical phenotype, reports from Europe and the USA describe at least 2 histopathologic patterns in patients diagnosed with AIP, namely lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct-centric pancreatitis (IDCP) or granulocytic epithelial lesion- positive pancreatitis. While the 2 entities share common histopathologic features (periductal lymphoplasmacytic infiltration and peculiar periductal fibrosis), expert pathologists can accurately distinguish them on the basis of other unique histopathologic features. Clinically, the 2 entities have a similar presentation (obstructive jaundice/pancreatic mass and a dramatic response to steroids), but they differ significantly in their demography, serology, involvement of other organs and disease relapse rate. While LPSP is associated with elevation of titers of nonspecific autoantibodies and serum IgG4 levels, IDCP does not have definitive serologic autoimmune markers. All experts agreed that the clinical phenotypes associated with LPSP and IDCP should be nosologically distinguished; however, their terminology was controversial. While most experts agreed that the entities should be referred to as type 1 and type 2 AIP, respectively, others had concerns regarding use of the term 'autoimmune' to describe IDCP. 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.)

Objectives: In a matched analysis, we investigated clinical, histopathological, and survival characteristics of small (2 cm. Two experienced pathologists, who were blinded to survival data, independently reviewed tumor stage and differentiation. Kaplan-Meier survival analysis and Cox proportional hazards models were applied for data analyses., Results: In patients with localized disease (stages I and II), survival was similar in small and large PaC but survival was significantly better in small PaC with regional nodal metastasis (stage III) as compared to similar stage large PaC (5-year survival 44 vs. 7%, median survival 58 vs.18 months, p < 0.001). Well-differentiated small and large PaC had similar median survival (76 vs. 74 months, p = NS). In multivariate analysis, tumor differentiation, not tumor size, was the only independent factor predicting survival in PaC (risk ratio, RR, for moderate vs. well- differentiated: 2.6, 95% confidence interval, CI, 1.5-4.5, and RR for poorly differentiated vs. well-differentiated: 5.0, 95% CI 2.4-10.1)., Conclusion: Tumor differentiation may be a better predictor of survival in resectable PaC than tumor stage., (Copyright 2008 S. Karger AG, Basel and IAP.)

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/aims: There is scant information in the literature about the outcomes of endoscopic retrograde cholangiopancreatography (ERCP)-induced severe acute pancreatitis (ESAP). Compared to other causes, higher morbidity and mortality have been reported in ERCP-induced acute pancreatitis. We undertook this study to determine the differences between ESAP and SAP due to other causes (OSAP)., Methods: We retrospectively identified all cases of SAP admitted to our institution during the years 1992-2001. We reviewed the medical records of all SAP patients to obtain information on demographics, interventions, local and systemic complications and outcomes., Results: We identified 207 patients with SAP, of whom 16 (7.7%) had ESAP and 191 OSAP. There was no difference between ESAP and OSAP with regard to demographics, clinical interventions, local and systemic complications and outcomes. Both groups had a similar mortality (25 vs. 18%)., Conclusion: ESAP has a similar morbidity and mortality compared to OSAP., (Copyright 2006 S. Karger AG, Basel and IAP.)

Background/aims: Defective DNA mismatch repair (MMR) in pancreatic cancer, reported in up to 13% of sporadic pancreatic cancers, may predict a good prognosis. To determine if long-term survival in pancreatic cancer could be attributed to defective DNA MMR, we ascertained its prevalence in 35 pancreatic cancer patients who survived > or =3 years after surgery., Methods: We performed immunohistochemistry (IHC) for MMR proteins hMLH1, hMSH2, and hMSH6 in all 35 tumors and microsatellite instability (MSI) studies in 34/35 tumors using 10 microsatellite markers in paired normal and tumor DNA. Defective DNA MMR was defined as absence of protein expression on IHC and/or MSI in > or =30% of markers studied., Results: On IHC, 3/35 (8.6%) tumors had defective DNA MMR. All 3 had absent expression of a DNA MMR protein (hMLH1 in 2 and hMSH2) and 2/3 also had MSI; the third could not be tested. Definitely 2, and probably all 3 patients had hereditary nonpolyposis colon cancer as determined by clinical and genetic profiles., Conclusion: Defective DNA MMR is uncommon in long-term survivors of pancreatic cancer and does not account for the survival benefit in those with sporadic pancreatic cancer.

Background/aims: To gain insights into pathogenesis of pancreatic cancer-associated diabetes., Methods: Using homeostasis model assessment (HOMA), we estimated beta-cell function (BCF) and insulin resistance (IR) from fasting plasma glucose (FPG) and insulin in 67 normoglycemic controls and 62 age- and BMI-matched normoglycemic pancreatic cancer patients. In addition, we studied 73 pancreatic cancer subjects with glucose intolerance; 21 had impaired FPG and 51 had diabetes., Results: BCF was similar in controls and normoglycemic pancreatic cancer subjects (64 +/- 5 vs. 78 +/- 9, p = ns), while IR was higher in pancreatic cancer subjects with normal FPG (1.6 +/- 0.6 vs. 1.1 +/- 0.1, p = 0.002). Among pancreatic cancer subjects, those with impaired FPG had markedly decreased BCF compared to those with normal FPG (44 +/- 5 vs. 78 +/- 9, p < 0.02) without significant difference in IR (1.9 +/- 0.2 vs. 1.6 +/- 0.6, p = ns). In cancer subjects, those with diabetes had markedly increased IR compared to those with impaired FPG (3.2 +/- 0.3 vs. 1.9 +/- 0.2, p < 0.0001), while the BCF was similar (37 +/- 4 vs. 44 +/- 5)., Conclusion: Diabetes associated with pancreatic cancer is likely due to a combination of marked decline in BCF and increased insulin resistance.