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Drug-induced pancreatitis is one of the top three causes of acute pancreatitis. A drug exposure is traditionally determined to be the cause of pancreatitis only after other possible and common causes of pancreatitis have been excluded.In this review, we challenge this traditional notion of drug-induced pancreatitis as a diagnosis of exclusion. Instead, we propose to shift the paradigm of conceptualizing what we term drug-associated pancreatic injury (DAPI); as a continuum of pancreatic injury that can be concomitant with other risk factors. The aims of this targeted review are to harness recent literature to build a foundation for conceptualizing DAPI, to highlight specific drugs associated with DAPI, and to describe a framework for future studies of DAPI.Our hope is that probing and characterizing the mechanisms underlying the various types of DAPI will lead to safer use of the DAPI-inducing drugs by minimizing the adverse event of pancreatitis.

Endoscopic retrograde cholangiopancreatography (ERCP) is commonly performed for the management of pancreaticobiliary disorders. The most troublesome ERCP-associated adverse event is post-ERCP pancreatitis (PEP), which occurs in up to 15% of all patients undergoing ERCP. A substantial body of preclinical data support a mechanistic rationale for calcineurin inhibitors in preventing PEP. The findings are coupled with recent clinical data suggesting lower rates of PEP in patients who concurrently use the calcineurin inhibitor tacrolimus (e.g., solid organ transplant recipients). In this review, we will firstly summarize data in support of testing the use of tacrolimus for PEP prophylaxis, either in combination with rectal indomethacin or by itself. Secondly, we propose that administering tacrolimus through the rectal route could be favorable for PEP prophylaxis over other routes of administration.

Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.

Background & objectives Acute pancreatitis is a common inflammatory disorder of the exocrine pancreas with no specific therapy. Intracellular nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) salvage pathway, is involved in many inflammatory disorders. In this study, we investigated the role of NAMPT in experimental acute pancreatitis. Methods Acute pancreatitis was induced in mice using three disparate models: (1) caerulein hyperstimulation, (2) ethanol plus palmitoleic acid, and (3) retrograde biliopancreatic ductal infusion of sodium taurocholate. The NAMPT inhibitor FK866 and NAMPT downstream product nicotinamide mononucleotide (NMN) was administered. Serum and pancreas were collected and analyzed biochemically and histologically. Bone marrow derived macrophages were isolated, cultured with cytokines or pancreatic acini, then analyzed by quantitative PCR and non-targeted metabolomics. Results The levels of pancreatic NAMPT and NAD were down-regulated upon acute pancreatitis. NAMPT inhibitor FK866 suppressed M1 macrophage polarization while NMN boosted it. In co-culture of macrophages with acinar cells, inhibition of NAMPT prevented M1-like macrophage differentiation induced by injured pancreatic acini. The injured pancreatic acinar milieu induced a unique metabolic signature linked to macrophage polarization, and inhibition of NAMPT reversed these metabolites changes. Furthermore, NMN supplementation aggravated caerulein hyperstimulation pancreatitis and alcoholic pancreatitis, and inhibition of NAMPT protected against caerulein hyperstimulation, alcoholic and biliary acute pancreatitis and reducing pancreatic macrophage infiltration in vivo. Conclusions NAMPT inhibition protects against acute pancreatitis via preventing M1 macrophage polarization and restoring the metabolites related to macrophage polarization and that NAMPT could be a promising therapeutic target for acute pancreatitis.

The aim of this article is to provide guidance to centers and organizations on the personnel (both physician and nonphysician) needed to create and sustain an optimal team, along with potential alternatives, to provide care to children with acute recurrent pancreatitis and chronic pancreatitis.This document was developed in collaboration with the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) Pancreas Committee and the National Pancreas Foundation (NPF) after several meetings.This document highlights both physician and nonphysician personnel needed to provide multidisciplinary care to children with pancreatitis per the recommendation of the NASPGHAN Pancreas Committee members in year 2021 and added to the currently published NPF criteria. We summarize how the NPF criteria would fit with the recently published pediatric pancreatitis society articles from the NASPGHAN.It is important to manage children with acute recurrent pancreatitis and chronic pancreatitis in a multidisciplinary setting. There is need to study the impact of these personnel on the outcomes of children with pancreatitis.

Acute pancreatitis (AP) was initiated within pancreatic parenchymal cells and sustained by uncontrolled inflammatory responses. AXL and MERTK receptor tyrosine kinases play a crucial role in negatively regulating the innate immunity. Therefore, this study aimed to investigate the role and underlying mechanism of AXL and MERTK in AP.Experimental AP was induced by ten hourly intraperitoneal administration of caerulein in global, hematopoietic- and pancreas-specific Axl and Mertk deficient mice. Pancreatitis severity was assessed biochemically and histologically. Pancreatic transcriptomics and pancreatic infiltrating immune cells were profiled. Some mice were given R428, an antagonist of AXL and MERTK. AXL and MERTK in peripheral leukocytes were measured by flow cytometry.The levels of AXL and MERTK in pancreatic tissue and pancreatic CD45Our findings reveal that specific AXL/MERTK antagonist may be a novel and potential early treatment for AP and the levels of MERTK in peripheral leukocytes may be a promising biomarker for predicting pancreatic severity in patients with AP.National Natural Science Foundation of China, Shanghai Natural Science Foundation, a Shanghai Young Talent Award and a Shanghai Young Orient Scholar Award.Evidence before this study Acute pancreatitis (AP) is a common inflammatory disorder of the exocrine pancreas, the severity of which was determined by the extent of pancreatic necrosis, with no targeted therapy. AP was initiated by signals within pancreatic parenchymal cells and sustained by uncontrolled innate immune responses. One of the three crucial regulatory roles for AXL and MERTK is to negatively regulate innate immune responses. Added value of this study Global and hematopoietic-, but not pancreas-specific Axl and Mertk deficiency protected against pancreatitis, primarily pancreatic necrosis. Deletion of Axl and Mertk selectively inhibited pancreatic neutrophil infiltration that was related to CXCL2 secreted by pro-inflammatory macrophages. AXL and MERTK antagonist similarly reduced pancreatitis severity via limiting CXCL2-mediated pancreatic neutrophil infiltration. Higher levels of MERTK, but not AXL in peripheral leukocytes were correlated with more severe form of acute pancreatitis. Implications of all the available evidence A specific AXL/MERTK antagonist may be a novel and potential early treatment for AP. The level of MERTK on peripheral leukocytes may be a promising biomarker for predicting disease severity in patients with AP.

Drug-induced pancreatitis is the second most common cause of acute pancreatitis (AP) in children and ranks as the third in adults. The aims of this targeted review are to provide a basis for conceptualizing drug-induced pancreatic injury (DIPI), to highlight specific drugs that are common or emerging risk factors, and to suggest a framework for future studies of DIPI. We challenge the traditional notion of diagnosing a drug exposure as the etiology of pancreatitis only after other etiologies could not be identified. Instead, we propose rethinking the disease process as a continuum of pancreatic injury due to drug exposure that can be concomitant with other risk factors. We favor a shift to use of the term drug-induced pancreatic injury (DIPI). There is a need to better characterize DIPI and to probe the mechanisms underlying the various types of DIPI, for the safer use of the DIPI inducing drugs by thwarting the adverse event of pancreatitis.

The reported incidence of pediatric pancreatitis is increasing. Noninvasive imaging, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), play important roles in the diagnosis, staging, follow-up, and management of pancreatitis in children. In this position paper, generated by members of the Pancreas Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the Abdominal Imaging Committee of The Society for Pediatric Radiology (SPR), we review the roles of noninvasive imaging in pediatric acute, acute recurrent, and chronic pancreatitis. We discuss available evidence related to noninvasive imaging, highlighting evidence specific to pediatric populations, and we make joint recommendations for use of noninvasive imaging. Further, we highlight the need for research to define the performance and role of noninvasive imaging in pediatric pancreatitis.

Item does not contain fulltext BACKGROUND: Acute pancreatitis remains the most common and morbid complication of endoscopic retrograde cholangiopancreatography (ERCP). The use of rectal indomethacin and pancreatic duct stenting has been shown to reduce the incidence and severity of post-ERCP pancreatitis (PEP), but these interventions have limitations. Recent clinical and translational evidence suggests a role for calcineurin inhibitors in the prevention of pancreatitis, with multiple retrospective case series showing a reduction in PEP rates in tacrolimus users. METHODS: The INTRO trial is a multicenter, international, randomized, double-blinded, controlled trial. A total of 4,874 patients undergoing ERCP will be randomized to receive either oral tacrolimus (5 mg) or oral placebo 1-2 h before ERCP, and followed for 30 days post-procedure. Blood and pancreatic aspirate samples will also be collected in a subset of patients to quantify tacrolimus levels. The primary outcome of the study is the incidence of PEP. Secondary endpoints include the severity of PEP, ERCP-related complications, adverse drug events, length of hospital stay, cost-effectiveness, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of tacrolimus immune modulation in the pancreas. CONCLUSIONS: The INTRO trial will assess the role of calcineurin inhibitors in PEP prophylaxis and develop a foundation for the clinical optimization of this therapeutic strategy from a pharmacologic and economic standpoint. With this clinical trial, we hope to demonstrate a novel approach to PEP prophylaxis using a widely available and well-characterized class of drugs. TRIAL REGISTRATION: NCT05252754, registered on February 14, 2022. 01 november 2022

Objectives Adults with chronic pancreatitis (CP) have a high risk for developing pancreatogenic diabetes mellitus (DM), but little is known regarding potential risk factors for DM in children with acute recurrent pancreatitis (ARP) or CP. We compared demographic and clinical features of children with ARP or CP, with and without DM, in the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE) registry. Methods We reviewed the INSPPIRE database for the presence or absence of physician-diagnosed DM in 397 children, excluding those with total pancreatectomy with islet autotransplantation, enrolled from August 2012 to August 2017. Patient demographics, BMI percentile, age at disease onset, disease risk factors, disease burden, and treatments were compared between children with DM (n = 24) and without DM (n = 373). Results Twenty-four children (6% of the cohort) had a diagnosis of DM. Five of 13 tested were positive for beta cell autoantibodies. The DM group was 4.2 years [95% confidence interval (CI) 3-5.4] older at first episode of acute pancreatitis, and tended to more often have hypertriglyceridemia [odds ratio (OR) 5.21 (1.33-17.05)], coexisting autoimmune disease [OR 3.94 (0.88-13.65)] or pancreatic atrophy [OR 3.64 (1.13, 11.59)]. Conclusion Pancreatic atrophy may be more common among children with DM, suggesting more advanced exocrine disease. However, data in this exploratory cohort also suggest increased autoimmunity and hypertriglyceridemia in children with DM, suggesting that risk factors for type 1 and type 2 DM, respectively may play a role in mediating DM development in children with pancreatitis.

Diabetes is known to predispose patients to the development of the life-threatening disorder pancreatitis and to cause a more severe course of pancreatitis. However, the mechanistic link between diabetes and pancreatitis is not clear. Aberrant cytosolic Ca2+ signals within the main parenchymal cell of the pancreas, the acinar cells, are central to the initiation of pancreatitis and can modulate its severity. The acinar cell Ca2+ signals are tightly regulated by a Ca2+ toolbox, which includes the plasma membrane Ca2+-ATPase (PMCA). A new paper by Bruce et al. shows that active extrusion of Ca2+through the PMCA protects acinar cells against the damage of pancreatitis in the setting of diabetes. The novelty of the finding here is that insulin receptors on the acinar cell transduce a glycolytic supply of ATP to fuel the PMCA and, thereby, link diabetes to pancreatitis through Ca2+signaling.

Acute lymphoblastic leukemia (ALL) is among the most common cancers in children. With improvements in combination chemotherapy regimens, the overall survival has increased to over 90%. However, the current challenge is to mitigate adverse events resulting from the complex therapy. Several chemotherapies intercept cancer metabolism, but little is known about their collective role in altering host metabolism. We profiled the metabolomic changes in plasma of ALL patients initial- and post- induction therapy. We exploited a biorepository of non-fasted plasma samples derived from the Dana Farber Cancer Institute ALL Consortium; these samples were obtained from 50 ALL patients initial- and post-induction therapy. Plasma metabolites and complex lipids were analyzed by high resolution tandem mass spectrometry and differential mobility tandem mass spectrometry. Data were analyzed using a covariate-adjusted regression model with multiplicity adjustment. Pathway enrichment analysis and co-expression network analysis were performed to identify unique clusters of molecules. More than 1200 metabolites and complex lipids were identified in the total of global metabolomics and lipidomics platforms. Over 20% of those molecules were significantly altered. In the pathway enrichment analysis, lipids, particularly phosphatidylethanolamines (PEs), were identified. Network analysis indicated that the bioactive fatty acids, docosahexaenoic acid (DHA)-containing (22:6) triacylglycerols (TAGs), were decreased in the post-induction therapy. Metabolomic profiling in ALL patients revealed a large number of alterations following induction chemotherapy. In particular, lipid metabolism was substantially altered. The changes in metabolites and complex lipids following induction therapy could provide insight into the adverse events experienced by ALL patients.

The Pancreas Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition aims to promote awareness of pediatric pancreatic diseases, support clinical and basic science research in the field, educate pediatric gastroenterologists, and advocate on behalf of pediatric patients with pancreatic disorders. At the 2017 Annual North American Society for Pediatric Gastroenterology, Hepatology and Nutrition meeting, the Pancreas Committee held a full day symposium on pediatric pancreatic diseases, entitled, "Frontiers in Pediatric Pancreatology." The symposium served as a timely and novel academic meeting that brought together individuals with a vested interest in the care of children with pancreatic disorders. The objective of this day-long course was to update practicing gastroenterologists on the latest advances in research, management algorithms, endoscopic therapies, radiographic resources, surgical approaches, and novel drug therapies targeted to pediatric pancreatitis. Presentations were divided into 4 modules: diagnosis, risk factors, and natural history of pancreatitis; pancreatic imaging and exocrine function; management of pancreatitis; and new frontiers in pediatric pancreatitis research. The course fostered a unique ecosystem for interdisciplinary collaboration, in addition to promoting discussion and stimulating new research hypotheses regarding pediatric pancreatic disorders. Oral presentations by experts in various fields of pancreatology led to thought-provoking discussion; in addition, a meet-the-professor luncheon stimulated critical evaluation of current research in pediatric pancreatic diseases, highlighting knowledge gaps and future research endeavors. The current report summarizes the major learning points from this novel symposium focusing on the growing demographic of pediatric pancreatic diseases.

10021 Background: Asparaginase is a key component of treatment of acute lymphoblastic leukemia (ALL), which is the most common cancer in the pediatric population. However, asparaginase is associated with many toxicities, including pancreatitis, which is observed in up to 10% of patients and can lead to severe sequelae. Methods: We performed analysis of (1) transcriptomic data from (a) asparaginase-treated leukemic cells, and (b) the pancreas of mice that were induced with a chemical form of pancreatitis; (2) the US FDA Adverse Reporting System (FAERS) and electronic health records (TriNetX); (3) global plasma metabolomic screen and dietary intake evaluation from ALL patients; and (4) experimental animal studies to identify factors that impact asparaginase-associated pancreatitis (AAP). Results: Connectivity map analysis showed that asparaginase-induced gene signatures are potentially reversed by the retinoids (vitamin A and its natural and synthetic analogs). Analysis of TriNetX and FAERES demonstrated a 2-fold reduction in AAP risk with concomitant exposure to vitamin A. Further, we performed a case-control metabolomic study of 50 subjects with ALL enrolled in the Dana-Farber Cancer Institute DFCI ALL clinical trial protocols 05-001 (NCT00400946) and 11-001 (NCT01574274). All subjects were given a single dose of pegylated E. Coli asparaginase during induction therapy. Twenty-four subjects developed pancreatitis within 9 months from the start of induction therapy and were considered cases. The median time to develop pancreatitis among cases was 3.68 months (interquartile range: 3.58 months). Twenty-six control subjects were identified among patients who did not develop pancreatitis within the same evaluation period. The controls were matched for age, sex, and initial ALL risk. The screening revealed that the plasma levels of carotene diol isomers, from the start of induction to its end, were reduced by about 60% in the cases compared to the controls. A detailed 30-day dietary recall showed that the cases had received less dietary vitamin A than the controls during induction therapy. Notably, the median value for the composite intake of vitamin A constituents, termed the RAE (retinol activity equivalents) was 656.92 mcg per day among the controls, but was 34.6% lower among in the cases (median of 429.40 mcg per day, which is just above the recommended dietary allowance level of 400 mcg per day for the 4–8 year-old age group). In mice, asparaginase administration as a single agent was sufficient to reduce circulating and hepatic retinol levels. Conclusions: Based on these data, we propose that circulating retinoids maintain pancreatic health, that asparaginase reduces circulating retinoids, and AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach provides the impetus to examine the role of dietary vitamin A supplementation for preventing or treating AAP.

We created the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE 2) cohort to study the risk factors, natural history, and outcomes of pediatric acute recurrent pancreatitis and chronic pancreatitis (CP). Patient and physician questionnaires collect information on demographics, clinical history, family and social history, and disease outcomes. Health-related quality of life, depression, and anxiety are measured using validated questionnaires. Information entered on paper questionnaires is transferred into a database managed by Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer's Coordinating and Data Management Center. Biosamples are collected for DNA isolation and analysis of most common pancreatitis-associated genes.Twenty-two sites (18 in the United States, 2 in Canada, and 1 each in Israel and Australia) are participating in the INSPPIRE 2 study. These sites have enrolled 211 subjects into the INSPPIRE 2 database toward our goal to recruit more than 800 patients in 2 years. The INSPPIRE 2 cohort study is an extension of the INSPPIRE cohort study with a larger and more diverse patient population. Our goals have expanded to include evaluating risk factors for CP, its sequelae, and psychosocial factors associated with pediatric acute recurrent pancreatitis and CP.

A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities on drug development for pancreatitis. This conference was held on July 25, 2018, and structured into 3 working groups (WG): acute pancreatitis (AP) WG, recurrent AP WG, and chronic pancreatitis WG. This article reports the outcome of the work accomplished by the AP WG to provide the natural history, epidemiology, and current management of AP; inform about the role of preclinical models in therapy selection; and discuss clinical trial designs with clinical and patient-reported outcomes to test new therapies.

The lack of effective therapeutic agents specifically tailored for chronic pancreatitis has hampered clinical care and negatively impacted patients’ lives. New mechanistic insights now point to novel therapies, which involve both recently developed and/or repurposed agents. This working group focused on two main outcomes for chronic pancreatitis: pain and progression of disease. The goal is to frame the essential aspects of trial design including patient-centered outcomes, proposed methods to measure the outcomes of pain and progression, and study design considerations for future trials to facilitate rapid drug development for patients with chronic pancreatitis.

ObjectiveChronic pancreatitis (CP) is a potentially fatal disease of the exocrine pancreas, with no specific or effective approved therapies. Due to difficulty in accessing pancreas tissues, little is known about local immune responses or pathogenesis in human CP. We sought to characterise pancreatic immune responses using tissues derived from patients with different aetiologies of CP and non-CP organ donors in order to identify key signalling molecules associated with human CP.DesignWe performed single-cell level cellular indexing of transcriptomes and epitopes by sequencing and T-cell receptor (TCR) sequencing of pancreatic immune cells isolated from organ donors, hereditary and idiopathic patients with CP who underwent total pancreatectomy. We validated gene expression data by performing flow cytometry and functional assays in a second patient with CP cohort.ResultsDeep single-cell sequencing revealed distinct immune characteristics and significantly enriched CCR6+ CD4+ T cells in hereditary compared with idiopathic CP. In hereditary CP, a reduction in T-cell clonality was observed due to the increased CD4+ T (Th) cells that replaced tissue-resident CD8+ T cells. Shared TCR clonotype analysis among T-cell lineages also unveiled unique interactions between CCR6+ Th and Th1 subsets, and TCR clustering analysis showed unique common antigen binding motifs in hereditary CP. In addition, we observed a significant upregulation of the CCR6 ligand (CCL20) expression among monocytes in hereditary CP as compared with those in idiopathic CP. The functional significance of CCR6 expression in CD4+ T cells was confirmed by flow cytometry and chemotaxis assay.ConclusionSingle-cell sequencing with pancreatic immune cells in human CP highlights pancreas-specific immune crosstalk through the CCR6-CCL20 axis, a signalling pathway that might be leveraged as a potential future target in human hereditary CP.

Background And Aims Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies. Methods We performed single-cell mass Cytometry by Time Of Flight (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild AP (referred to as AP), severe AP (SAP), and recovery using 2 independent experimental models and blood from patients with AP and recurrent AP. Flow cytometric validation of monocytes subsets identified using CyTOF analysis was performed independently. Results Ly6C+ inflammatory monocytes were the most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified 7 novel subsets during AP and recovery, and 6 monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206+ macrophage population was observed during AP and recovery. Deeper profiling of the CD206+ macrophage identified 7 novel subsets during AP, recovery, and SAP. Differential expression analysis of these novel monocyte and CD206+ macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, podoplanin) and functional markers (interferon-γ, interleukin 4, interleukin 22, latency associated peptide-transforming growth factor–β, tumor necrosis factor-α, T-bet, RoRγt) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206+ macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14+CD16-) and novel subsets in patients with AP and recurrent AP. Conclusions We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.

This position paper summarizes the current understanding of the medical management of chronic pancreatitis (CP) in children in light of the existing medical literature, incorporating recent advances in understanding of nutrition, pain, lifestyle considerations, and sequelae of CP. This article complements and is intended to integrate with parallel position papers on endoscopic and surgical aspects of CP in children. Concepts and controversies related to pancreatic enzyme replacement therapy (PERT), the use of antioxidants and other CP medical therapies are also reviewed. Highlights include inclusion of tools for medical decision-making for PERT, CP-related diabetes, and multimodal pain management (including an analgesia ladder). Gaps in our understanding of CP in children and avenues for further investigations are also reviewed.

The reported incidence of pediatric pancreatitis is increasing. Noninvasive imaging, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), play important roles in the diagnosis, staging, follow-up, and management of pancreatitis in children. In this position paper, generated by members of the Pancreas Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the Abdominal Imaging Committee of The Society for Pediatric Radiology (SPR), we review the roles of noninvasive imaging in pediatric acute, acute recurrent, and chronic pancreatitis. We discuss available evidence related to noninvasive imaging, highlighting evidence specific to pediatric populations, and we make joint recommendations for use of noninvasive imaging. Further, we highlight the need for research to define the performance and role of noninvasive imaging in pediatric pancreatitis.

Endoscopic pancreatic function testing (ePFT) is one of the few ways to directly diagnose exocrine pancreatic insufficiency, and considerable confusion regarding indications, utility, and interpretation of the test remains. This position paper of the Pancreas Committee of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition reviews the history and indications for ePFT in children. We compare various methods in current practice and determine their strengths and limitations, and based on data from children and adults we provide guidance on a protocol on how to perform ePFT in children. Lastly, we pose areas in need of further research relating to ePFT in children.

ObjectiveThe aim of the study was to determine whether clinical characteristics and management of pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) differ across INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a cuRE) sites.Study designData were collected from INSPPIRE and analyzed per US regions and "non-US" sites. Between-group differences were compared by Pearson chi-square test. Differences in disease burden were compared by Kruskal-Wallis test.ResultsOut of the 479 subjects, 121 (25%) were enrolled in West, 151 (32%) Midwest, 45 Northeast (9%), 78 (16%) South, and 84 (18%) at non-US sites. Hispanic ethnicity was more common in South (P

The pancreas avidly takes up and synthesizes the amino acid asparagine (Asn), in part, to maintain an active translational machinery that requires incorporation of the amino acid. The de novo synthesis of Asn in the pancreas occurs through the enzyme asparagine synthetase (ASNS). The pancreas has the highest expression of ASNS of any organ, and it can further upregulate ASNS expression in the setting of amino acid depletion. ASNS expression is driven by an intricate feedback network within the integrated stress response (ISR), which includes the amino acid response (AAR) and the unfolded protein response (UPR). Asparaginase is a cancer chemotherapeutic drug that depletes plasma Asn. However, asparaginase-associated pancreatitis (AAP) is a major medical problem and could be related to pancreatic Asn depletion. In this review, we will provide an overview of ASNS and then describe its role in pancreatic health and in the exocrine disorders of pancreatitis and pancreatic cancer. We will offer the overarching perspective that a high abundance of ASNS expression is hardwired in the exocrine pancreas to buffer the high demands of Asn for pancreatic digestive enzyme protein synthesis, that perturbations in the ability to express or upregulate ASNS could tip the balance towards pancreatitis, and that pancreatic cancers exploit ASNS to gain a metabolic survival advantage.

Background/objectives Drug induced acute pancreatitis (DIAP) as one of the acute pancreatitis (AP) risks factors is a poorly understood entity. The aim of the current study was to compare the characteristics and course of DIAP cases in children presenting with a first attack of AP. Methods Patients presenting with AP were included in a prospective database. We enrolled 165 AP patients that met criteria for inclusion. DIAP patients were included in that group if they were exposed to a drug known to be associated with AP and the rest were included in the non-drug induced-acute pancreatitis (non-DIAP) group. Results DIAP was observed in 40/165 (24%) of cases, 24 cases had drug-induced as the sole risk factor, and 16 had DIAP with another risk factor(s). The two groups were similar in intravenous fluid and feeding managements, but ERCP was more commonly performed in the non- DIAP group, 14 (11%), vs 0% in the DIAP group, p = 0.02. Moderately severe [9 (23%) vs 11 (9%)] and severe AP [7 (18%) vs 6 (5%)] were more commonly associated with DIAP than non- DIAP, p = 0.001. DIAP was more commonly associated with ICU stay, 10 (25%), vs 12 (10%), p = 0.01, hospital stay was longer in DIAP median (IQR) of 6 (3.9–11) days vs 3.3 (2–5.7) days in non- DIAP, p = 0.001. The DIAP group had a significantly higher proportion of comorbidities (p Conclusions DIAP is a leading risk factor for a first attack of AP in children and is associated with increased morbidity and severity of the pancreatitis course. DIAP warrants further investigation in future studies.

Introduction Pediatric chronic pancreatitis is increasingly diagnosed. Endoscopic methods [endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP)] are useful tools to diagnose and manage chronic pancreatitis. Pediatric knowledge and use of these modalities is limited and warrants dissemination. Methods Literature review of publications relating to use of ERCP and EUS for diagnosis and/or management of chronic pancreatitis with special attention to studies involving 0--18 years old subjects was conducted with summaries generated. Recommendations were developed and voted upon by authors. Results Both EUS and ERCP can be used even in small children to assist in diagnosis of chronic pancreatitis in cases where cross-sectional imaging is not sufficient to diagnose or characterize the disease. Children under 15 kg for EUS and 10 kg for ERCP can be technically challenging. These procedures should be done optimally by appropriately trained endoscopists and adult gastroenterology providers with appropriate experience treating children. EUS and ERCP-related risks both include perforation, bleeding and pancreatitis. EUS is the preferred diagnostic modality over ERCP because of lower complication rates overall. Both modalities can be used for management of chronic pancreatitis -related fluid collections. ERCP has successfully been used to manage pancreatic duct stones. Conclusion EUS and ERCP can be safely used to diagnose chronic pancreatitis in pediatric patients and assist in management of chronic pancreatitis-related complications. Procedure-related risks are similar to those seen in adults, with EUS having a safer risk profile overall. The recent increase in pediatric-trained specialists will improve access of these modalities for children.

Background & Aims Calcineurin is a ubiquitously expressed central Ca2+-responsive signaling molecule that mediates acute pancreatitis, but little is known about its effects. We compared the effects of calcineurin expression by hematopoietic cells vs pancreas in mouse models of pancreatitis and pancreatitis-associated lung inflammation. Methods We performed studies with mice with hematopoietic-specific or pancreas-specific deletion of protein phosphatase 3, regulatory subunit B, alpha isoform (PPP3R1, also called CNB1), in mice with deletion of CNB1 (Cnb1UBC△/△) and in the corresponding controls for each deletion of CNB1. Acute pancreatitis was induced in mice by administration of caerulein or high-pressure infusion of radiocontrast into biliopancreatic ducts; some mice were also given intraductal infusions of an adeno-associated virus vector that expressed nuclear factor of activated T -cells (NFAT)–luciferase into pancreas. Pancreas, bone marrow, liver, kidney, heart, and lung were collected and analyzed by histopathology, immunohistochemistry, and immunoblots; levels of cytokines were measured in serum. Mouse and human primary pancreatic acinar cells were transfected with a vector that expressed NFAT-luciferase and incubated with an agent that blocks interaction of NFAT with calcineurin; cells were analyzed by immunofluorescence. Calcineurin-mediated neutrophil chemotaxis and reactive oxygen species production were measured in neutrophils from mice. Results Mice with hematopoietic-specific deletion of CNB1 developed the same level of local pancreatic inflammation as control mice after administration of caerulein or infusion of radiocontrast into biliopancreatic ducts. Cnb1UBC△/△ mice or mice with pancreas-specific deletion of CNB1 developed less severe pancreatitis and reduced pancreatic inflammation after administration of caerulein or infusion of radiocontrast into biliopancreatic ducts compared with control mice. NFAT was activated in pancreas of Swiss Webster mice given caerulein or infusions of radiocontrast into biliopancreatic ducts. Blocking the interaction between calcineurin and NFAT did not reduce pancreatic acinar cell necrosis in response to caerulein or infusions of radiocontrast. Mice with hematopoietic-specific deletion of CNB1 (but not mice with pancreas-specific deletion of CNB1) had reduced infiltration of lung tissues by neutrophils. Neutrophil chemotaxis and production of reactive oxygen species were decreased after incubation with a calcineurin inhibitor. Conclusions Hematopoietic and neutrophil expression of calcineurin promotes pancreatitis-associated lung inflammation, whereas pancreatic calcineurin promotes local pancreatic inflammation. The findings indicate that the protective effects of blocking or deleting calcineurin on pancreatitis are mediated by the source of its expression. This information should be used in the development of strategies to inhibit calcineurin for the prevention of pancreatitis and pancreatitis-associated lung inflammation.

The exocrine pancreas expresses the highest concentrations of fibroblast growth factor 21 (FGF21) in the body, where it maintains acinar cell proteostasis. Here, we showed in both mice and humans that acute and chronic pancreatitis is associated with a loss of FGF21 expression due to activation of the integrated stress response (ISR) pathway. Mechanistically, we found that activation of the ISR in cultured acinar cells and mouse pancreata induced the expression of ATF3, a transcriptional repressor that directly bound to specific sites on the Fgf21 promoter and resulted in loss of FGF21 expression. These ATF3 binding sites are conserved in the human FGF21 promoter. Consistent with the mouse studies, we also observed the reciprocal expression of ATF3 and FGF21 in the pancreata of human patients with pancreatitis. Using three different mouse models of pancreatitis, we showed that pharmacologic replacement of FGF21 mitigated the ISR and resolved pancreatitis. Likewise, inhibition of the ISR with an inhibitor of the PKR-like endoplasmic reticulum kinase (PERK) also restored FGF21 expression and alleviated pancreatitis. These findings highlight the importance of FGF21 in preserving exocrine pancreas function and suggest its therapeutic use for prevention and treatment of pancreatitis.

OBJECTIVES:Autoimmune pancreatitis (AIP) represents a complex immune-mediated pancreas disorder. Pediatric AIP (P-AIP) is rare. We have recently summarized the characteristic features of P-AIP. We now aim to develop recommendation statements to standardize the diagnostic and therapeutic approach to P-AIP and facilitate future research in the field. METHODS:A panel of pediatric gastroenterologists participating in the International Study Group of Pediatric Pancreatitis: In search for a cuRE was formed to discuss and then vote on 15 recommendation statements. A consensus of at least 80% was obtained following 3 voting rounds and revision of the statements. RESULTS:We have now generated 15 statements to help standardize the approach to diagnosis and management of P-AIP. CONCLUSIONS:The first P-AIP recommendation statements developed by the International Study Group of Pediatric Pancreatitis: In search for a cuRE group are intended to bring standardization to the diagnosis and treatment of this rare childhood disorder. These statements may help guide a uniform approach to patient care and facilitate future research studies.

Background:Although the incidence of acute pancreatitis (AP) in children is increasing, management recommendations rely on adult published guidelines. Pediatric-specific recommendations are needed.Methods:The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pan

Goals To evaluate potential risk factors for the development of asparaginase-associated pancreatitis (AAP), we performed a systematic review of the current literature from January 1946 through May 2015. Background Asparaginase, a primary treatment for the most common childhood cancer, acute lymphoblastic leukemia (ALL), is a well-described cause of pancreatitis. Further, pancreatitis is among the most burdensome and common complications of asparaginase treatment and represents a major reason for early-drug termination and inferior outcomes. The literature lacks clarity about the risk factors for AAP, and this knowledge gap has hampered the ability to reliably predict which patients are likely to develop AAP. Study In an expansive screen, 1842 citations were funneled into a review of 59 full articles, of which 10 were deemed eligible based on predetermined inclusion criteria. Results Of the 10 identified studies, only 2 studies showed that children above 10 years of age had a >2-fold risk of AAP compared with younger children. Patients placed in high-risk ALL categories had a greater incidence of pancreatitis in 2 studies. In addition, use of pegylated asparaginase resulted in a higher incidence of AAP in 1 study. Conclusions In this systematic review, older age, asparaginase formulation, higher ALL risk stratification, and higher asparaginase dosing appear to play a limited role in the development of AAP. Further studies are needed to probe the underlying mechanisms contributing to the development of pancreatitis in patients receiving asparaginase.