Publications by authors named "Sohail Z Husain"

93 Publications

Medical Management of Chronic Pancreatitis in Children: A Position Paper by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee.

J Pediatr Gastroenterol Nutr 2021 Feb;72(2):324-340

Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Abstract: 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.
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http://dx.doi.org/10.1097/MPG.0000000000003001DOI Listing
February 2021

North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the Society for Pediatric Radiology Joint Position Paper on Noninvasive Imaging of Pediatric Pancreatitis: Literature Summary and Recommendations.

J Pediatr Gastroenterol Nutr 2021 Jan;72(1):151-167

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.

Abstract: 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.
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http://dx.doi.org/10.1097/MPG.0000000000002964DOI Listing
January 2021

Endoscopic Pancreatic Function Testing (ePFT) in Children: A Position Paper From the NASPGHAN Pancreas Committee.

J Pediatr Gastroenterol Nutr 2021 Jan;72(1):144-150

Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA.

Abstract: 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.
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http://dx.doi.org/10.1097/MPG.0000000000002931DOI Listing
January 2021

The role of asparagine synthetase on nutrient metabolism in pancreatic disease.

Pancreatology 2020 Sep 8;20(6):1029-1034. Epub 2020 Aug 8.

Division of Gastroenterology, Department of Pediatrics, Stanford University and Lucile Packard Children's Hospital at Stanford, Stanford, CA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pan.2020.08.002DOI Listing
September 2020

Drug induced pancreatitis is the leading known cause of first attack acute pancreatitis in children.

Pancreatology 2020 Sep 24;20(6):1103-1108. Epub 2020 Jul 24.

Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

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 < 0.0001).

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.
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http://dx.doi.org/10.1016/j.pan.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492485PMC
September 2020

The Protective Effects of Calcineurin on Pancreatitis in Mice Depend on the Cellular Source.

Gastroenterology 2020 Sep 20;159(3):1036-1050.e8. Epub 2020 May 20.

Division of Pediatric Gastroenterology, Department of Pediatrics, Stanford University, Palo Alto, California. Electronic address:

Background & Aims: Calcineurin is a ubiquitously expressed central Ca-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 (Cnb1) 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. Cnb1 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.
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http://dx.doi.org/10.1053/j.gastro.2020.05.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502475PMC
September 2020

Patient Passport for Pediatric Acute Recurrent and Chronic Pancreatitis.

J Pediatr Gastroenterol Nutr 2020 07;71(1):e51-e53

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto.

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http://dx.doi.org/10.1097/MPG.0000000000002754DOI Listing
July 2020

The Roles of Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography in the Evaluation and Treatment of Chronic Pancreatitis in Children: A Position Paper From the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee.

J Pediatr Gastroenterol Nutr 2020 05;70(5):681-693

Montreal Children's Hospital, Division of Pediatric Gastroenterology and Nutrition. McGill University Health Center, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1097/MPG.0000000000002664DOI Listing
May 2020

Clinical and Practice Variations in Pediatric Acute Recurrent or Chronic Pancreatitis: Report From the INSPPIRE Study.

J Pediatr Gastroenterol Nutr 2020 07;71(1):112-118

Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE.

Objective: The 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 Design: Data 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.

Results: Out 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 < 0.0001); white race in Northeast (P = 0.009). CP was less common and time from diagnosis of first acute pancreatitis to CP was longer in children at non-US sites (P = 0.0002 and P = 0.011, respectively). Genetic mutations were most common among all groups; PRSS1 variants predominated in Midwest (P = 0.002). Gallstones were more frequent in South (P = 0.002). Endoscopic retrograde cholangiopancreatography (ERCP) and computed tomography (CT) imaging were more commonly utilized in United States compared with non-United States (P < 0.0001), but there were no differences in the use of MRI/MRCP. Disease burden was highest in the West and Midwest, possibly as total pancreatectomy and islet autotransplantation (TPIAT) referral sites were located in these regions. All therapies were less commonly administered in non-US sites (P < 0.0001).

Conclusions: This is the first study to describe geographical variations in the INSPPIRE cohort, which possibly reflect variations in practice and referral patterns. The underlying reason behind the lower frequency of CP and fewer treatments in non-United States sites need to be further explored.
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http://dx.doi.org/10.1097/MPG.0000000000002661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305964PMC
July 2020

Pancreatitis is an FGF21-deficient state that is corrected by replacement therapy.

Sci Transl Med 2020 01;12(525)

Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.

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 promoter and resulted in loss of FGF21 expression. These ATF3 binding sites are conserved in the human 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.
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http://dx.doi.org/10.1126/scitranslmed.aay5186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034981PMC
January 2020

Web-based cognitive-behavioral intervention for pain in pediatric acute recurrent and chronic pancreatitis: Protocol of a multicenter randomized controlled trial from the study of chronic pancreatitis, diabetes and pancreatic cancer (CPDPC).

Contemp Clin Trials 2020 01 19;88:105898. Epub 2019 Nov 19.

University of Iowa, Stead Family Children's Hospital, Iowa City, IA, USA.

Introduction: Abdominal pain is common and is associated with high disease burden and health care costs in pediatric acute recurrent and chronic pancreatitis (ARP/CP). Despite the strong central component of pain in ARP/CP and the efficacy of psychological therapies for other centralized pain syndromes, no studies have evaluated psychological pain interventions in children with ARP/CP. The current trial seeks to 1) evaluate the efficacy of a psychological pain intervention for pediatric ARP/CP, and 2) examine baseline patient-specific genetic, clinical, and psychosocial characteristics that may predict or moderate treatment response.

Methods: This single-blinded randomized placebo-controlled multicenter trial aims to enroll 260 youth (ages 10-18) with ARP/CP and their parents from twenty-one INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE) centers. Participants will be randomly assigned to either a web-based cognitive behavioral pain management intervention (Web-based Management of Adolescent Pain Chronic Pancreatitis; WebMAP; N = 130) or to a web-based pain education program (WebED; N = 130). Assessments will be completed at baseline (T1), immediately after completion of the intervention (T2) and at 6 months post-intervention (T3). The primary study outcome is abdominal pain severity. Secondary outcomes include pain-related disability, pain interference, health-related quality of life, emotional distress, impact of pain, opioid use, and healthcare utilization.

Conclusions: This is the first clinical trial to evaluate the efficacy of a psychological pain intervention for children with CP for reduction of abdominal pain and improvement of health-related quality of life. Findings will inform delivery of web-based pain management and potentially identify patient-specific biological and psychosocial factors associated with favorable response to therapy. Clinical Trial Registration #: NCT03707431.
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http://dx.doi.org/10.1016/j.cct.2019.105898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952537PMC
January 2020

Diabetes Mellitus in Children with Acute Recurrent and Chronic Pancreatitis: Data From the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE Cohort.

J Pediatr Gastroenterol Nutr 2019 11;69(5):599-606

University of Iowa, Iowa City, IA.

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.
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http://dx.doi.org/10.1097/MPG.0000000000002482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834233PMC
November 2019

Factors Associated With Frequent Opioid Use in Children With Acute Recurrent and Chronic Pancreatitis.

J Pediatr Gastroenterol Nutr 2020 01;70(1):106-114

Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA.

Objectives: The aim of the study was to understand the association of frequent opioid use with disease phenotype and pain pattern and burden in children and adolescents with acute recurrent (ARP) or chronic pancreatitis (CP).

Methods: Cross-sectional study of children <19 years with ARP or CP, at enrollment into the INSPPIRE cohort. We categorized patients as opioid "frequent use" (daily/weekly) or "nonfrequent use" (monthly or less, or no opioids), based on patient and parent self-report.

Results: Of 427 children with ARP or CP, 17% reported frequent opioid use. More children with CP (65%) reported frequent opioid use than with ARP (41%, P = 0.0002). In multivariate analysis, frequent opioid use was associated with older age at diagnosis (odds ratio [OR] 1.67 per 5 years, 95% confidence interval [CI] 1.13-2.47, P = 0.01), exocrine insufficiency (OR 2.44, 95% CI 1.13-5.24, P = 0.02), constant/severe pain (OR 4.14, 95% CI 2.06-8.34, P < 0.0001), and higher average pain impact score across all 6 functional domains (OR 1.62 per 1-point increase, 95% CI 1.28-2.06, P < 0.0001). Children with frequent opioid use also reported more missed school days, hospitalizations, and emergency room visits in the past year than children with no frequent use (P < 0.0002 for each). Participants in the US West and Midwest accounted for 83% of frequent opioid users but only 56% of the total cohort.

Conclusions: In children with CP or ARP, frequent opioid use is associated with constant pain, more healthcare use, and higher levels of pain interference with functioning. Longitudinal and prospective research is needed to identify risk factors for frequent opioid use and to evaluate nonopioid interventions for reducing pain and disability in these children.
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http://dx.doi.org/10.1097/MPG.0000000000002502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934913PMC
January 2020

Asparagine Synthetase Is Highly Expressed at Baseline in the Pancreas Through Heightened PERK Signaling.

Cell Mol Gastroenterol Hepatol 2020 14;9(1):1-13. Epub 2019 Aug 14.

Department of Pediatrics, Stanford University, Palo Alto, California. Electronic address:

Asparaginase (ASNase) causes pancreatitis in approximately 10% of leukemia patients, and the mechanisms underlying this painful complication are not known. ASNase primarily depletes circulating asparagine, and the endogenously expressed enzyme, asparagine synthetase (ASNS), replenishes asparagine. ASNS was suggested previously to be highly expressed in the pancreas. In this study, we determined the expression pattern of ASNS in the pancreas and the mechanism for increased pancreatic ASNS abundance. Compared with other organs, ASNS was highly expressed in both the human and mouse pancreas, and, within the pancreas, ASNS was present primarily in the acinar cells. The high baseline pancreatic ASNS was associated with higher baseline activation of protein kinase R-like endoplasmic reticulum kinase (PERK) signaling in the pancreas, and inhibition of PERK in acinar cells lessened ASNS expression. ASNase exposure, but not the common pancreatitis triggers, uniquely up-regulated ASNS expression, indicating that the increase is mediated by nutrient stress. The up-regulation of acinar ASNS with ASNase exposure was owing to increased transcriptional rather than delayed degradation. Knockdown of ASNS in the 266-6 acinar cells provoked acinar cell injury and worsened ASNase-induced injury, whereas ASNS overexpression protected against ASNase-induced injury. In summary, ASNS is highly expressed in the pancreatic acinar cells through heightened basal activation of PERK, and ASNS appears to be crucial to maintaining acinar cell integrity. The implications are that ASNS is especially hardwired in the pancreas to protect against both baseline perturbations and nutrient deprivation stressors, such as during ASNase exposure.
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http://dx.doi.org/10.1016/j.jcmgh.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881672PMC
August 2019

Animal Models: Challenges and Opportunities to Determine Optimal Experimental Models of Pancreatitis and Pancreatic Cancer.

Pancreas 2019 07;48(6):759-779

Department of Medicine, University of Pittsburgh, Pittsburgh, PA.

At the 2018 PancreasFest meeting, experts participating in basic research met to discuss the plethora of available animal models for studying exocrine pancreatic disease. In particular, the discussion focused on the challenges currently facing the field and potential solutions. That meeting culminated in this review, which describes the advantages and limitations of both common and infrequently used models of exocrine pancreatic disease, namely, pancreatitis and exocrine pancreatic cancer. The objective is to provide a comprehensive description of the available models but also to provide investigators with guidance in the application of these models to investigate both environmental and genetic contributions to exocrine pancreatic disease. The content covers both nongenic and genetically engineered models across multiple species (large and small). Recommendations for choosing the appropriate model as well as how to conduct and present results are provided.
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http://dx.doi.org/10.1097/MPA.0000000000001335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581211PMC
July 2019

Risk Factors for Rapid Progression From Acute Recurrent to Chronic Pancreatitis in Children: Report From INSPPIRE.

J Pediatr Gastroenterol Nutr 2019 08;69(2):206-211

University of Iowa Stead Family Children's Hospital, Iowa City, IA.

Objective: The aim of the study was to determine the rate of progression from acute recurrent pancreatitis (ARP) to chronic pancreatitis (CP) in children and assess risk factors.

Study Design: Data were collected from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) cohort. Kaplan-Meier curves were constructed to calculate duration of progression from initial attack of acute pancreatitis (AP) to CP. Log-rank test was used to compare survival (nonprogression) probability distribution between groups. Cox proportional hazard regression models were fitted to obtain hazard ratio (with 95% confidence interval [CI]) of progression for each risk variable.

Results: Of 442 children, 251 had ARP and 191 had CP. The median time of progression from initial attack of AP to CP was 3.79 years. The progression was faster in those ages 6 years or older at the first episode of AP compared to those younger than 6 years (median time to CP: 2.91 vs 4.92 years; P = 0.01). Children with pathogenic PRSS1 variants progressed more rapidly to CP compared to children without PRSS1 variants (median time to CP: 2.52 vs 4.48 years; P = 0.003). Within 6 years after the initial AP attack, cumulative proportion with exocrine pancreatic insufficiency was 18.0% (95% CI: 12.4%, 25.6%); diabetes mellitus was 7.7% (95% CI: 4.2%, 14.1%).

Conclusions: Children with ARP rapidly progress to CP, exocrine pancreatic insufficiency, and diabetes. The progression to CP is faster in children who were 6 years or older at the first episode of AP or with pathogenic PRSS1 variants. The factors that affect the aggressive disease course in childhood warrant further investigation.
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http://dx.doi.org/10.1097/MPG.0000000000002405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699635PMC
August 2019

The Orai Ca channel inhibitor CM4620 targets both parenchymal and immune cells to reduce inflammation in experimental acute pancreatitis.

J Physiol 2019 06 22;597(12):3085-3105. Epub 2019 May 22.

Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Key Points: This work confirms previous reports that CM4620, a small molecule inhibitor of Ca entry via store operated Ca entry (SOCE) channels formed by stromal interaction molecule 1 (STIM1)/Orai complexes, attenuates acinar cell pathology and acute pancreatitis in mouse experimental models. Here we report that intravenous administration of CM4620 reduces the severity of acute pancreatitis in the rat, a hitherto untested species. Using CM4620, we probe further the mechanisms whereby SOCE via STIM1/Orai complexes contributes to the disease in pancreatic acinar cells, supporting a role for endoplasmic reticulum stress/cell death pathways in these cells. Using CM4620, we show that SOCE via STIM1/Orai complexes promotes neutrophil oxidative burst and inflammatory gene expression during acute pancreatitis, including in immune cells which may be either circulating or invading the pancreas. Using CM4620, we show that SOCE via STIM1/Orai complexes promotes activation and fibroinflammatory gene expression within pancreatic stellate cells.

Abstract: Key features of acute pancreatitis include excess cellular Ca entry driven by Ca depletion from the endoplasmic reticulum (ER) and subsequent activation of store-operated Ca entry (SOCE) channels in the plasma membrane. In several cell types, including pancreatic acinar, stellate cells (PaSCs) and immune cells, SOCE is mediated via channels composed primarily of Orai1 and stromal interaction molecule 1 (STIM1). CM4620, a selective Orai1 inhibitor, prevents Ca entry in acinar cells. This study investigates the effects of CM4620 in preventing or reducing acute pancreatitis features and severity. We tested the effects of CM4620 on SOCE, trypsinogen activation, acinar cell death, activation of NFAT and NF-κB, and inflammatory responses in ex vivo and in vivo rodent models of acute pancreatitis and human pancreatic acini. We also examined whether CM4620 inhibited cytokine release in immune cells, fibro-inflammatory responses in PaSCs, and oxidative burst in neutrophils, all cell types participating in pancreatitis. CM4620 administration to rats by i.v. infusion starting 30 min after induction of pancreatitis significantly diminished pancreatitis features including pancreatic oedema, acinar cell vacuolization, intrapancreatic trypsin activity, cell death signalling and acinar cell death. CM4620 also decreased myeloperoxidase activity and inflammatory cytokine expression in pancreas and lung tissues, fMLF peptide-induced oxidative burst in human neutrophils, and cytokine production in human peripheral blood mononuclear cells (PBMCs) and rodent PaSCs, indicating that Orai1/STIM1 channels participate in the inflammatory responses of these cell types during acute pancreatitis. These findings support pathological Ca entry-mediated cell death and proinflammatory signalling as central mechanisms in acute pancreatitis pathobiology.
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http://dx.doi.org/10.1113/JP277856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582954PMC
June 2019

Chronic Pancreatitis: Pediatric and Adult Cohorts Show Similarities in Disease Progress Despite Different Risk Factors.

J Pediatr Gastroenterol Nutr 2019 04;68(4):566-573

Department of Medicine.

Objectives: The aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared.

Methods: Demographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables.

Results: Alcohol was a risk in 53% of adults and 1% of children (P < 0.0001); tobacco in 50% of adults and 7% of children (P < 0.0001). Obstructive factors were more common in children (29% vs 19% in adults, P = 0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, P = 0.107). Diabetes was more common in adults than children (36% vs 4% respectively, P < 0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared with INSPPIRE subjects. These 2 cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, P = 0.011).

Conclusions: Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.
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http://dx.doi.org/10.1097/MPG.0000000000002279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492264PMC
April 2019

Updates in Pediatric Pancreatology: Proceedings of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Frontiers in Pediatric Pancreatology Symposium.

J Pediatr Gastroenterol Nutr 2019 02;68(2):e27-e33

Division of Pediatric Gastroenterology and Nutrition, Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1097/MPG.0000000000002186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444930PMC
February 2019

Pancreatitis in Children.

Gastroenterology 2019 05 1;156(7):1969-1978. Epub 2019 Feb 1.

Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

Acute, acute recurrent, and chronic forms of pancreatitis have been increasingly diagnosed in children in the past 2 decades. Risk factors in the pediatric group are broad and appear to be strikingly different compared with the adult cohort. However, the disease burden and impact on quality of life are surprisingly similar in children and adults. This review summarizes the definitions, epidemiology, risk factors, diagnosis, and management of pediatric pancreatitis, identifies features that are unique to the childhood-onset disease, identifies gaps, and proposes recommendations for future opportunities.
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http://dx.doi.org/10.1053/j.gastro.2018.12.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730664PMC
May 2019

INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE Cohort Study: Design and Rationale for INSPPIRE 2 From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer.

Pancreas 2018 Nov/Dec;47(10):1222-1228

Department of Pediatrics, Washington University School of Medicine, St Louis, MO.

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.
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http://dx.doi.org/10.1097/MPA.0000000000001172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195325PMC
March 2019

Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis: Summary of the Working Group on Drug Development and Trials in Chronic Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

Pancreas 2018 Nov/Dec;47(10):1200-1207

Division of Gastroenterology, University of Pittsburgh, Pittsburgh, PA.

The lack of effective therapeutic agents specifically tailored for chronic pancreatitis (CP) 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 2 main outcomes for CP: 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 CP.
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http://dx.doi.org/10.1097/MPA.0000000000001174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196743PMC
March 2019

Rapid Progression of Acute Pancreatitis to Acute Recurrent Pancreatitis in Children.

J Pediatr Gastroenterol Nutr 2019 01;68(1):104-109

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center.

Objective: Research is lacking on the natural history of acute pancreatitis (AP) progression to acute recurrent pancreatitis (ARP). The aim of this project was to study the progression from AP to ARP among pediatric patients with pancreatitis to better understand the presentation and natural history of pancreatitis.

Methods: Patients presenting with AP were included in a prospective database in Research Electronic Data Capture. We enrolled 115 patients with AP from March 2013 to November 2016. Physicians completed surveys regarding clinical data for patients with first attack of AP. Patients were followed prospectively, with data on progression entered when patients presented with ARP.

Results: The most common etiologies for the first attack of AP were idiopathic (31%), toxic/drug-related (23%), and biliary/gallstone (18%). Twenty of the 115 patients (17%) developed ARP during the follow-up period. Seventy percent (14/20) of patients with ARP progressed from AP to ARP within 5 months from first diagnosis. A comparison of patients who rapidly progressed to ARP within 3 months (n = 12) to those followed for >3 months without progression in 3 months (n = 97) revealed associations with a higher weight percentile for age (P = 0.045), male sex (P = 0.03), and presence of pancreatic necrosis during first AP attack (P = 0.004). Progression to ARP significantly differed by etiology group with genetics having the highest risk for ARP progression over time and patients with gallstone/biliary, viral/systemic, and obstructive (nongallstone) having the lowest risk for ARP progression over time (P = 0.02).

Conclusions: Most patients who progressed from AP to ARP progressed within 5 months. The presence of a higher weight percentile for age, male sex, and pancreatic necrosis during the first AP attack are associated with rapid progression to ARP.
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http://dx.doi.org/10.1097/MPG.0000000000002145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310081PMC
January 2019

Impact of Obesity on Pediatric Acute Recurrent and Chronic Pancreatitis.

Pancreas 2018 09;47(8):967-973

Department of Pediatrics, Washington University School of Medicine, St Louis, MO.

Objective: The aim of this study was to assess the impact of obesity on pediatric acute recurrent pancreatitis or chronic pancreatitis (CP).

Methods: We determined body mass index (BMI) status at enrollment in INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) cohort using CDC criteria for pediatric-specific BMI percentiles. We used the Cochran-Armitage test to assess trends and the Jonckheere-Terpstra test to determine associations.

Results: Of 446 subjects (acute recurrent pancreatitis, n = 241; CP, n = 205), 22 were underweight, 258 normal weight, 75 overweight, and 91 were obese. The BMI groups were similar in sex, race, and age at presentation. Hypertriglyceridemia was more common in overweight or obese. Obese children were less likely to have CP and more likely to have acute inflammation on imaging. Compared with children with normal weight, obese or overweight children were older at first acute pancreatitis episode and diagnosed with CP at an older age. Obese or overweight children were less likely to undergo medical or endoscopic treatment, develop exocrine pancreatic insufficiency, and require total pancreatectomy with islet autotransplantation. Diabetes was similar among all groups.

Conclusions: Obesity or overweight seems to delay the initial acute pancreatitis episode and diagnosis of CP compared with normal weight or underweight. The impact of obesity on pediatric CP progression and severity deserves further study.
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http://dx.doi.org/10.1097/MPA.0000000000001120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095802PMC
September 2018

Transient High Pressure in Pancreatic Ducts Promotes Inflammation and Alters Tight Junctions via Calcineurin Signaling in Mice.

Gastroenterology 2018 10 19;155(4):1250-1263.e5. Epub 2018 Jun 19.

Department of Pediatric Gastroenterology, University of Pittsburgh and the Children's Hospital of Pittsburgh of UMPC, Pittsburgh, Pennsylvania. Electronic address:

Background & Aims: Pancreatitis after endoscopic retrograde cholangiopancreatography (PEP) is thought to be provoked by pancreatic ductal hypertension, via unknown mechanisms. We investigated the effects of hydrostatic pressures on the development of pancreatitis in mice.

Methods: We performed studies with Swiss Webster mice, B6129 mice (controls), and B6129 mice with disruption of the protein phosphatase 3, catalytic subunit, βisoform gene (Cnab mice). Acute pancreatitis was induced in mice by retrograde biliopancreatic ductal or intraductal infusion of saline with a constant hydrostatic pressure while the proximal common bile duct was clamped -these mice were used as a model of PEP. Some mice were given pancreatic infusions of adeno-associated virus 6-nuclear factor of activated T-cells-luciferase to monitor calcineurin activity or the calcineurin inhibitor FK506. Blood samples and pancreas were collected at 6 and 24 hours and analyzed by enzyme-linked immunosorbent assay, histology, immunohistochemistry, or fluorescence microscopy. Ca signaling and mitochondrial permeability were measured in pancreatic acinar cells isolated 15 minutes after PEP induction. Ca-activated phosphatase calcineurin within the pancreas was tracked in vivo over 24 hours.

Results: Intraductal pressures of up to 130 mm Hg were observed in the previously reported model of PEP; we found that application of hydrostatic pressures of 100 and 150 mm Hg for 10 minutes consistently induced pancreatitis. Pancreatic tissues had markers of inflammation (increased levels of interleukin [IL] 6, IL1B, and tumor necrosis factor), activation of signal transducer and activator of transcription 3, increased serum amylase and IL6, and loss of tight junction integrity. Transiently high pressures dysregulated Ca processing (reduced Ca oscillations and an increased peak plateau Ca signal) and reduced the mitochondrial membrane potential. We observed activation of pancreatic calcineurin in the pancreas in mice. Cnab mice, which lack the catalytic subunit of calcineurin, and mice given FK506 did not develop pressure-induced pancreatic inflammation, edema, or loss of tight junction integrity.

Conclusions: Transient high ductal pressure produces pancreatic inflammation and loss of tight junction integrity in a mouse model of PEP. These processes require calcineurin signaling. Calcineurin inhibitors might be used to prevent acute pancreatitis that results from obstruction.
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http://dx.doi.org/10.1053/j.gastro.2018.06.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174093PMC
October 2018

New Management Guidelines for Both Children and Adults With Acute Pancreatitis.

Gastroenterology 2018 07 8;155(1):234-235. Epub 2018 Jun 8.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, McGill University, Montreal, Canada.

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http://dx.doi.org/10.1053/j.gastro.2018.03.068DOI Listing
July 2018

Pancreas Divisum in Pediatric Acute Recurrent and Chronic Pancreatitis: Report From INSPPIRE.

J Clin Gastroenterol 2019 07;53(6):e232-e238

Department of Pediatrics, Stead Family Children's Hospital, University of Iowa, Iowa City, IA.

Introduction: The significance of pancreas divisum (PD) as a risk factor for pancreatitis is controversial. We analyzed the characteristics of children with PD associated with acute recurrent or chronic pancreatitis to better understand its impact.

Patients And Methods: We compared children with or without PD in the well-phenotyped INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) cohort. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables, Pearson χ or Fisher exact test for categorical variables.

Results: PD was found in 52 of 359 (14.5%) subjects, a higher prevalence than the general population (∼7%). Females more commonly had PD (71% vs. 55%; P=0.02). Children with PD did not have a higher incidence of mutations in SPINK1, CFTR, CTRC compared with children with no PD. Children with PD were less likely to have PRSS1 mutations (10% vs. 34%; P<0.01) or a family history of pancreatitis (P<0.05), and more likely to have hypertriglyceridemia (11% vs. 3%; P=0.03). Children with PD underwent significantly more endoscopic procedures and pancreatic sphincterotomy. Patients with PD had fewer attacks of acute pancreatitis (P=0.03) and were less likely to develop exocrine pancreatic insufficiency (P=0.01). Therapeutic endoscopic retrograde cholangiopancreatography was considered most helpful if pancreatic duct was impacted with stones (83% helpful).

Conclusions: PD is likely a risk factor for acute recurrent pancreatitis and chronic pancreatitis in children that appears to act independently of genetic risk factors. Patients with PD and stones obstructing the pancreatic duct benefit most from therapeutic endoscopic retrograde cholangiopancreatography.
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http://dx.doi.org/10.1097/MCG.0000000000001063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275137PMC
July 2019

Recommendations for Diagnosis and Management of Autoimmune Pancreatitis in Childhood: Consensus From INSPPIRE.

J Pediatr Gastroenterol Nutr 2018 08;67(2):232-236

Hospital for Sick Children, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1097/MPG.0000000000002028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059991PMC
August 2018

Pancreatic gene expression during recovery after pancreatitis reveals unique transcriptome profiles.

Sci Rep 2018 01 23;8(1):1406. Epub 2018 Jan 23.

Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15224, USA.

It is well known that pancreatic recovery after a single episode of injury such as an isolated bout of pancreatitis occurs rapidly. It is unclear, however, what changes are inflicted in such conditions to the molecular landscape of the pancreas. In the caerulein hyperstimulation model of pancreatitis, the murine pancreas has the ability to recover within one week based on histological appearance. In this study, we sought to characterize by RNA-sequencing (RNA-seq) the transcriptional profile of the recovering pancreas up to two weeks post-injury. We found that one week after injury there were 319 differentially expressed genes (DEGs) compared with baseline and that after two weeks there were 53 DEGs. Forty (12.5%) of the DEGs persisted from week one to week two, and another 13 DEGs newly emerged in the second week. Amongst the top up-regulated DEGs were several trypsinogen genes (trypsinogen 4, 5, 12, 15, and 16). To our knowledge, this is the first characterization of the transcriptome during pancreatic recovery by deep sequencing, and it reveals on a molecular basis that there is an ongoing recovery of the pancreas even after apparent histological resolution. The findings also raise the possibility of an emerging novel transcriptome upon pancreatic recovery.
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http://dx.doi.org/10.1038/s41598-018-19392-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780441PMC
January 2018