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To determine if islet autotransplantation (IAT) independently improves the quality of life (QoL) in patients after total pancreatectomy and islet autotransplantation (TP-IAT).TP-IAT is increasingly being used for intractable chronic pancreatitis. However, the impact of IAT on long-term islet function and QoL is unclear.TP-IAT patients at our center1 year after TP-IAT with ≥1 Short Form-36 QoL measure were included. Patients were classified as insulin-independent or insulin-dependent, and as having islet graft function or failure by C-peptide. The associations of insulin use and islet graft function with QoL measures were analyzed by using a linear mixed model, accounting for time since transplant and within-person correlation.Among 817 islet autograft recipients, 564 patients [median (interquartile range) age: 34 (20, 45) years, 71% female] and 2161 total QoL surveys were included. QoL data were available for5 years after TP-IAT for 42.7% and for10 years for 17.3%. Insulin-independent patients exhibited higher QoL in 7 of 8 subscale domains and for Physical Component Summary and Mental Component Summary scores ( P0.05 for all). Physical Component Summary was 2.91 (SE=0.57) higher in insulin-independent patients ( P0.001). No differences in QoL were observed between those with and without graft function, but islet graft failure was rare (15% of patients). However, glycosylated hemoglobin was much higher with islet graft failure.QoL is significantly improved when insulin independence is present, and glycosylated hemoglobin is lower with a functioning islet graft. These data support offering IAT, rather than just performing total pancreatectomy and treating with exogenous insulin.

BACKGROUND Total pancreatectomy with islet autotransplantation (TPIAT) involves pancreatectomy, splenectomy, and reinjection of the patient's pancreatic islets into the portal vein. This process triggers a local inflammatory reaction and increase in portal pressure, threatening islet survival and potentially causing portal vein thrombosis. Recent research has highlighted a high frequency of extreme thrombocytosis (platelets ≥1000 × 109/L) after TPIAT, but its cause and association with thrombotic risk remain unclear. METHODS This retrospective single-site study of a contemporary cohort of 409 pediatric and adult patients analyzed the frequency of thrombocytosis, risk factors for thrombosis, and antiplatelet and anticoagulation strategies. RESULTS Of 409 patients, 67% developed extreme thrombocytosis, peaking around postoperative day 16. Extreme thrombocytosis was significantly associated with infused islet volumes. Thromboembolic events occurred in 12.2% of patients, with portal vein thromboses occurring significantly earlier than peripheral thromboses. Portal vein thromboses were associated with infused islet volumes and portal pressures but not platelet counts or other measures. Most thromboembolic events (82.7%) occurred before the postoperative day of maximum platelet count. Only 4 of 27 (14.8%) of portal vein thromboses occurred at platelet counts ≥500 × 109/L. Perioperative heparin was given to all patients. Treatment of reactive thrombocytosis using aspirin in adults and hydroxyurea in children was not associated with significantly decreased thromboembolic risk. CONCLUSIONS These results suggest that post-TPIAT thrombocytosis and portal vein thromboses may be linked to the islet infusion inflammation, not directly to each other, and further reducing this inflammation may reduce thrombosis and thrombocytosis frequencies simultaneously.

A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities in pancreatic pain. The event was held on July 21, 2021, and structured into 4 sessions: (1) pathophysiology; (2) biomarkers, mediators, and pharmacology of pain; (3) pain assessment; and (4) pain treatment challenges and opportunities. The current state of knowledge was reviewed; many knowledge gaps and research needs were identified that require further investigation. Common themes included the need to better understand the underlying mechanisms of pain in pancreatic diseases, the relationship of visceral neural pathways and central pain centers, the role of behavioral factors and disorders on the perception of pain, and differences in pain perception and processes in children when compared with adults. In addition, the role of genetic risk factors for pain and the mechanisms and role of placebos in pain treatment were discussed. Methods of pain assessment including quantitative sensory testing were examined, as well as the process of central sensitization of pain. Finally, newer approaches to pain management including cognitive behavioral therapy, nerve stimulation, experimental (nonopioid) drugs, and cannabinoid compounds were covered.

The prevalence of fat-soluble vitamin (FSV) deficiency in children undergoing total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis (CP) is unknown. We quantified FSV deficiency in 100 children (age ≤18) undergoing TPIAT. FSV levels (vitamins A, E, D) and clinical history were abstracted from medical records. Vitamin A was low in 4% before and 7% at 1 year after TPIAT, vitamin E in 17% and 18%, and vitamin D in 22% and 24%, respectively, regardless of pancreatic enzyme or vitamin supplement dosing. Longer duration of CP was associated with pre-TPIAT vitamin D insufficiency (P = 0.0002). This remained significant in a multivariate regression model (adjusted P = 0.01). On multivariate analysis, there were no significant predictors of low FSV levels post-TPIAT. FSV deficiencies are common among children undergoing TPIAT and patients who have had longer disease duration may be at increased risk. All children should be monitored for FSV deficiency after TPIAT.

OBJECTIVES The objective of this study was to evaluate potential safety and clinical benefit of low-molecular-weight dextran (dextran) use in patients undergoing total pancreatectomy with islet auto transplantation (TPIAT). METHODS We evaluated 124 children undergoing TPIAT at a single institution, either with (n = 72) or without (n = 52) perioperative dextran infusion. Data on islet graft function and postoperative complications were collected through electronic medical records and patient-reported outcomes from research questionnaires. RESULTS Islet graft failure was less likely at 1 year (odds ratio, 0.186; 95% confidence interval, 0.04-0.65) and 2 years (odds ratio, 0.063; 95% confidence interval, 0.003-0.35) post-TPIAT in the dextran group. This finding remained significant at 2 years in multivariate logistic regression modeling adjusting for islet mass, body surface area, and sex. Likewise, in multivariate regression, the odds of partial islet graft function were higher at 1 and 2 years in the dextran group. Dextran use was overall safe, although it did lead to a higher incidence of postoperative bleeding requiring blood transfusions (P < 0.001). CONCLUSIONS These findings suggest that dextran use may increase the likelihood for sustained post-TPIAT islet graft function, potentially mitigating severity of postoperative diabetes for these children.

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.

Background A total pancreatectomy and intraportal islet cell autotransplant (TPIAT) is increasingly being offered to patients with chronic pancreatitis (CP). The benefits include removal of the root cause of pain and amelioration of diabetes. However, the long-term durability of this operation remains unclear. Study Design Of the 742 patients who have undergone a TPIAT at our center, 215 who did so between 1998 and 2008 now have at least 10 years of follow-up time and were eligible for this single-center observational study. Our outcomes measures included abdominal pain relief, narcotic use, islet graft function (subdivided into 3 groups: insulin independence; partial graft function, defined by C-peptide level > 0.6 mg/dL; and no function, defined by C-peptide level Results The 10-year actuarial survival rate was 72%. A BMI > 30 kg/m2 (p = 0.04) predicted 10-year mortality. The rates of pain relief were 82% at 10 years and 90% at 15 years. Narcotic use declined with time: the rates were 50% at 5 years and 37% at 10 years. At 10 years, the rate of insulin independence was 20%; the rate of partial graft function, 32%. Transplantation of islet equivalents/kg > 4,000 was the strongest predictor of islet graft function at 10 years. Pediatric patients were more likely to have islet function than adults (p = 0.01). Health-related quality of life continued to improve at 10 years, even in patients on narcotics. Conclusions This represents the first and largest series to examine long-term outcomes (10 years or more) in TPIAT patients. In our series, this dual procedure produced durable pain relief and sustained islet graft function, even past 10 years postoperatively.

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.

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.

OBJECTIVES Chronic pancreatitis (CP) is an infrequent but debilitating complication associated with CFTR mutations. Total pancreatectomy with islet autotransplantation (TPIAT) is a treatment option for CP that provides pain relief and preserves β-cell mass, thereby minimizing the complication of diabetes mellitus. We compared outcomes after TPIAT for CP associated with CFTR mutations to CP without CTFR mutations. METHODS All TPIATs performed between 2002 and 2014 were retrospectively reviewed: identifying 20 CFTR homozygotes (cystic fibrosis [CF] patients), 19 CFTR heterozygotes, and 20 age-/sex-matched controls without CFTR mutations. Analysis of variance and χ tests were used to compare groups. RESULTS Baseline demographics were not different between groups. Postoperative glycosylated hemoglobin and C-peptide levels were similar between groups, as were islet yield and rate of postoperative complications. At 1 year, 40% of CF patients, 22% of CFTR heterozygotes, and 35% of control patients were insulin independent. CONCLUSION Total pancreatectomy with islet autotransplantation is a safe, effective treatment option for CF patients with CP, giving similar outcomes for those with other CP etiologies.

Objectives:Fear of diabetes and major surgery may prohibit referral of young children severely affected by pancreatitis for total pancreatectomy with islet autotransplant (TPIAT). We evaluated outcomes in our youngest TPIAT recipients, 3 to 8 years of age at surgery.Methods:Medical records w

ObjectivesAcute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) have been diagnosed in children at increasing rates during the past decade. As pediatric ARP and CP are still relatively rare conditions, little quality evidence is available on which to base the diagnosis and determination of etiology. The aim of the study was to review the current state of the literature regarding the etiology of these disorders and to developed a consensus among a panel of clinically active specialists caring for children with these disorders to help guide the diagnostic evaluation and identify areas most in need of future research.MethodsA systematic review of the literature was performed and scored for quality, followed by consensus statements developed and scored by each individual in the group for level of agreement and strength of the supporting data using a modified Delphi method. Scores were analyzed for the level of consensus achieved by the group.ResultsThe panel reached consensus on 27 statements covering the definitions of pediatric ARP and CP, evaluation for potential etiologies of these disorders, and long-term monitoring. Statements for which the group reached consensus to make no recommendation or could not reach consensus are discussed.ConclusionsThis consensus helps define the minimal diagnostic evaluation and monitoring of children with ARP and CP. Even in areas in which we reached consensus, the quality of the evidence is weak, highlighting the need for further research. Improved understanding of the underlying cause will facilitate treatment development and targeting.

Diagnosis of non-calcific chronic pancreatitis (NCCP) in patients presenting with chronic abdominal pain is challenging and controversial. Contrast-enhanced magnetic resonance imaging (MRI) with secretin-stimulated MRCP (sMRCP) offers a safe and noninvasive modality to diagnose mild CP, but its findings have not been correlated with histopathology. We aimed to assess the correlation of a spectrum of MRI/sMRCP findings with surgical histopathology in a cohort of NCCP patients undergoing total pancreatectomy with islet autotransplantation (TPIAT).Adult patients undergoing TPIAT for NCCP between 2008 and 2013 were identified from our institution's surgery database and were included if they had MRI/sMRCP within a year before surgery. Histology was obtained from resected pancreas at the time of TPIAT by wedge biopsy of head, body, and tail, and was graded by a gastrointestinal pathologist who was blinded to the imaging features. A fibrosis score (FS) of 2 or more was considered as abnormal, with FS ≥6 as severe fibrosis. A multivariate regression analysis was performed for MRI features predicting fibrosis, after taking age, sex, smoking, alcohol, and body mass index (BMI) into consideration. A quantitative receiver operating characteristic (ROC) curve analysis was performed and Spearman rank correlation coefficient (r) was calculated.Fifty-seven patients (females=49, males=8) with NCCP and MRI/sMRCP were identified. ROC curve analysis showed that two or more MRI/sMRCP features provided the best balance of sensitivity (65%), specificity (89%), and accuracy (68%) to differentiate abnormal (FS≥2) from normal pancreatic tissue. Two or more features provided the best cutoff (sensitivity 88%, specificity 78%) for predicting severe fibrosis (FS≥6). There was a significant correlation between the number of features and severity of fibrosis (r=0.6, P0.0001). A linear regression after taking age, smoking, and BMI into consideration showed that main pancreatic duct irregularity, T1-weighted signal intensity ratio between pancreas and paraspinal muscle, and duodenal filling after secretin injection to be significant independent predictors of fibrosis.A strong correlation exists between MRI/sMRCP findings and histopathology of NCCP.

A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases focused on research gaps and opportunities in total pancreatectomy with islet autotransplantation (TPIAT) for the management of chronic pancreatitis (CP). The session was held on July 23, 2014, and structured into 5 sessions: (1) patient selection, indications, and timing; (2) technical aspects of TPIAT; (3) improving success of islet autotransplantation; (4) improving outcomes after total pancreatectomy; and (5) registry considerations for TPIAT. The current state of knowledge was reviewed; knowledge gaps and research needs were specifically highlighted. Common themes included the need to identify which patients best benefit from and when to intervene with TPIAT, current limitations of the surgical procedure, diabetes remission and the potential for improvement, opportunities to better address pain remission, gastrointestinal complications in this population, and unique features of children with CP considered for TPIAT. The need for a multicenter patient registry that specifically addresses the complexities of CP and total pancreatectomy outcomes as well as postsurgical diabetes outcomes was repeatedly emphasized.

Describe the surgical technique, complications, and long-term outcomes of total pancreatectomy and islet autotransplantation (TP-IAT) in a large series of pediatric patients.Surgical management of childhood pancreatitis is not clear; partial resection or drainage procedures often provide transient pain relief, but long-term recurrence is common due to the diffuse involvement of the pancreas. Total pancreatectomy (TP) removes the source of the pain, whereas islet autotransplantation (IAT) potentially can prevent or minimize TP-related diabetes.Retrospective review of 75 children undergoing TP-IAT for chronic pancreatitis who had failed medical, endoscopic, or surgical treatment between 1989 and 2012.Pancreatitis pain and the severity of pain statistically improved in 90% of patients after TP-IAT (P0.001). The relief from narcotics was sustained. Of the 75 patients undergoing TP-IAT, 31 (41.3%) achieved insulin independence. Younger age (P = 0.032), lack of prior Puestow procedure (P = 0.018), lower body surface area (P = 0.048), higher islet equivalents (IEQ) per kilogram body weight (P = 0.001), and total IEQ (100,000) (P = 0.004) were associated with insulin independence. By multivariate analysis, 3 factors were associated with insulin independence after TP-IAT: (1) male sex, (2) lower body surface area, and (3) higher total IEQ per kilogram body weight. Total IEQ (100,000) was the single factor most strongly associated with insulin independence (odds ratio = 2.62; P0.001).Total pancreatectomy and islet autotransplantation provides sustained pain relief and improved quality of life. The β-cell function is dependent on islet yield. Total pancreatectomy and islet autotransplantation is an effective therapy for children with painful pancreatitis that failed medical and/or endoscopic management.