The instant blood-mediated inflammatory response (IBMIR) causes islet loss and compromises diabetes outcomes after total pancreatectomy with islet autotransplant (TPIAT). We previously reported a possible benefit of etanercept in maintaining insulin secretion 3 months post-TPIAT. Here, we report 2-year diabetes outcomes and peri-operative inflammatory profiles from a randomized trial of etanercept and alpha-1 antitrypsin (A1AT) in TPIAT. We randomized 43 TPIAT recipients to A1AT (90 mg/kg IV x6 doses, n = 13), etanercept (50 mg then 25 mg SQ x 5 doses, n = 14), or standard care (n = 16). Inflammatory cytokines, serum A1AT and unmethylated insulin DNA were drawn multiple times in the perioperative period. Islet function was assessed 2 years after TPIAT with mixed meal tolerance test, intravenous glucose tolerance test and glucose-potentiated arginine induced insulin secretion. Cytokines, especially IL-6, IL-8, IL-10, and MCP-1, were elevated during and after TPIAT. However, only TNFα differed significantly between groups, with highest levels in the etanercept group (p = 0.027). A1AT increased after IAT in all groups (p < 0.001), suggesting endogenous upregulation. Unmethylated insulin DNA ratios (a marker of islet loss) and 2 years islet function testing were similar in the three groups. To conclude, we found no sustained benefit from administering etanercept or A1AT in the perioperative period.

Children with intractable chronic pancreatitis may require total pancreatectomy with islet autotransplantation (TPIAT) for pain relief. The IAT reduces the severity of post- pancreatectomy diabetes. We analyzed 635 mixed meal tolerance tests (MMTT) in 134 children undergoing TPIAT to determine whether superior survival of islet grafts explains higher rates of insulin independence previously reported in young children (n = 52, age 3-11 years) versus adolescents (n = 82, age 12-18 years). For MMTT, children consumed Boost HP and we sampled C-peptide and glucose repeatedly over 2 h. The trajectory of outcomes before and after TPIAT was compared between children and adolescents using data from pre-TPIAT and 3, 6 months, 1, 2, 3, and 4 years post-TPIAT and mixed linear models with a random effect for child. Cox regression was used to analyze time outcomes (e.g., time to first off insulin). Islet mass transplanted, measured as islet equivalents (IEQ), was higher in adolescents (p = .003) but IEQ/kg was higher in young children (p < .001) because of their lower weight. AUC C-peptide in young children increased somewhat over 4 years, but was stable in adolescents (p = .0013). AUC glucose increased more in adolescents over time post-TPIAT (p = .0024). Islet function by AUC C-peptide:AUC glucose ratio was better preserved in young children (p < .001). Adolescents were less likely to wean off insulin (hazard ratio .44 [95% CI .28, .69]). These data support an advantage of young age in islet graft survival after TPIAT. The greater likelihood of insulin independence in young children may be driven by better islet survival after transplant.

We previously published that insulin pump initiation immediately after IV insulin therapy was associated with improved post-surgical glycemic outcomes compared to multiple daily injections (MDI) in pediatric patients following a total pancreatectomy with islet autotransplantation (TPIAT). We investigated metabolic outcomes of this population at one-year post-TPIAT to assess if the improved outcomes in the early pump group were sustained over time. We retrospectively reviewed 40 patients post-TPIAT previously studied at 10-days post-surgery (15 used MDI and 25 used pump therapy immediately post-ICU, and all were discharged on pump therapy). Data analyzed included: demographics, islet equivalents per kilogram (IEQ/kg) transplanted, exogenous insulin use, and baseline vs. one-year (via mixed meal testing) HbA1c, fasting glucose, insulinogenic index, and the area under the curve (AUC) for insulin and c-peptide. More patients were off insulin at one year in the early pump group compared to the MDI group (45% vs. 13%, p = 0.07). Of all patients off insulin, 100% of the early pump users weaned off by six months post-TPIAT compared to 30% of the MDI users. Two known variables associated with favorable insulin outcomes, lower age and higher IEQ/kg, were not significantly different between groups. Fasting glucose was lower in the early pump group compared to the MDI group (median 97 vs. 122 mg/dL, p = 0.003), while AUC c-peptide was greater in early pump users at one-year post-TPIAT but did not reach significance (median 57.0 vs. 50.3 ng/mL × minutes, p = 0.14). Other metabolic outcomes did not differ between groups. Despite lower median age and higher IEQ/kg in the MDI group, the early pump group had a lower fasting glucose. Younger TPIAT age (p = 0.02) and early pump users (p = 0.04) were significantly associated with insulin independence at one year. This study was limited by sample size. Early pump use may have long-term benefits in post-TPIAT endogenous insulin secretion.

BACKGROUND: In total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence.
METHODS: We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT.
RESULTS: We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females.
CONCLUSIONS: Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment.
UNASSIGNED: This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).

Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical procedure undertaken in some patients with severe pain or disability from recurrent acute and chronic pancreatitis (CP). TPIAT provides a rare opportunity to study human pancreas tissue from patients affected with pancreatitis, and particularly from patients with genetic forms of pancreatitis. Research to date suggests distinct histopathology and potentially differential pathophysiology of distinct etiologies of CP. Histopathology specimens have helped better define the success and limitations of clinical diagnostic imaging tools, such as magnetic retrograde cholangiopancreatography and endoscopic ultrasound.

Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical procedure for patients with chronic pancreatitis and poor quality of life. Euglycemia is critical for islet cell survival and engraftment. We reviewed clinical care practice and hypothesized that early in-hospital transition from intravenous insulin to insulin pump therapy, managed by an endocrine unit trained on post-surgical care, would improve glucose control and impact the length of hospital stay. We completed a retrospective analysis of 40 pediatric patients who underwent TPIAT. Comparative hospitalized postoperative groups included those who received insulin intravenously, followed by multiple daily injections, subsequently managed by pump therapy (n = 14), versus those who received insulin intravenously followed by early pump therapy provided on the endocrine unit trained to manage post-surgical patients (n = 26). The outcomes analyzed included percentage of blood glucoses in target (4.44-6.66 mmol/L (80-120 mg/dL)), hypoglycemia (<3.33 mmol/L (<60 mg/dL)) and hyperglycemia (>7.77 mmol/L (>140 mg/dL)), blood glucose variability, and length of hospital unit stay post-ICU. Hospitalized patients with early transition to pump therapy on a specialized endocrine unit had a higher proportion of glucose values in the target range (61% vs. 51%, p = 0.0003), a lower proportion of hyperglycemia (15% vs. 19%, p = 0.04), and a lower proportion of hypoglycemia, though not statistically significant (3.4% vs. 4.4%, p = 0.33). Early pump users also had lower variability in glucose values over 10 days post-intravenous insulin (p = 0.001), and the post-transition median length of stay was shorter by 5 days (median: 11.5 vs. 16.5 days, p = 0.005). Early in-hospital pump therapy managed by the specialized endocrine unit improved glucose outcomes and reduced the duration of in-unit stay.

Several cytokines and chemokines are elevated after islet infusion in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT), including CXCL8 (also known as interleukin-8), leading to islet loss. We investigated whether use of reparixin for blockade of the CXCL8 pathway would improve islet engraftment and insulin independence after TPIAT. Adults without diabetes scheduled for TPIAT at nine academic centers were randomized to a continuous infusion of reparixin or placebo (double-blinded) for 7 days in the peri-transplant period. Efficacy measures included insulin independence (primary), insulin dose, hemoglobin A1c (HbA1c ), and mixed meal tolerance testing. The intent-to-treat population included 102 participants (age 39.5 ± 12.2 years, 69% female), n = 50 reparixin-treated, n = 52 placebo-treated. The proportion insulin-independent at Day 365 was similar in reparixin and placebo: 20% vs. 21% (p = .542). Twenty-seven of 42 (64.3%) in the reparixin group and 28/45 (62.2%) in the placebo group maintained HbA1c ≤6.5% (p = .842, Day 365). Area under the curve C-peptide from mixed meal testing was similar between groups, as were adverse events. In conclusion, reparixin infusion did not improve diabetes outcomes. CXCL8 inhibition alone may be insufficient to prevent islet damage from innate inflammation in islet autotransplantation. This first multicenter clinical trial in TPIAT highlights the potential for future multicenter collaborations.

BACKGROUND: Chronic pancreatitis (CP) is associated with poor quality of life. Total pancreatectomy with islet autotransplantation (TPIAT) has traditionally been reserved for patients with refractory disease. We hypothesized TPIAT would lead to decreased costs and resource utilization after operation in children.
METHODS: Retrospective review of 39 patients who underwent TPIAT at a single children\'s hospital was performed. All inpatient admissions, imaging, endoscopic procedures, and operations were recorded for the year prior to and following operation. Costs were determined from Centers for Medicare and Medicaid Services.
RESULTS: Median hospital admissions before operation was 5 (IQR:2-7) and decreased to 2 (IQR:1-3) after (p < 0.01). Median total cost for the year before operation was $36,006 (IQR:$19,914-$47,680), decreasing to $24,900 postoperatively (IQR:$17,432-$44,005, p = 0.03). Removing cost of TPIAT itself, total cost was further reduced to $10,564 (IQR:$3096-$29,669, p < 0.01).
CONCLUSIONS: In children with debilitating CP, TPIAT has favorable impact on cost reduction, hospitalizations, and invasive procedures. Early intervention at a specialized pancreas center of excellence should be considered to decrease future resource utilization and costs among children.

We present a patient with intractable and debilitating pain secondary to chronic pancreatitis who was effectively treated with total pancreatectomy with islet autotransplantation (TPIAT). Islets engrafted into his liver significantly contributed to improved blood glucose control and quality of life. Subsequently, the patient developed alcohol related acute liver failure and en bloc liver and pancreas transplantation was performed to replace the failing liver with engrafted islets. Pancreas transplantation was required to resolve his life-threatening severe hypoglycemic episodes. Herein, we detail an innovative and multidisciplinary management of this complex medical problem.

BACKGROUND: Predicting post-operative glycemic control in children undergoing total pancreatectomy with islet autotransplantation (TPIAT) remains difficult. The purpose of our study was to explore preoperative imaging as a marker for islet yield and insulin need in pediatric patients undergoing TPIAT.
METHODS: This was a retrospective study of children (≤18 years) who had undergone TPIAT between April 2015 and December 2018 and had 6 or more months of post-TPIAT follow-up. Patient specific factors (height, weight, body mass index [BMI], body surface area [BSA]) and pancreas volume segmented from the most recent pre-operative cross-sectional imaging were explored as predictors of islet yield (total islet counts [TIC], total islet equivalents [TIE], islet equivalents per kilogram body weight [IEQ/kg]) and glycemic control (total daily dose of insulin per kilogram body weight [TDD/kg], insulin independence) using Pearson correlation and univariate and multiple regression.
RESULTS: Thirty-three patients, median age 13 years (IQR: 10-15 years), 64% female (21/33) met inclusion criteria. Nine patients (27%) achieved insulin independence at six months. Median TIE isolated was 310,000 (IQR: 200,000-460,000). Segmented pancreas volume was moderately associated with TIE (coefficient estimate = 0.34, p = 0.034). On multiple regression analysis, there was no significant predictor of insulin independence but number of attacks of pancreatitis (estimate = 0.024; p = 0.018) and segmented pancreas volume by body weight (estimate = -0.71; p < 0.001) were significant predictors of insulin TDD/kg.
CONCLUSIONS: Pancreas volume segmented from pre-TPIAT imaging has predictive performance for post-TPIAT insulin need in children.