Faculty Bibliography

OBJECTIVES:A selective therapy for pancreatitis is total pancreatectomy and islet autotransplantation. Outcomes and geographical variability of patients who had total pancreatectomy (TP) alone or total pancreatectomy with islet autotransplantation (TPIAT) were assessed. METHODS:Data were obtained from the Healthcare Cost and Utilization Project National Inpatient Sample database. Weighed univariate and multivariate analyses were performed to determine the effect of measured variables on outcomes. RESULTS:Between 2002 and 2013, there were 1006 TP and 825 TPIAT in patients with a diagnosis of chronic pancreatitis, and 1705 TP and 830 TPIAT for any diagnosis of pancreatitis. The majority of the TP and TPIAT were performed in larger urban hospitals. Costs were similar for TP and TPIAT for chronic pancreatitis but were lower for TPIAT compared with TP for any type of pancreatitis. The trend for TP and TPIAT was significant in all geographical areas during the study period. CONCLUSIONS:There is an increasing trend of both TP and TPIAT. Certain groups are more likely to be offered TPIAT compared with TP alone. More data are needed to understand disparities and barriers to TPIAT, and long-term outcomes of TPIAT such as pain control and glucose intolerance need further study.

Stresses encountered during human islet isolation lead to unavoidable β-cell death after transplantation. This reduces the chance of insulin independence in chronic pancreatitis patients undergoing total pancreatectomy and islet autotransplantation. We tested whether harvesting islets in carbon monoxide-saturated solutions is safe and can enhance islet survival and insulin independence after total pancreatectomy and islet autotransplantation. Chronic pancreatitis patients who consented to the study were randomized into carbon monoxide (islets harvested in a carbon monoxide-saturated medium) or control (islets harvested in a normal medium) groups. Islet yield, viability, oxygen consumption rate, β-cell death (measured by unmethylated insulin DNA), and serum cytokine levels were measured during the peri-transplantation period. Adverse events, metabolic phenotypes, and islet function were measured prior and at 6 months post-transplantation. No adverse events directly related to the infusion of carbon monoxide islets were observed. Carbon monoxide islets showed significantly higher viability before transplantation. Subjects receiving carbon monoxide islets had less β-cell death, decreased CCL23, and increased CXCL12 levels at 1 or 3 days post transplantation compared with controls. Three in 10 (30%) of the carbon monoxide subjects and none of the control subjects were insulin independent. This pilot trial showed for the first time that harvesting human islets in carbon monoxide-saturated solutions is safe for total pancreatectomy and islet autotransplantation patients.

OBJECTIVES:Many patients with recurrent acute and chronic pancreatitis who are candidates for total pancreatectomy and islet cell autotransplantation (TPIAT) undergo endoscopic retrograde cholangiopancreatography (ERCP). However, little is known on the impact of ERCP on TPIAT outcomes. We aimed to explore the effect of antecedent ERCP on islet yield and postoperative insulin requirement after TPIAT. METHODS:Through a prospectively maintained database, we identified patients who underwent TPIAT at our institution between 2009 and 2016. After adjusting for confounders, islet cell yield and postoperative insulin requirement were compared between subjects who did and did not undergo ERCP within 2 years prior to TPIAT. RESULTS:Data were available on 167 TPIAT patients during the study period; 105 (62.9%) had undergone ERCP within 2 years prior. Prior ERCP was not associated with a reduction in islet equivalents per patient kilogram (odds ratio, 1.37; 95% confidence interval, 0.75-2.5; P = 0.31). Antecedent ERCP was not associated with increased postoperative insulin requirement among patients with no diabetes undergoing TPIAT (odds ratio, 0.85; 95% confidence interval, 0.39-1.83; P = 0.67). CONCLUSIONS:Antecedent ERCP does not appear to have a deleterious impact on islet cell yield during TPIAT. Additional multicenter data are needed to more clearly determine the impact of ERCP in this context.

BACKGROUND AND AIMS/OBJECTIVE:ERCP has largely replaced common bile duct exploration for therapy of common bile duct pathology, yet its use as a purely diagnostic test has declined. Among inpatients, we hypothesized that timing between ERCP and cholecystectomy (CCY) has changed. The objectives were to measure temporal trends in the timing between inpatient ERCP and CCY and to examine factors associated with delays. METHODS:We used the National Inpatient Sample between 1998 and 2013 to classify admissions for gallstone-related diagnoses undergoing inpatient CCY and ERCP by timing relative to CCY: within (±) 1 day, ≥2 days before, and ≥2 days after. Logistic regression and Poisson regression were used to determine pattern utilization and association of ERCP timing on hospital length of stay. RESULTS:Between 1998 and 2013, the proportion of admissions for CCY associated with same-stay ERCP increased (14.5% in 1998 to 17.3% in 2013, P < .001), and approximately two-thirds of ERCPs were performed within 1 day of CCY. After adjusting for covariates, the mean adjusted length of stay remained significantly shorter for patients who underwent CCY within 1 day of ERCP (5.13 vs 7.48 days for ERCP ≥2 days before and vs 7.41 days for ERCP ≥2 days after, P < .001). CONCLUSIONS:Use of inpatient ERCP in conjunction with CCY has increased minimally between 1998 and 2013, whereas length of stay has decreased. ERCPs performed within 1 day of CCY were associated with shorter hospital length of stay, suggesting delays between inpatient procedures should be minimized unless medical comorbidities preclude it.

BACKGROUND/OBJECTIVES/OBJECTIVE:Total pancreatectomy with islet autotransplantation (TPIAT) is considered for managing chronic pancreatitis in selected patients when medical and endoscopic interventions have not provided adequate relief from debilitating pain. Although more centers are performing TPIAT, we lack large, multi-center studies to guide decisions about selecting candidates for and timing of TPIAT. METHODS:Multiple centers across the United States (9 to date) performing TPIAT are prospectively enrolling patients undergoing TPIAT for chronic pancreatitis into the Prospective Observational Study of TPIAT (POST), a NIDDK funded study with a goal of accruing 450 TPIAT recipients. Baseline data include participant phenotype, pancreatitis history, and medical/psychological comorbidities from medical records, participant interview, and participant self-report (Medical Outcomes Survey Short Form-12, EQ-5D, andPROMIS inventories for pain interference, depression, and anxiety). Outcome measures are collected to at least 1 year after TPIAT, including the same participant questionnaires, visual analog pain scale, pain interference scores, opioid requirements, insulin requirements, islet graft function, and hemoglobin A1c. Health resource utilization data are collected for a cost-effectiveness analysis. Biorepository specimens including urine, serum/plasma, genetic material (saliva and blood), and pancreas tissue are collected for future study. CONCLUSIONS:This ongoing multicenter research study will enroll and follow TPIAT recipients, aiming to evaluate patient selection and timing for TPIAT to optimize pain relief, quality of life, and diabetes outcomes, and to measure the procedure's cost-effectiveness. A biorepository is also established for future ancillary studies.

BACKGROUND:Best practice to select patients with chronic pancreatitis for surgical management with total pancreatectomy with islet autotransplantation (TPIAT) is in evolution as new discoveries are made in the pathogenesis of chronic pancreatitis. STUDY DESIGN:A prospectively maintained database of patients undergoing TPIAT was reviewed. Islet function was inferred from daily insulin requirement. Pain relief was evaluated by healthcare use and narcotic use. Quality of life (QOL) was measured with the RAND 12-Item Short Form Survey. RESULTS:) underwent TPIAT. Mean duration of disease before operation was 8.1 years. Fifty-six (29%) patients had pancreatic operations before TPIAT, 37 (19%) patients were diabetic preoperatively, and 52 (27%) patients were smokers. A mean of 3,253 islet equivalents transplanted/kg were harvested. Insulin independence was achieved in 29%, 28%, and 23% of patients at 1, 2, and 5 years postoperative. Nonsmokers with a shorter duration of chronic pancreatitis and no earlier pancreas operation were more likely to be insulin free. Median number of preoperative emergency department visits and hospitalizations were 6.6 and 4.3 annually, respectively, compared with 0 at 1, 2, and 5 years postoperative. Median oral morphine equivalents were 214 mg/kg preoperation and 60, 64, 69, at 1, 2, 5 years postoperative. Preoperative, 1, 2, 5 years postoperative QOL scores were 29, 36, 34, and 33 (physical; p < 0.01) and 39, 44, 42, and 42 (mental health; p < 0.02). Genetic pancreatitis patients were more often narcotic free and had better QOL than patients with pancreatitis of other causes. At 5 years, overall survival was 92.3%. CONCLUSIONS:Total pancreatectomy with islet autotransplantation is a durable operation, with islet function, pain relief, and QOL improvements persisting to 5 years postoperative. Patients with genetic pancreatitis, short duration of disease, and nonsmokers have superior outcomes.

Islet engraftment after transplantation is impaired by high rates of islet/β cell death caused by cellular stressors and poor graft vascularization. We studied whether cotransplantation of ex vivo expanded autologous bone marrow-derived mesenchymal stem cells (MSCs) with islets is safe and beneficial in chronic pancreatitis patients undergoing total pancreatectomy with islet autotransplantation. MSCs were harvested from the bone marrow of three islet autotransplantation patients and expanded at our current Good Manufacturing Practices (cGMP) facility. On the day of islet transplantation, an average dose of 20.0 ± 2.6 ×10⁶ MSCs was infused with islets via the portal vein. Adverse events and glycemic control at baseline, 6, and 12 months after transplantation were compared with data from 101 historical control patients. No adverse events directly related to the MSC infusions were observed. MSC patients required lower amounts of insulin during the peritransplantation period (p = .02 vs. controls) and had lower 12-month fasting blood glucose levels (p = .02 vs. controls), smaller C-peptide declines over 6 months (p = .01 vs. controls), and better quality of life compared with controls. In conclusion, our pilot study demonstrates that autologous MSC and islet cotransplantation may be a safe and potential strategy to improve islet engraftment after transplantation. (Clinicaltrials.gov registration number: NCT02384018). Stem Cells Translational Medicine 2018;7:11-19.

BACKGROUND:Chronic pancreatitis has surgical options including total pancreatectomy to control pain. To avoid surgical diabetes, the explanted pancreas can have islets harvested and transplanted. Immediately following total pancreatectomy with islet autotransplantation (TP-IAT), many islet cells die due to isolation and transplantation stresses. The percentage of patients remaining insulin free after TP-IAT is therefore low. We determined whether cotransplantation of adipose-derived mesenchymal stem cells (ASCs) from chronic pancreatitis patients (CP-ASCs) would protect islets after transplantation. METHODS:Profiler™ Apoptosis PCR Array. The impact of insulin-like growth factor-1 (IGF-1) on islet apoptosis was determined in islets stimulated with cytokines (IL-1β and IFN-γ) in the presence and absence of CP-ASC conditioned medium. RESULTS:CP-ASC-treated mice were more often normoglycemic compared to mice receiving islets alone. ASC cotransplantation reduced macrophage infiltration, β-cell death, suppressed expression of TNF-α and Bcl-2 modifying factor (BMF), and upregulated expressions of IGF-1 and TNF Receptor Superfamily Member 11b (TNFRSF11B) in islet grafts. Islets cultured in conditioned medium from CP-ASCs showed reduced cell death. This protective effect was diminished when IGF-1 was blocked in the conditioned medium by the anti-IGF-1 antibody. CONCLUSION:Cotransplantation of islets with ASCs from the adipose of chronic pancreatitis patients improved islet survival and islet function after transplantation. The effects are in part mediated by paracrine secretion of IGF-1, suppression of inflammation, and promotion of angiogenesis. ASCs from chronic pancreatitis patients have the potential to be used as a synergistic therapy to enhance the efficacy of islet transplantation following pancreatectomy.

Chronic pancreatitis (CP) is a progressive inflammatory disease, which leads to loss of pancreatic function and other disease-related morbidities. A group of academic physicians and scientists developed comprehensive guidance statements regarding the management of CP that include its epidemiology, diagnosis, medical treatment, surgical treatment, and screening. The statements were developed through literature review, deliberation, and consensus opinion. These statements were ultimately used to develop a conceptual framework for the multidisciplinary management of chronic pancreatitis referred to as an academic pancreas center of excellence (APCOE).

Islet cell transplantation has limited effectiveness because of an instant blood-mediated inflammatory reaction (IBMIR) that occurs immediately after cell infusion and leads to dramatic β-cell death. In intraportal islet transplantation models using mouse and human islets, we demonstrated that α-1 antitrypsin (AAT; Prolastin-C), a serine protease inhibitor used for the treatment of AAT deficiency, inhibits IBMIR and cytokine-induced inflammation in islets. In mice, more diabetic recipients reached normoglycemia after intraportal islet transplantation when they were treated with AAT compared with mice treated with saline. AAT suppressed blood-mediated coagulation pathways by diminishing tissue factor production, reducing plasma thrombin-antithrombin complex levels and fibrinogen deposition on islet grafts, which correlated with less graft damage and apoptosis. AAT-treated mice showed reduced serum tumor necrosis factor-α levels, decreased lymphocytic infiltration, and decreased nuclear factor (NF)-κB activation compared with controls. The potent anti-inflammatory effect of AAT is possibly mediated by suppression of c-Jun N-terminal kinase (JNK) phosphorylation. Blocking JNK activation failed to further reduce cytokine-induced apoptosis in β-cells. Taken together, AAT significantly improves islet graft survival after intraportal islet transplantation by mitigation of coagulation in IBMIR and suppression of cytokine-induced JNK and NF-κB activation. AAT-based therapy has the potential to improve graft survival in human islet transplantation and other cellular therapies on the horizon.