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Mesenchymal stem cells (MSCs) are proven to be beneficial in islet transplantation, suggesting a potential therapeutic role of them in total pancreatectomy with islet autotransplantation (TP-IAT) for chronic pancreatitis (CP) patients. We investigated whether MSCs derived from CP patients are suitable for use in autologous cell therapy. MSCs from healthy donors (H-MSCs) and CP patients (CP-MSCs) were studied for phenotype, colony formation potential, multilineage differentiation ability, proliferation, senescence, secretory characters, and immunosuppressive functions. The potential protective effect of CP-MSCs was evaluated on hypoxia-induced islet cell death. Cell surface markers were similar between H-MSCs and CP-MSCs, as well as the ability of colony formation, multilineage differentiation, secretion of vascular endothelial growth factor and transforming growth factor (TGF-β), senescence, and inhibition of T cells proliferation in vitro. We found that growth differentiation factor 6 and hepatocyte growth factor (HGF) were significantly downregulated, whereas TGFβ and matrix metalloproteinase-2 were significantly upregulated in CP-MSCs compared with H-MSCs, among 84 MSC-related genes investigated in this study. MSCs from CP patients secreted less HGF, compared with the H-MSCs. A higher interferon-γ-induced indoleamine 2,3-dioxygenase expression was observed in CP-MSCs compared to H-MSCs. Moreover, CP-MSCs prevented hypoxia-induced β cell deaths to a similar extent as H-MSCs. Regardless of moderate difference in gene expression, CP-MSCs possess similar immunomodulatory and prosurvival functions to H-MSCs, and may be suitable for autologous cell therapy in CP patients undergoing TP-IAT. Stem Cells Translational Medicine 2019;8:418–429

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 One hundred and ninety-five patients (141 women, aged 40.3 years, BMI 26.5 kg/m 2 ) 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 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: {"type":"clinical-trial","attrs":{"text":"NCT02384018","term_id":"NCT02384018"}}NCT02384018). stem cells translational medicine 2018;7:11–19

Total pancreatectomy with immediate islet autotransplantation (IAT) can be an effective therapy in patients with chronic pancreatitis. Patient selection criteria for radical resection are not well defined. The impact of prior pancreatic surgery on quality of life outcomes in patients undergoing IAT is evaluated. A retrospective review of a prospectively collected database of patients undergoing pancreatectomy with islet autotransplantation was undertaken. Patients having undergone prior pancreatic resection and/or drainage procedures were compared with those without prior pancreatic operative history. Sixty-one patients underwent pancreatectomy with IAT for pancreatitis. Twenty-three patients had a prior history of pancreatic surgery (Group S); 38 had no prior history of pancreatic surgery (Group NS). Demographics between the groups were similar. Patients in Group S took more daily oral morphine equivalents and had a lower psychological quality of life preoperatively. Operative times and blood loss were similar between the patient groups. Islet yields were lower for patients in Group S. Postoperatively, daily insulin requirements at 6 months and 1 year trended higher in Group S. Postoperative quality of life scores at 6 months were improved and similar between the groups. Quality of life metrics continued to improve beyond 1 year of follow-up, with a trend toward greater improvement in the NS Group. Total pancreatectomy for chronic pancreatitis improves quality of life in patients with and without a prior history of pancreatic surgery. This study demonstrates that IAT without preceding pancreatic surgery may enhance outcomes measured by long term insulin requirements and quality of life.

Selected patients with chronic pancreatitis can benefit from total pancreatectomy with islet autotransplantation. Patient selection is challenging and outcomes assessment is essential.A prospective database of total pancreatectomy with islet autotransplantation patients was reviewed. Attention was given to psychometric assessments, including Short Form-12 Quality of Life Survey (SF-12), Center for Epidemiologic Studies 10-Item Depression scale, and Current Opioid Misuse Measure in the preoperative period, and SF-12 in the postoperative period.One hundred and twenty-seven patients (76% women, mean age 40.5 years) underwent total pancreatectomy with islet autotransplantation. Preoperatively, the mean SF-12 physical quality of life score (physQOL) was 27.24 (SD 9.9) and the mean psychological QOL score (psychQOL) was 38.5 (SD 12.8), with a score of 50 representing the mean of a healthy population. Mean improvements in physQOL relative to baseline at 1 year, 2 years, and 3 years post surgery were 7.1, 5.8, and 7.8, respectively, which represented significant change (all p0.001). Mean improvements in psychQOL relative to baseline at 1 year, 2 years, and 3 years post surgery were 3.9, 4.9, and 6.6, which also represented significant improvement (all p0.001). The percentages of patients evidencing at least a 3-point improvement in physQOL at 1 year, 2 years, and 3 years post surgery were 65%, 60%, and 61%, respectively. The percentages of patients evidencing at least a 3-point improvement in psychQOL at 1 year, 2 years, and 3 years post surgery were 49%, 58%, and 66%, respectively. Exploratory regression analyses of SF-12, Current Opioid Misuse Measure, and Center for Epidemiologic Studies 10-Item Depression scale data revealed limited baseline predictability of surgical response; however, higher opioid misuse scores at baseline were significantly and positively related to physQOL improvement at 2 years (r[54] = 0.33, p = 0.02).Total pancreatectomy with islet autotransplantation improves QOL for selected patients with chronic pancreatitis. The physQOL improves quickly after surgery, and psychQOL improvements are more gradual. Opioid misuse can predict physQOL improvement.

BackgroundIn selected patients, total pancreatectomy with islet autotransplantation (TPIAT) effectively relieves pain caused by chronic pancreatitis and ameliorates the brittle diabetes of the apancreatic state. Patients often undergo multiple endoscopic and surgical interventions prior to TPIAT, increasing the risk for pancreas colonization with enteric microorganisms. Little is known of the safety of transplanting islet cells with microbial contamination.MethodsA prospectively collected database of 80 patients submitted to TPIAT at the Medical University of South Carolina from March 2009 to February 2012 was retrospectively reviewed. Patient charts were reviewed for postoperative infectious complications and organisms identified were compared with those identified in pre-transplant islet cultures.ResultsA total of 35 patients (43.8%) had a positive pre-transplant islet cell Gram stain or islet cell culture from the final islet preparation solution. Of these 35 patients, 33 (94.3%) were given antibiotics prophylactically post-transplant for a positive islet Gram stain or culture. Twenty patients (57.1%) receiving Gram stain- or culture-positive islets developed postoperative infectious complications, but only four patients (11.4%) developed infections that concorded with their pre-transplant islet product.ConclusionsIslet transplant solutions are frequently culture-positive, presumably as a result of prior pancreas intervention. Microbial contamination of islet preparations should not preclude autotransplantation.