Mesenchymal Stem Cells from Chronic Pancreatitis Patients Show Comparable Potency Compared to Cells from Healthy Donors.

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-ß), 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 TGFß 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 ß 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.

Patient Selection for Total Pancreatectomy with Islet Autotransplantation in the Surgical Management of Chronic Pancreatitis.

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/m2) 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.

Autologous Mesenchymal Stem Cell and Islet Cotransplantation: Safety and Efficacy.

Islet engraftment after transplantation is impaired by high rates of islet/ß 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.

Enhanced Recovery After Surgery Protocols Are Valuable in Pancreas Surgery Patients.

BACKGROUND: There is increasing interest in implementing comprehensive perioperative protocols, including preoperative optimization and education, perioperative goal-directed fluid management, and postoperative fast tracking, to enhance recovery after surgery. Data on the outcomes of these protocols in pancreatic surgery, however, are limited. STUDY DESIGN: A retrospective review of a prospectively maintained pancreas surgery database at a single institution from August 2012 to April 2015 was undertaken. An enhanced recovery protocol was initiated in October 2014, and patients were divided into groups according to preprotocol or postprotocol implementation. Preoperative, intraoperative, and postoperative data were tabulated. Statistical analysis was performed with Student's t-test and Fisher's exact tests, as well as equality of variances where appropriate, using SAS System software (SAS Institute). RESULTS: Three hundred and seventy-eight patients (181 men, mean age 54 years, BMI 28 kg/m(2)) underwent elective pancreatic surgery during the study period, 297 patients preprotocol and 81 postprotocol. There were no significant differences in preoperative or intraoperative characteristics. Mean postoperative length of stay was significantly lower in the Enhanced Recovery After Surgery group (7.4 vs 9.2 days; p < 0.0001). Hospital costs were similarly lower in the Enhanced Recovery After Surgery group ($23,307.90 vs $27,387.80; p < 0.0001). Readmission (29% vs 32%) and pancreatic fistula (26% vs 28%) rates were similar between groups. Delayed gastric emptying was lower in the Enhanced Recovery After Surgery group (26% vs 13%; p = 0.03). CONCLUSIONS: Implementation of an enhanced recovery after pancreatic surgery protocol significantly decreased length of stay and hospital cost without increasing readmission or morbidity. Despite patient complexity and the potential need for individualization of care, enhanced recovery protocols can be valuable and effective in high-risk patient populations, including pancreatic surgery patients.

How are select chronic pancreatitis patients selected for total pancreatectomy with islet autotransplantation? Are there psychometric predictors?

BACKGROUND: Selected patients with chronic pancreatitis can benefit from total pancreatectomy with islet autotransplantation. Patient selection is challenging and outcomes assessment is essential. STUDY DESIGN: 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. RESULTS: 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 p < 0.001). 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 p < 0.001). 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). CONCLUSIONS: 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.

Screening for current opioid misuse and associated risk factors among patients with chronic nonalcoholic pancreatitis pain.

OBJECTIVE: The objective of this study is to assess clinical variables that may be associated with risk for opioid misuse in individuals with chronic pancreatitis. DESIGN: This study utilized a descriptive, quasi-experimental, cross sectional design. SETTING AND PATIENTS: Three hundred seven individuals with nonalcoholic chronic pancreatitis engaged in chronic opioid therapy for pain presented to an outpatient specialty clinic at an academic medical center. MEASURES: Participants completed the Current Opioid Misuse Measure (COMM), Brief Pain Inventory (BPI), Short Form (SF)-12 Quality of Life Measure, Center for Epidemiological Studies 10-item Depression Scale (CESD), and a single item asking about current alcohol use. Mean scores on the CESD, COMM, BPI, SF-12, and factors associated with opioid misuse measures from regression analyses were the outcome measures. RESULTS: Mean scores on the CESD, COMM, BPI pain-on-average item, and the SF-12 physical and psychological quality of life factors (t scores) were 11.2 (standard deviation [SD] = 6.7), 8.5 (SD = 7.3), 4.8 (SD = 2.8), 39.7 (SD = 7.0), and 45 (SD = 9.0), respectively. Descriptive analyses revealed that 55% of participants scored above the clinical cutoff for depression on the CESD, and 39% scored above the cutoff for opioid misuse concerns on the COMM. Regression analyses identified several factors associated with higher opioid misuse measure scores, including increased depressive symptoms from the CESD (ß = 0.38, P < 0.0001), increased pain rating at the time of the office visit (ß = 0.16, P = 0.03), impairment of psychological quality of life (ß = -0.27, P = 0.001) and endorsement of alcohol use (ß = 0.16, P = 0.03). These factors accounted for 37% of the variance in current opioid misuse scores. CONCLUSIONS: Depression, quality of life, pain intensity and alcohol use may be good candidate variables for prospective studies to determine clinical risk factors for opioid misuse among patients with pancreatitis.

Autotransplantation of culture-positive islet product: is dirty always bad?

BACKGROUND: In 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. METHODS: A 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. RESULTS: A 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. CONCLUSIONS: Islet transplant solutions are frequently culture-positive, presumably as a result of prior pancreas intervention. Microbial contamination of islet preparations should not preclude autotransplantation.

Depressive Symptoms, Pain, and Quality of Life among Patients with Nonalcohol-Related Chronic Pancreatitis.

Objective. The present study was conducted to determine if depressive symptoms were associated with variability in pain perception and quality of life among patients with nonalcohol-related chronic pancreatitis. Methods. The research design was cross-sectional, and self-report data was collected from 692 patients with nonalcohol-related, intractable pancreatitis. The mean age of the sample was 52.6 (SD = 14.7); 41% of the sample were male. Participants completed the MOS SF12 Quality of Life Measure, the Center for Epidemiological Studies 10-item Depression Scale (CESD), and a numeric rating scale measure of "pain on average" from the Brief Pain Inventory. Results. Depressive symptoms were significantly related to participants' reports of increased pain and decreased quality of life. The mean CESD score of the sample was 10.6 (SD = 6.5) and 52% of the sample scored above the clinical cutoff for the presence of significant depressive symptomology. Patients scoring above the clinical cutoff on the depression screening measure rated their pain as significantly higher than those below the cutoff (P < 0.0001) and had significantly lower physical quality of life (P < 0.0001) and lower mental quality of life (P < 0.0001). Conclusion. Although causality cannot be determined based on cross-sectional, correlational data, findings suggest that among patients with nonalcoholic pancreatitis, the presence of depressive symptoms is common and may be a risk factor associated with increased pain and decreased quality of life. Thus, routine screening for depressive symptomology among patients with nonalcoholic pancreatitis may be warranted.

Total pancreatectomy with islet autotransplantation for chronic pancreatitis: do patients with prior pancreatic surgery have different outcomes?

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.

Pain control and quality of life after pancreatectomy with islet autotransplantation for chronic pancreatitis.

INTRODUCTION: In selected patients with chronic pancreatitis, total pancreatectomy with islet autotransplantation can be effective for the treatment of intractable pain while ameliorating postoperative diabetes. Improved quality of life scores and decreased daily narcotic use, as indicators of successful pain relief, are expected after total pancreatectomy. These outcomes and their relationship have not been well examined in this patient group. METHODS: A prospectively collected database of patients undergoing extensive pancreatectomy with islet autotransplantation for pancreatitis was reviewed. Data pertaining to daily oral morphine equivalents (MEs) and quality of life (QOL), as measured by the SF-12 questionnaire, in the preoperative and postoperative period were reviewed. Approval from the IRB for the evaluation of human subjects was obtained. RESULTS: Over a 20-month period, 33 patients (25 women, median age 42) underwent extensive pancreatectomy with islet autotransplantation for pancreatitis. Mean follow-up was 9 months with a range of 6-12 months. Postoperative complications occurred in 16 patients (48%). Preoperative QOL scores were a mean 25 for physical component and 32 for mental health component. Postoperatively, physical component scores averaged 33 at 6 months (p = 0.025) and 36 at 12 months (mean increase of 11); the mental health component scores averaged 43 at 6 months (p = 0.007) and 44 at 12 months (mean increase of 12). Preoperative MEs averaged 357 mg daily. At discharge from the hospital, this number increased to 536 mg average MEs daily, a 50% increase, as expected after major surgery in the chronic pain patient. At 6 months, 15 out of 31 patients (48%) required less daily MEs than preoperatively and averaged 161 mg daily (-55%). By 12 months, 11 out of 17 patients (65%) required less daily MEs than preoperatively and averaged 128 mg daily (-64%); four were narcotic-free (23%). Of the six patients who did not decrease their analgesic requirements at 1 year, five (83%) still had an improved physical QOL score (one patient was unchanged) and all six had an improved mental health QOL. CONCLUSION: Total pancreatectomy with islet autotransplant is an effective surgery for end-stage chronic pancreatitis. Quality of life improves early postoperatively while decreased narcotic analgesia requirements occur later. Both improved quality of life and decreased narcotic analgesia requirements continue to occur at least up to 1 year postoperatively. Further investigation is needed to assess the durability of total pancreatectomy with islet autotransplantation for severe chronic pancreatitis with respect to pain relief and improved quality of life.