Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

Total pancreatectomy (TP) is increasingly being utilized for definitive treatment in patients with debilitating chronic pancreatitis (CP). In an effort to prevent surgical diabetes, the procedure can be performed in conjunction with transplantation of islets of Langerhans recovered from the patients\' own resected pancreas (autologous islet transplantation, AIT). Given that patients undergoing TP and AIT are traditionally assumed not to be at risk for the development of beta-cell autoimmunity, it is possible that the presence of autoimmune islet graft failure has been overlooked and underreported in this patient population. Herein, we describe two cases who underwent TP and AIT and later developed new-onset beta-cell autoimmunity (as evidenced by de novo glutamic acid decarboxylase antibody positivity), accompanied by complete insulin-dependent states. These cases emphasize the need for considering a possible autoimmune phenomenon in the workup of TP and AIT patients who manifest with unexpected and rapid deterioration in their glycemic control.

We assessed whether positive microbiological cultures from the islet preparation had any effect on the risk of infectious complications (IC) after total pancreatectomy with islet autotransplantation (TPIAT) in our center.
We analyzed preservation fluid and final islet product surveillance cultures with reference to clinical data of patients undergoing TPIAT. All patients received routine prophylactic broad-spectrum antibiotics.
The study involved 10 men and 18 women with a median age of 39 years. Over 30% of surveillance cultures during pancreas processing grew bacterial strains with predominantly polymicrobial contaminations (13 of 22 (59%)). At least one positive culture was identified in almost half of the patients (46%) undergoing TPIAT and a third had both surveillance cultures positive. Infectious complications affected 50% of patients. After excluding cases of PICC line-associated bacteremia/fungemia present on admission, incidence of IC was higher in cases of positive final islet product culture than in those with negative result (57% vs. 21%), which also corresponded with the duration of chronic pancreatitis (p = 0.04). Surgical site infections were the most common IC, followed by fever of unknown origin. There was no concordance between pathogens isolated from the pancreas and those identified during the infection.
While IC was common among TPIAT patients, we found no concordance between pathogens isolated from the pancreas and those identified during infection. Contamination of the final islet product was of clinical importance and could represent a surrogate marker for higher susceptibility to infection.

We investigated six indices based on a single fasting blood sample for evaluation of the beta-cell function after total pancreatectomy with islet autotransplantation (TP-IAT). The Secretory Unit of Islet Transplant Objects (SUITO), transplant estimated function (TEF), homeostasis model assessment (HOMA-2B%), C-peptide/glucose ratio (CP/G), C-peptide/glucose creatinine ratio (CP/GCr) and BETA-2 score were compared against a 90-min serum glucose level, weighted mean C-peptide in mixed meal tolerance test (MMTT), beta score and the Igls score adjusted for islet function in the setting of IAT. We analyzed values from 32 MMTTs in 15 patients after TP-IAT with a follow-up of up to 3 years. Four (27%) individuals had discontinued insulin completely prior to day 75, while 6 out of 12 patients (50%) did not require insulin support at 1-year follow-up with HbA1c 6.0% (5.5-6.8). BETA-2 was the most consistent among indices strongly correlating with all reference measures of beta-cell function (r = 0.62-0.68). In addition, it identified insulin independence (cut-off = 16.2) and optimal/good versus marginal islet function in the Igls score well, with AUROC of 0.85 and 0.96, respectively. Based on a single fasting blood sample, BETA-2 score has the most reliable discriminant value for the assessment of graft function in patients undergoing TP-IAT.

Pancreatectomy and autologous islet transplantation (AIT) are performed in highly specialized centers to alleviate abdominal pain and preserve endocrine function in patients with chronic pancreatitis. We aimed at initiating AIT studies in India for the first time in patients undergoing distal pancreatectomy (DP) to prevent development of diabetes. Four out of 14 chronic pancreatitis patients screened underwent DP with AIT. Pancreatectomy specimen preserved in Wisconsin solution was subjected to islet isolation employing standard protocol using collagenase V. Isolated islets were infused into the liver through portal vein after quality assessment and the four patients were followed for 1 year. During the study period, blood glucose, fasting insulin, and C-peptide were analyzed and glucose tolerance was assessed. Three patients could be infused with islets (4363 Islet equivalents, IEQ/kg, 3860 IEQ/kg, 3600 IEQ/kg) into liver without any infusion-related complications. Two of these patients maintained glucose tolerance and glycemic control (HbA1c: 6.0%) and one became diabetic at the end of 1 year (HbA1c: 7.5%). Circulating fasting insulin increased (2.7-24.4 μU/mL and 4.0-21.2 μU/mL) and C-peptide levels increased (2.2 to 3.6, 3.4-5.6 ng/mL) in these two patients. Circulating insulin was 2.7 μU/mL and C-peptide was 2.4 ng/mL in the patient who became diabetic at the end of 1 year, while insulin was 2.3 μU/mL and C-peptide was 1.2 ng/mL in the patient who could not be infused with islets after DP. Safety and feasibility of autologous islet transplantation is established in India for the first time.

Blood flow regulation in pancreatic islets is critical for function but poorly understood. Here, we establish an in vivo imaging platform in a non-human primate where islets transplanted autologously into the anterior chamber of the eye are monitored non-invasively and longitudinally at single-cell resolution. Engrafted islets were vascularized and innervated and maintained the cytoarchitecture of in situ islets in the pancreas. Blood flow velocity in the engrafted islets was not affected by increasing blood glucose levels and/or the GLP-1R agonist liraglutide. However, islet blood flow was dynamic in nature and fluctuated in various capillaries. This was associated with vasoconstriction events resembling a sphincter-like action, most likely regulated by adrenergic signaling. These observations suggest a mechanism in primate islets that diverts blood flow to cell regions with higher metabolic demand. The described imaging technology applied in non-human primate islets may contribute to a better understanding of human islet pathophysiology.

The purpose of this study was to determine whether bacterial contamination of islets affects graft success after total pancreatectomy with islet autotransplantation (TPIAT).
Factors associated with insulin independence after TPIAT are inconclusive. Although bacterial contamination does not preclude transplantation, the impact of bacterial contamination on graft success is unknown.
Patients who received TPIAT at the University of Virginia between January 2007 and January 2016 were reviewed. Patient charts were reviewed for bacterial contamination and patients were prospectively contacted to assess rates of insulin independence.
There was no significant difference in demographic or perioperative data between patients who achieved insulin independence and those who did not. However, six of 27 patients analyzed (22.2%) grew bacterial contaminants from culture of the final islet preparations. These patients had significantly lower islet yield and C-peptide at most recent follow-up (P<.05), and none of these patients achieved insulin independence.
Islet transplant solutions are often culture positive, likely secondary to preprocurement pancreatic manipulation and introduction of enteric flora. Although autotransplantation of culture-positive islets is safe, it is associated with higher rates of graft failure and poor islet yield. Consideration should be given to identify patients who may develop refractory chronic pancreatitis and offer early operative management to prevent bacterial colonization.

OBJECTIVE: Autologous islet transplantation (IAT) following pancreatectomy is now a recognized, albeit highly specialized procedure carried out in a small number of centers worldwide. Current clinical principles and best practice with emphasis on examining the technical aspects of surgery in centers with significant IAT experience are reviewed.
METHODS: Literature search for studies discussing any technical aspect of pancreatectomy with intraportal IAT was included.
RESULTS: Thirty-five papers were included; all were single-center case series. The indications, surgical approach to pancreatectomy with IAT, islet yield, static pancreas preservation prior to islet digestion, portal vein access, absolute islet infusion volumes, and portal venous pressure changes during transfusion evaluated.
CONCLUSIONS: IAT is considered a \"last resort\" when alternative approaches have been exhausted. Pre-morbid histology and prior surgical drainage adversely influence islet yields and may influence the clinical decision to perform pancreatectomy and IAT. Following pancreas digestion, absolute numbers of islets recovered and smaller islet size predict rates of insulin independence following IAT. Islet volumes and portal venous pressure changes are important factors for the development of complications. Surgical access for IAT includes intra-operative, immediate or delayed infusion via an \"exteriorized\" vein, and radiological percutaneous approaches. Delayed infusion can be combined with pancreas preservation techniques prior to islet isolation.

We analyzed the pretransplant continuous glucose monitoring (CGM) data of 45 patients that underwent total pancreatectomy followed by autologous islet transplantation (AIT) at the University of Arizona Medical Center. Traditional and novel metrics of CGM time series were correlated to the total islet count (TIC), islet equivalents (IEQs), and weight-normalized IEQs (IEQ/kg). In a subset cohort (n = 26) we analyzed the relationship among the infused number of islets, the CGM indicators, and the first recorded insulin requirement after the procedure. We conclude that receiving a high islet yield is sufficient yet not necessary to achieve low or null insulin requirements within the first 50 days after surgery. Furthermore, CGM inertia and CGM length of curve (2 novel CGM indicators) are shown to be correlated to islet yield, and the CGMs normalized area (Ao) and time ratio above hyperglycemic level (To) are strongly correlated to insulin requirement. A screening test based on To is shown to have 100% sensitivity and 88% specificity discriminating insulin independence upon discharge.

OBJECTIVE: To evaluate the safety and feasibility of laparoscopic spleen-preserving distal pancreatectomy (LSPDP) with autologous islet transplantation (AIT) for benign tumors of the pancreatic body-neck.
METHODS: Three non-diabetic, female patients (age 37, 44 and 35 years, respectively) were declared candidates for surgery, between May and September 2011, because of pancreatic body/neck cystic lesions. The planned operation was an LSPDP associated with AIT from the normal pancreas distal to the neoplasm. Islets isolation was performed on the residual pancreatic parenchyma after frozen section examination of the margin. Purified autologous islets were infused into the portal vein by a percutaneous transhepatic approach the day after surgery.
RESULTS: The procedure was performed successfully in all the three cases, and the spleen was preserved along with its vessels. Mean operation time was 283 ± 52 min and average blood loss was 133 ± 57 mL. Residual pancreas weights were 33, 22 and 30 g, and 105.200, 40.390 and 94.790 islet equivalents were isolated, respectively. Surgical complications occurred in one patient (grade A pancreatic fistula). Postoperative stays were 6, 6 and 7 d, respectively. Histopathological evaluation revealed mucinous cystic neoplasm in cases 1 and 3, and serous cystic neoplasm in patient 2. No postoperative insulin administration was required. One patient developed a transient partial portal thrombosis 2 mo after islet infusion. Patients are insulin independent at a mean follow up of 8 ± 2 mo.
CONCLUSIONS: Combination of LSPDP and AIT is feasible and could be effective to minimize the surgical impact for benign neoplasm of pancreatic body-neck.