Total Pancreatectomy with Islet Auto Transplantation Outcomes in Pancreatitis Patients of Genetic Etiology: A Single Center Experience with a Large Cohort of Patients.

PURPOSE: Total pancreatectomy with islet autotransplantation (TPIAT) is an effective treatment for patients with chronic pancreatitis (CP) when other interventions are unsuccessful. CP has many etiologies including heredity. Metabolic and pain relief outcomes following TPIAT are presented among patients with a genetic CP etiology when compared to those with a nongenetic etiology in a large cohort of patients who underwent this procedure at our center. METHODS: A retrospective analysis was performed of 237 TPIAT patients from 2006 to 2023. We analyzed the differences in patients with genetic (n = 56) versus nongenetic (n = 181) CP etiologies in terms of pre-TPIAT factors including patient characteristics and disease state, results from the isolation process, and outcomes such as long-term glycemic and pain control. RESULTS: Patients with genetic CP underwent TPIAT at a significantly younger age (32.3 years vs 41.3 years nongenetic, p < 0.0001) and endured symptoms for a significantly longer period (10 vs 6 years, p < 0.01). A significantly lower mass of islets was isolated from patients with genetic CP (p < 0.01), which increased with body mass index in both groups. Despite lower yields, genetic CP patients maintained metabolic function like nongenetic CP patients, as indicated by insulin independence and C-peptide, blood glucose, and hemoglobin A1c levels after TPIAT. Posttransplant narcotic usage and pain scores significantly decreased compared to pre-TPIAT, and more genetic CP patients were pain free and narcotic free post-TPIAT. CONCLUSIONS: Our data validate TPIAT as a beneficial procedure for patients enduring CP of genetic etiology. Pain that is inevitably recurrent after minor interventions due to the nature of the disease and favorable TPIAT outcomes should be considered in the decision to perform early TPIAT in cases of genetic CP.

Clinical and biological significance of circulating miRNAs in chronic pancreatitis patients undergoing total pancreatectomy with islet autotransplantation.

BACKGROUND: Specific microRNAs (miRNAs) were elevated in chronic pancreatitis (CP) patients during islet infusion after total pancreatectomy (TPIAT). We aimed to identify circulating miRNA signatures of pancreatic damage, predict miRNA-mRNA networks to identify potential links to CP pathogenesis and identify islet isolation and transplantation functional outcomes. METHODS: Small RNA sequencing was performed to identify distinct circulating miRNA signatures in CP. Plasma miRNAs were measured using miRCURY LNA SYBR green quantitative real-time polymerase chain reaction assays. Correlation analyses were performed using R software. The miRNA target and disease interactions were determined using miRNet and the miRNA enrichment and annotation tool. RESULTS: Alterations were found in circulating miRNAs in CP patients compared to healthy controls. Further studies were conducted on 12 circulating miRNAs enriched in the pancreas, other tissues and other diseases including cancer and fibrosis. Approximately 2888 mRNAs in the pancreas were their targets, demonstrating interactions with 76 small molecules. Three miRNAs exhibited interactions with morphine and five exhibited interactions with glucose. The miRNA panel targeted 22 genes associated with pancreatitis. The islet-specific, acinar cell-specific and liver-specific miRNAs were elevated at 6 h after islet infusion and returned to baseline levels 3 months after TPIAT. Circulating levels of miRNAs returned to pre-transplant levels 1-year post-transplant. Circulating miRNAs measured before and 6 h after islet infusion were directly or inversely associated with metabolic outcomes at 3 and 6 months post-transplant. CONCLUSIONS: miRNAs may contribute to CP pathogenesis, and elevated circulating levels may be specific to pancreatic inflammation and fibrosis, warranting further investigation.

Improved Quality of Life Among Chronic Pancreatitis Patients Undergoing Total Pancreatectomy With Islet Autotransplantation-Single Center Experience With Large Cohort of Patients.

Total pancreatectomy with islet autotransplantation (TPIAT) is the treatment of choice to preserve pancreatic endocrine function, alleviate pain, and improve quality of life (QoL) when other strategies are ineffective for chronic pancreatitis (CP) patients. This study utilized pancreatic disease-specific surveys developed by the European Organisation for Research and Treatment of Cancer (EORTC) to conduct a comprehensive, single-center examination of a large cohort of patients to gain understanding of QoL post-TPIAT. Two validated QoL surveys of the EORTC-QLQ-C30 and QLQ-PAN26-were administered in a prospective cohort of CP patients during pre-and post-operative scheduled visits. A total of 116 patients responded to the preoperative survey and were included in this study. The global health scale of QLQ-C30 was significantly improved after TPIAT when compared to baseline with delta scores of 24.26, 20.54, and 26.7 at 1, 2, and 3 years post-TPIAT (p < 0.001). The EORTC-PAN26 revealed significant improvements in symptom scales for pancreatic pain, bloating, digestive symptoms, taste, indigestion, weight loss, body image, and future worries. The comprehensive surveys in such a large cohort expands the QoL criterion in CP patients and indicates significant improvement in QoL post-TPIAT, further validating TPIAT as a treatment option for refractory CP.

Role of Exosomes in Islet Transplantation.

Exosomes are known for their ability to transport nucleic acid, lipid, and protein molecules, which allows for communication between cells and tissues. The cargo of the exosomes can have a variety of effects on a wide range of targets to mediate biological function. Pancreatic islet transplantation is a minimally invasive cell replacement therapy to prevent or reverse diabetes mellitus and is currently performed in patients with uncontrolled type 1 diabetes or chronic pancreatitis. Exosomes have become a focus in the field of islet transplantation for the study of diagnostic markers of islet cell viability and function. A growing list of miRNAs identified from exosomes collected during the process of isolating islets can be used as diagnostic biomarkers of islet stress and damage, leading to a better understanding of critical steps of the isolation procedure that can be improved to increase islet yield and quality. Exosomes have also been implicated as a possible contributor to islet graft rejection following transplantation, as they carry donor major histocompatibility complex molecules, which are then processed by recipient antigen-presenting cells and sensed by the recipient immune cells. Exosomes may find their way into the therapeutic realm of islet transplantation, as exosomes isolated from mesenchymal stem cells have shown promising results in early studies that have seen increased viability and functionality of isolated and grafted islets in vitro as well as in vivo. With the study of exosomes still in its infancy, continued research on the role of exosomes in islet transplantation will be paramount to understanding beta cell regeneration and improving long-term graft function.