Autologous Pancreatic Islet Cell Transplantation Following Pancreatectomy for Pancreas Diseases Other Than Chronic Pancreatitis: A 15-y Study of the Milan Protocol

Abstract

Background: Pancreatogenic diabetes, a consequence of pancreatic tissue loss following pancreatectomy, poses a significant challenge for patients undergoing pancreatic surgery. Islet autotransplantation (IAT) offers a promising approach to prevent or alleviate pancreatogenic diabetes, but its application has been limited to individuals with painful chronic pancreatitis.

Methods: This study presents a 15-y clinical experience with the Milan Protocol, which expands IAT after pancreatectomy to a broader spectrum of patients with malignant and nonmalignant pancreatic diseases. The analysis evaluates feasibility, efficacy, and safety of IAT. Modified Igls criteria validated through the arginine test and mixed meal tolerance tests were used to assess long-term metabolic outcomes.

Results: Between November 2008 and June 2023, IAT procedures were performed on 114 of 147 candidates. IAT-related complications occurred in 19 of 114 patients (16.7%), with 5 being potentially serious. Patients exhibited sustained C-peptide secretion over the 10-y follow-up period, demonstrating a prevalence of optimal and good beta-cell function. Individuals who underwent partial pancreatectomy demonstrated superior metabolic outcomes, including sustained C-peptide secretion and a reduced risk of developing diabetes or insulin dependence compared with those who underwent total pancreatectomy. For patients who had total pancreatectomy, the quantity of infused islets and tissue volume were identified as critical factors influencing metabolic outcomes. An increased risk of recurrence or progression of baseline diseases was not observed in subjects with neoplasms.

Conclusions: These findings provide valuable insights into the benefits and applications of IAT as a therapeutic option for pancreatogenic diabetes after pancreatic surgery, expanding its potential beyond painful chronic pancreatitis.

FIGURE 1.

Patient disposition for islet isolation during the study. ITT, intention to treat.

FIGURE 2.

Probability of undergoing IAT as determined by logistic regression analysis. Univariate and multivariate odds ratios for IAT are presented. Logistic regression was used to evaluate the associations between patient characteristics and IAT. All presurgery variables that were analyzed are included. The dots represent the odds ratio after log transformation, whereas the lines indicate the 95% confidence intervals. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CRP, C-reactive protein; EGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; Hb, hemoglobin; HbA1c, glycated hemoglobin; HOMA, homeostasis model assessment; IAT, islet autotransplantation; PLT, platelet; WBC, white blood cell.

FIGURE 3.

Follow-up: overall survival. The probability of survival in patients receiving IAT is presented using Kaplan-Meier analysis (upper panel). The associations between patient characteristics and overall survival were evaluated using Cox regression analysis (lower panel). All presurgery variables that were analyzed are included in the analysis. The dots in the figure represent the hazard ratio after log transformation, and the lines represent the corresponding 95% confidence intervals. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CRP, C-reactive protein; EGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; Hb, hemoglobin; HbA1c, glycated hemoglobin; HOMA, homeostasis model assessment; IE, islet equivalent; PLT, platelet; WBC, white blood cell.

FIGURE 4.

Metabolic outcome of IAT according to Igls criteria. The β-cell graft function of 114 IAT cases was evaluated and classified into 4 categories: “optimal,” “good,” “marginal,” or “failure” based on the revised Igls criteria (Table 1). Of 204 arginine tests performed, 58, 58, 57, and 31 results fell into the categories of optimal, good, marginal, and failed beta-cell function, respectively. Similarly, among 169 MMTTs conducted, 106, 22, 26, and 15 results corresponded to optimal, good, marginal, and failed beta-cell function, respectively. The upper panel presents the β-cell graft function outcomes according to the Igls criteria during a 10-y follow-up period. The lower panels display the distribution of metabolic parameters using box plots. The centerline of the box plot represents the median value, and the box encompasses the interquartile range of the data set. The whiskers extend to the 1st and 99th percentiles. Values beyond these bounds are considered outliers and are depicted as black dots. Statistical analysis was conducted using the Kruskal-Wallis test, followed by post hoc Dunn’s multiple comparison test. The results of the analysis are as follows: ^aall groups showed statistically significant differences, except for the comparison between the “marginal” and “failed” groups; ^ball groups exhibited statistically significant differences from each other; ^call groups demonstrated statistically significant differences, except for the comparison between the “optimal” and “good” groups; and ^dthe “failed” group exhibited statistically significant differences from all other groups. HbA1c, glycated hemoglobin; IAT, islet autotransplantation; MMTT, mixed meal tolerance test.

FIGURE 5.

Metabolic outcome of IAT according to the extent of pancreas resection. The functional outcomes of β-cell replacement therapy were evaluated separately for the 2 distinct groups of patients who underwent different types of pancreatectomy: total pancreatectomy (n = 74) and partial pancreatectomy (n = 40). The upper panel displays the outcomes based on the Igls criteria during a 10-y follow-up period. The lower panels present Kaplan-Meier analyses, showcasing the overall, disease-free, diabetes-free, and insulin-free survival rates, along with the probability of sustained (>0.5 ng/mL) or minimal (>0.3 ng/mL) C-peptide secretion. IAT, islet autotransplantation.

FIGURE 6.

Metabolic follow-up: C-peptide secretion maintenance in totally pancreatectomized patients. Cox regression analysis was used to examine the associations between patient characteristics and the risk of losing C-peptide secretion. All presurgery variables that were analyzed are included. The dots in the figure represent the hazard ratio after log transformation, and the lines represent the corresponding 95% confidence intervals. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BM, bone marrow; BMI, body mass index; CRP, C-reactive protein; EGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; Hb, hemoglobin; HbA1c, glycated hemoglobin; HOMA, homeostasis model assessment; IA, islet absolute number; IAT, islet autotransplantation; IEQ, islet equivalent quantity; PLT, platelet; WBC, white blood cell.

FIGURE 7.

Metabolic follow-up in totally pancreatectomized patients according to the received islet yield. Patients were categorized into 3 groups according to the received islet yield in tertiles: >2060 IEQ/kg (n = 25), between 2060 and 1426 IEQ/kg (n = 25), and <1426 IEQ/kg (n = 24). The left panel displays outcomes using Igls criteria during a 10-y follow-up. The right panels present Kaplan-Meier analysis for the probability of sustained (>0.5 ng/mL) or minimal (>0.3 ng/mL) C-peptide secretion. P values are from the log-rank (Mantel-Cox) test, assessing differences in C-peptide secretion among the groups. IEQ, islet equivalent quantity.