Assessment of long-term graft function following total pancreatectomy and autologous islet transplantation: the Leicester experience.

Background: Total pancreatectomy and islet autotransplantation (TPIAT) is a recognised treatment for chronic pancreatitis (CP) with the potential to mitigate or prevent pancreatogenic diabetes. We present our 10-year follow-up of TPIAT patients. Methods: The University Hospitals of Leicester performed 60 TPIAT procedures from September 1994 to May 2011. Seventeen patients completed their 10-year assessment and were grouped using the modified Auto-Igls criteria; good response, n=5 (insulin-independent for first 5 years post-TPIAT); partial response, n=6 (insulin requirements <20 iU/day post-TPIAT) and poor response, n=6 (insulin requirements ≥20 iU/day post-TPIAT). C-peptide, haemoglobin A1c (HbA1c) and oral glucose tolerance test (OGTT) were undertaken preoperatively (baseline), then at 3, 6 months and then yearly for 10 years. Data was analysed using analysis of variance (ANOVA). Results: Median C-peptide levels were significantly higher, 120 minutes following OGTT, in the "good response" compared to "partial" and "poor" groups (two-way ANOVA test, P<0.0001). All groups demonstrated preservation of C-peptide release. HbA1c levels were significantly lower in the "good response" compared to "partial" and "poor" groups (two-way ANOVA test, P<0.0003 and P<0.0001). Median fasting glucose levels at 30 and 120 min following OGTT, were significantly lower in the "good response" compared to "partial" and "poor" groups (two-way ANOVA test, P<0.0001 and P<0.0001). Conclusions: TPIAT preserves long-term islet graft functions in 10-year follow up. Even in patients in the poor response group, there is evidence of C-peptide release (>0.5 ng/mL) after OGTT stimulation potentially preventing long-term diabetes-related complications.

A comparison of the inflammatory response following autologous compared with allogenic islet cell transplantation.

BACKGROUND: The initial response to islet transplantation and the subsequent acute inflammation is responsible for significant attrition of islets following both autologous and allogenic procedures. This multicentre study compares this inflammatory response using cytokine profiles and complement activation. METHODS: Inflammatory cytokine and complement pathway activity were examined in two cohorts of patients undergoing total pancreatectomy followed either by autologous (n=11) or allogenic (n=6) islet transplantation. Two patients who underwent total pancreatectomy alone (n=2) served as controls. RESULTS: The peak of cytokine production occurred immediately following induction of anaesthesia and during surgery. There was found to be a greater elevation of the following cytokines: TNF-alpha (P<0.01), MCP-1 (P=0.0013), MIP-1α (P=0.001), MIP-1ß (P=0.00020), IP-10 (P=0.001), IL-8 (P=0.004), IL-1α (P=0.001), IL-1ra (0.0018), IL-10 (P=0.001), GM-CSF (P=0.001), G-CSF (P=0.0198), and Eotaxin (P=0.01) in the allogenic group compared to autografts and controls. Complement activation and consumption was observed in all three pathways, and there were no significant differences in between the groups although following allogenic transplantation ∆IL-10 and ∆VEGF levels were significantly elevated those patients who became insulin-independent compared with those who were insulin-dependent. CONCLUSIONS: The cytokine profiles following islet transplantation suggests a significantly greater acute inflammatory response following allogenic islet transplantation compared with auto-transplantation although a significant, non-specific inflammatory response occurs following both forms of islet transplantation.

Pilot study: deficiency of mannose-binding lectin-dependent lectin pathway, a novel modulator in outcome from pancreatic islet auto-transplantation.

BACKGROUND: Numerous factors influence pancreatic islet survival following auto-transplantation. Of these, the host immune response in the early peri-operative period is one of the most important. In this study we investigated the role of the mannose-binding lectin (MBL)-dependent pathway in a group of total pancreatectomy (TP) islet auto-transplantation (TPIAT) patients and classified them as competent or deficient in MBL activity. Complement pathway activities, MBL protein and inflammatory cytokine concentrations were evaluated from eleven pancreatic islet auto-transplant patients from two institutions. METHODS: Eleven patients from two institutions were prospectively recruited. Serum was screened at different time points for 29 different cytokines and compared according to their MBL deficient or competent status. Twelve patients from previous TPIAT patients also underwent screening of MBL pathway activity. RESULTS: A total nine of twenty three patients (39%) were MBL pathway deficient. MCP-1, IL-7 and IL-1a concentrations were significantly lower in the MBL deficient cohort compared to the normal MBL group (P=0.0237, 0.0001 and 0.0051 respectively). IL-6 and IL-8 concentrations were significantly raised in the normal MBL group. MBL functional activity was lower in insulin-independent group compared to the insulin-dependent group. CONCLUSIONS: Complement activation is an important, possibly damaging response during intra-portal islet infusion. MBL pathway deficiency appears common in this population and the cytokine response was attenuated in MBL pathway deficient patients. Therapeutic MBL pathway blockade during and following islet auto-transplantation (IAT) may improve islet survival and function and thereby clinical outcome.

Case report of mannose-binding lectin (MBL) deficiency and postoperative sepsis and coagulopathy in a patient following total pancreatectomy for chronic pancreatitis.

CONTEXT: Complement plays a central role against infection and coordinates the activity of coagulation and fibrinolysis. In this report we present a patient that underwent total pancreatectomy experienced sepsis, coagulopathy and bleeding that endangered the postoperative course. CASE REPORT: A sixty-five-year-old woman underwent total pancreatectomy for intractable pain without islet transplant, this patient was diagnosed as AP and MBL deficient from a blood test performed preoperatively. On the postoperative course she experienced severe haemorrhages and sepsis for 3 weeks postoperatively. An analysis of serial perioperative serum samples conducted which showed further depletion of the alternate and MBL complement pathway without restoration to baseline levels. CONCLUSION: This is the first reported case of alternative and mannose-binding lectin pathways depletion associated with major postoperative bleeding and sepsis following pancreatic surgery. Future research should examine the relationship between complement pathways activity and postoperative complications in order to possibly introduce it as a preoperative screening and possible replacement therapy prior to any major surgical intervention.

Patient satisfaction and cost-effectiveness following total pancreatectomy with islet cell transplantation for chronic pancreatitis.

OBJECTIVES: Chronic pancreatitis (CP) results in an extremely poor quality of life and substantially increases health care utilization. Few data exist regarding the cost-effectiveness of surgical treatment for CP. METHODS: This article examined the cost-effectiveness of total pancreatectomy (TP) with islet cell autotransplantation (IAT) for CP. RESULTS: Sixty patients undergoing TP + IAT and 37 patients undergoing TP were identified. Surgery resulted in significant reduction in opiate use, frequency of hospital admissions, and length of stay as well as visual analog scale scores for pain. Total pancreatectomy + IAT resulted in longer survival than TP alone (16.6 vs 12.9 years); 21.6% of patients with TP + IAT were insulin-independent, and those requiring insulin have reduced daily requirements compared with those having TP alone (22 vs 35 IU). The cost of TP + IAT with attendant admission and analgesia costs over the 16-year survival period was £110,445 compared with £101,608 estimated 16-year costs if no TP + IAT was undertaken. CONCLUSIONS: Total pancreatectomy + IAT is effective in improving pain and reducing analgesia. Islet cell transplantation offers the chance of insulin independence and results in lower insulin requirements, as well as conferring a survival advantage when compared with TP alone. Total pancreatectomy + IAT is cost-neutral when compared with nonsurgical or segmental surgical therapy.

Total pancreatectomy with and without islet cell transplantation for chronic pancreatitis: a series of 85 consecutive patients.

OBJECTIVES: This study examined 85 consecutive patients undergoing total pancreatectomy (+/-islet cell transplant), examining pain relief, insulin requirements, and glycemic control postoperatively. METHODS: A prospective database of all patients undergoing total pancreatectomy for chronic pancreatitis was used to record preoperative and postoperative details from 1996 to 2006. RESULTS: There were 3 postoperative deaths (1 islet recipient and 2 nonislet patients). The median number of acute admissions for pain fell from 5 to 2 after pancreatectomy, and the median length of stay from 6.2 days to 3.3 days. At 12 months postoperatively, the number of patients on regular opiate analgesia fell from 90.6% to 40.2% and by 5 years to 15.9%. There was a significant reduction in the patients' visual analogue pain score after surgery from 9.7 to 3.7 (P < 0.001). Five patients were insulin independent at 5 years. Median 24-hour insulin requirements were significantly lower in the islet group (15.5 vs 40 units at 5 years postoperatively; P < 0.001). CONCLUSIONS: Total pancreatectomy is effective in reducing pain and dependence on opioid analgesia in patients with chronic pancreatitis. The addition of an islet cell transplant results in a reduction in 24-hour insulin demands, as well as potentially achieving insulin independence.

Total pancreatectomy with islet autotransplantation: an overview.

Pain control is one of the most challenging aspects in the management of chronic pancreatitis. Total pancreatectomy can successfully relieve the intractable abdominal pain in these patients but will inevitably result in insulin-dependent diabetes. Islet autotransplantation aims to preserve, as far as possible, the insulin secretory function of the islet cell mass thereby reducing (or even removing) the requirement for exogenous insulin administration after a total pancreactomy. Despite the relatively small number of centres able to perform these procedures, there are important technical variations in the details of their approaches. The aim of this review is to provide details of the current surgical practice for total pancreatectomy combined with islet autotransplantation, and outline the potential advantages and disadvantages of the variations adopted in each centre.

Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function.

UNLABELLED: Total pancreatectomy is considered the final resort in the treatment of chronic pancreatitis; however, here we show that simultaneous islet autotransplantation can abrogate the onset of diabetes. METHODS: : In Leicester, 46 patients have now undergone total pancreatectomy with immediate islet auto transplant, and they have received a median of 2246 islet equivalent (IEQ)/kg body weight (range, 405-20,385 IEQ/kg body weight). RESULTS: : Twelve patients have shown periods of insulin independence, for a median of 16.5 months (range, 2-63 months), and 5 remain insulin independent. Over the 10 years of follow-up, there has been a notable increase in insulin requirement per kilogram per day, and percentage of glycosylated hemoglobin levels have increased significantly (r = 0.66, P = 0.01). However, 100% of patients tested were C-peptide positive at their most recent assessment, and high fasting and stimulated C-peptide values recorded at 10 years after transplantation, 1.44 (range, 1.09-1.8 ng/mL) and 2.86 ng/mL (range, 1.19-4.53 ng/mL), respectively, suggest significant graft function in the long term. In addition, median serum creatinine has increased very little after the operation (71 nmol/L [range, 49-125 nmol/L] atpreoperation vs 76.5 nmol/L [range 72-81 nmol/L] at year 10), suggesting no diabetic nephropathy. CONCLUSIONS: : Although there is a notable decline in islet function after islet auto transplant, there is still evidence of significant long-term insulin secretion and possible protection against diabetic complications.