Percutaneous Image-Guided Irreversible Electroporation for the Treatment of Unresectable, Locally Advanced Pancreatic Adenocarcinoma.

PURPOSE: To describe safety and effectiveness of percutaneous irreversible electroporation (IRE) for treatment of unresectable, locally advanced pancreatic adenocarcinoma (LAPC). MATERIALS AND METHODS: This retrospective study included 50 patients (23 women, 27 men; age range, 46-91 y; median age, 62.5 y) with biopsy-proven, unresectable LAPC who received percutaneous computed tomography (CT)-guided IRE. The primary objective was to assess the safety profile of the procedure; the secondary objective was to determine overall survival (OS). All patients had prior chemotherapy (1-5 lines, median 2), and 30 (60%) of 50 patients had prior radiation therapy. Follow-up included CT at 1 month and at 3-month intervals thereafter. RESULTS: There were no treatment-related deaths and no 30-day mortality. Serious adverse events occurred in 10 (20%) of 50 patients (abdominal pain [n = 7], pancreatitis [n = 1], sepsis [n = 1], gastric leak [n = 1]). Median OS was 27.0 months (95% confidence interval [CI], 22.7-32.5 months) from time of diagnosis and 14.2 months (95% CI, 9.7-16.2 months) from time of IRE. Patients with tumors ≤ 3 cm (n = 24) had significantly longer median OS than patients with tumors > 3 cm (n = 26): 33.8 vs 22.7 months from time of diagnosis (P = .002) and 16.2 vs 9.9 months from time of IRE (P = .031). Tumor size was confirmed as the only independent predictor of OS at multivariate analysis. CONCLUSIONS: Percutaneous image-guided IRE of unresectable LAPC is associated with an acceptable safety profile.

Liver Function Tests Following Irreversible Electroporation of Liver Tumors: Experience in 174 Procedures.

Irreversible electroporation (IRE) is a relatively new ablation modality that uses electric currents to cause cell death. It is commonly used to treat primary and secondary liver tumors in patients with normal liver function and preexisting cirrhosis. Retrospective analysis of 205 procedures sought to evaluate changes in liver function after IRE. Liver function tests (LFTs) results before and after IRE were evaluated from 174 procedures in 124 patients. Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase (ALKP), and total bilirubin levels were analyzed. The study was Health Insurance Portability and Accountability Act compliant and institutional review board approved. Informed consent was waived. Changes in LFT results after IRE were compared with baseline and were followed up over time to see if they resolved. Changes were compared with volume of ablation. The greatest perturbations were in transaminase levels. The levels increased sharply within 24 hours after IRE in 129 (74.1%) procedures to extreme levels (more than 20 times the upper limit of normal in one-third of cases). Resolution occurred in 95% and was demonstrated to have occurred by a mean of approximately 10 weeks, many documented as early as 7 days after procedure. ALKP levels elevated in 10% procedures, was slower to increase, and was less likely to resolve. Total bilirubin level demonstrated 2 different patterns of elevation--early and late--and similar to ALKP, it was more likely to remain elevated. There was no increased risk in patients with cirrhosis or cholangiocarcinoma. There was no correlation of levels with volume of ablation. IRE results in significant abnormalities in LFT results, but in most of the cases, these are self-limiting, do not preclude treatment, and are similar to the changes seen after radiofrequency and cryoablation in the liver.

Is Antibiotic Prophylaxis for Percutaneous Radiofrequency Ablation (RFA) of Primary Liver Tumors Necessary? Results From a Single-Center Experience.

PURPOSE: The purpose of this study was to evaluate need for antibiotic prophylaxis for radiofrequency ablation (RFA) of liver tumors in patients with no significant co-existing risk factors for infection. MATERIALS AND METHODS: From January 2004 to September 2013, 83 patients underwent 123 percutaneous RFA procedures for total of 152 hepatocellular carcinoma (HCC) lesions. None of the patients had pre-existing biliary enteric anastomosis (BEA) or any biliary tract abnormality predisposing to ascending biliary infection or uncontrolled diabetes mellitus. No pre- or post-procedure antibiotic prophylaxis was provided for 121 procedures. Data for potential risk factors were reviewed retrospectively and analyzed for the frequency of infectious complications, including abscess formation. RESULTS: One patient (1/121 (0.8%) RFA sessions) developed a large segment 5 liver abscess/infected biloma communicating with the gallbladder 7 weeks after the procedure, successfully treated over 10 weeks with IV and PO antibiotic therapy and percutaneous catheter drainage. This patient did not receive any antibiotics prior to RFA. During the procedure, there was inadvertent placement of RFA probe tines into the gallbladder. No other infectious complications were documented. CONCLUSION: These data suggest that the routine use of prophylactic antibiotics for liver RFA is not necessary in majority of the patients undergoing liver ablation for HCC and could be limited to patients with high-risk factors such as the presence of BEA or other biliary abnormalities, uncontrolled diabetes mellitus, and large centrally located tumors in close proximity to central bile ducts. Larger randomized studies are needed to confirm this hypothesis.

Percutaneous irreversible electroporation for the treatment of colorectal cancer liver metastases with a proposal for a new response evaluation system.

PURPOSE: To describe an initial experience with irreversible electroporation (IRE) in patients with colorectal liver metastasis (CLM). MATERIALS AND METHODS: A retrospective analysis of patients undergoing IRE for the management of CLM was performed. Procedures were done percutaneously under general anesthesia. Patients were then followed for adverse events, tumor response, and survival. RESULTS: Between March 2010 and February 2013, 29 patients underwent percutaneous ablation of 58 tumors in 36 IRE sessions. Most patients (89%) had an absolute or relative contraindication to thermal ablation. The median age was 62 years, and the median time from diagnosis to IRE was 28 months. The median number of lesions treated per patient was two, and the median tumor size was 2.7 cm. Patients had received previous chemotherapy regimens (range, 1-5 per patient). A new Metabolic Imaging And Marker Integration response evaluation criteria was used for response assessment, and was a predictor of progression-free and overall survival. The 2-year progression-free survival rate was 18% (95% confidence interval, 0%-35%), and the 2-year overall survival rate was 62% (95% confidence interval, 37%-87%). Complications included arrhythmias (n = 1) and postprocedure pain (n = 1). Both patients recovered without sequelae. CONCLUSIONS: Percutaneous IRE of CLM is feasible and safe. A new response evaluation system for colorectal cancer appears to be prognostic.

Irreversible electroporation of hepatic malignancy.

Hepatocellular carcinoma (HCC) is a worldwide problem of epidemic proportions, best treated in a multidisciplinary setting. Major advances have been made in all specialties that manage patients with HCC, with surgical options at one end of the spectrum and palliative chemotherapy on the other, and the vast majority of patients require the involvement and expertise of interventional oncology. Several ablative and transarterial technologies are currently available. Irreversible electroporation (IRE) is a new ablative technology that uses high-voltage, low-energy DC current to create nanopores in the cell membrane, disrupting the homeostasis mechanism and inducing cell death by initiating apoptosis. This article discusses the evolution of IRE as well as its safety and efficacy in the context of other ablative therapies in the treatment of hepatic malignancies.

Pain analysis in patients with hepatocellular carcinoma: irreversible electroporation versus radiofrequency ablation-initial observations.

PURPOSE: To retrospectively compare the postprocedure pain of hepatocellular carcinoma treated with irreversible electroporation (IRE) with radiofrequency ablation (RFA). METHODS: This Health Insurance Portability and Accountability Act-compliant, institutional review board-approved study compared postprocedure pain in 21 patients (15 men, six women; mean age 61.5 years) who underwent IRE of 29 intrahepatic lesions (mean size 2.20 cm) in 28 IRE sessions with 22 patients (16 men, six women; mean age 60.2 years) who underwent RFA of 27 lesions (mean size 3.38 cm) in 25 RFA sessions. Pain was determined by patient-disclosed scores with an 11-point numerical rating scale and 24 h cumulative hydromorphone use from patient-controlled analgesia pump. Complications were noted. Statistical significance was evaluated by Fisher's exact test, the Chi-square test, and Student's t test. RESULTS: There was no significant difference in the cumulative hydromorphone dose (1.54 mg (IRE) vs. 1.24 mg (RFA); P = 0.52) and in the mean pain score (1.96 (IRE) vs. 2.25 (RFA); P = 0.70). In nine (32.14 %) of 28 IRE sessions and 11 (44.0 %) of 25 RFA sessions, patients reported no pain. Complications occurred in three (10.7 %) of 28 IRE treatments and included pneumothorax (n = 1), pleural effusion (n = 1), and bleeding in the form of hemothorax (n = 1); one (4 %) of 25 RFA treatments included burn. CONCLUSION: IRE is comparable to RFA in the amount of pain that patients experience and the amount of pain medication self-administered. Both modalities were well tolerated by patients. Prospective, randomized trials are necessary to further evaluate these findings.

Percutaneous irreversible electroporation for downstaging and control of unresectable pancreatic adenocarcinoma.

PURPOSE: Treatment of unresectable locally advanced pancreatic cancer (LAPC) usually includes chemotherapy and/or radiation therapy in an attempt to downstage these tumors to the extent of resectability, but outcomes remain poor. Irreversible electroporation (IRE) is an ablative modality that may be useful in this population. The aim of this study was to evaluate the safety of percutaneous IRE in patients with pancreatic adenocarcinoma. MATERIALS AND METHODS: IRE was performed in patients with pancreatic cancer whose tumors remained unresectable after, or who were intolerant of, standard therapy. The procedures were all done percutaneously under general anesthesia. Patients were then followed for adverse events, tumor response, and survival. RESULTS: Fifteen IRE procedures were performed in 14 patients (one was treated twice). Three patients had metastatic disease and 11 had LAPC. All patients had received chemotherapy previously, and 11 had received radiation. The median tumor size was 3.3 cm (range, 2.5-7 cm). Immediate and 24-hour postprocedural scans demonstrated patent vasculature in the treatment zone in all patients. Two patients underwent surgery 4 and 5 months after IRE, respectively. Both had margin-negative resections, and one had a pathologic complete response; both remain disease-free after 11 and 14 months, respectively. Complications included spontaneous pneumothorax during anesthesia (n = 1) and pancreatitis (n = 1), and both patients recovered completely. There were no deaths directly related to the procedure. All three patients with metastatic disease at IRE died from progression of their disease. CONCLUSIONS: Percutaneous IRE for pancreatic adenocarcinoma is feasible and safe. A prospective trial is being planned.

Nonalbumin proteinuria in islet transplant recipients.

The aim of this study was to evaluate the importance of nonalbumin-predominant proteinuria on kidney function (KF) after islet transplantation (ITx). Twenty-four-hour proteinuria and albuminuria were available in 27 recipients. KF was assessed by serum creatinine and estimated glomerular filtration rate (eGFR) was calculated by Modification of Diet in Renal Disease formula. Correlations between eGFR and albuminuria (r = -0.422, p < 0.001) were higher than with proteinuria (r = -0.223, p < 0.001; p = 0.006 for comparison between correlations). Nineteen (70%) subjects had proteinuria >or= 300 mg/24 h during the follow-up. Subjects were divided into three groups according to urinary protein excretion patterns: no proteinuria (n = 8), nonalbumin-predominant (n = 8), and albumin-predominant (n = 11) proteinuria. Proteinuria >or= 500 mg/24 h was observed only among patients with albumin-predominant proteinuria (64%; p = 0.002) and these patients had the lowest eGFR means post-ITx (no proteinuria: 84.2 +/- 16.4 vs. nonalbumin: 69.1 +/- 13.8 vs. albumin-predominant proteinuria: 65.5 +/- 16.6 ml/min/1.73 m(2), p = 0.044 for first vs. last group). In conclusion, high frequency of proteinuria was observed after ITx. However, it seems to be milder and have less impact on KF when albumin is not the major source of proteinuria. Prospective evaluation of proteinuria, including tubular function markers, should be performed to elucidate the mechanisms of kidney damage in this population.

Long-term metabolic and hormonal effects of exenatide on islet transplant recipients with allograft dysfunction.

The initial success of islet transplantation (ITx) is followed by graft dysfunction (GDF) and insulin reintroduction. Exenatide, a GLP-1 agonist, increases insulin and decreases glucagon secretion and has potential for beta-cell regeneration. To improve functional islet mass, exenatide treatment was given to ITx recipients with GDF. The objective of this study was to assess metabolic and hormonal effects of exenatide in GDF. In this prospective, single-arm, nonrandomized study, 11 type 1 diabetes recipients of ITx with GDF had HbA1c, weight, insulin requirements, and 5-h mixed meal tolerance test (MMTT; with/without exenatide given before test) at baseline, 3, 6, and 12 months after initiating exenatide treatment. Baseline MMTT showed postprandial hyperglycemia and hyperglucagonemia. Daily exenatide treatment resulted in improved glucose, increased amylin/insulin ratio, and decreased proinsulin/insulin ratio as assessed by MMTT. Glucagon responses remained unchanged. Exenatide administration 1 h before MMTT showed decreased glucagon and glucose at 0 min and attenuation in their postprandial rise. Time-to-peak glucose was delayed, followed by insulin, proinsulin, amylin, and C-peptide, indicating glucose-driven insulin secretion. Five subjects completed 12-month follow-up. Glucose and glucagon suppression responses after MMTT with exenatide were no longer observed. Retrospective 3-month analysis of these subjects revealed higher and sustained glucagon levels that did not suppress as profoundly with exenatide administration, associated with higher glucose levels and increased C-peptide responses. In conclusion, Exenatide suppresses the abnormal postprandial hyperglucagonemia and hyperglycemia observed in GDF. Changes in amylin and proinsulin secretion may reflect more efficient insulin processing. Different degrees of responsiveness to exenatide were identified. These may help guide the clinical management of ITx recipients.

Clinical use of fructosamine in islet transplantation.

Many islet transplant recipients have medical conditions that could interfere with the accuracy of HbA1c measurements (e.g., anemia/dapsone use). Fructosamine is less prone to have clinical interferences and reflects glucose control in a shorter period of time than HbA1c. This study aimed to validate fructosamine use in islet transplant subjects and to evaluate its effectiveness as a predictor for islet graft dysfunction. Thirty-three islet transplant recipients who had concomitant fructosamine and HbA1c data available were retrospectively analyzed. HbA1c, fructosamine, mean capillary blood glucose, and islet graft function (fasting C-peptide/glucose ratio) were assessed. There was a significant and positive association between fructosamine and HbA1c (p < 0.0001). Both variables were also positively associated with mean overall and fasting capillary glucose. Neither fructosamine nor HbA1c was shown by ROC analysis to significantly discriminate between periods with and without subsequent graft dysfunction. HbA1c >6% was predictive of this outcome 1 month in advance (OR 2.95, p = 0.003). However, although significantly associated with graft dysfunction, use of this cutoff as a predictor of dysfunction has poor sensitivity (50%) and specificity (77.6%). Fructosamine above the normal range (>270 mumol/L Quest Diagnostics) was also predictive of ensuing dysfunction (OR 2.47, p = 0.03); however, it had similarly poor sensitivity (62%) and specificity (64%). Fructosamine can be used as an alternative to HbA1c for glycemic assessment in islet transplant recipients in situations with HbA1c assay interference. Neither HbA1c nor fructosamine are good predictors of islet graft dysfunction.

Stable renal function after islet transplantation: importance of patient selection and aggressive clinical management.

BACKGROUND: Proteinuria development and decrease in glomerular filtration rate (GFR) have been observed after successful islet transplantation. The aim of this study was to determine clinical, laboratory, and immunosuppressant-related factors associated with kidney dysfunction in islet transplant recipients. METHODS: A retrospective cohort study was conducted in 35 subjects submitted to pancreatic islet transplantation for treatment of unstable type 1 diabetes mellitus. Demographic, anthropometrical, and laboratory data, as well as immunosuppressive and antihypertensive therapy were recorded. Kidney function was assessed by albuminuria and estimated GFR (eGFR), calculated by modification of diet in renal disease formula. RESULTS: Age was the only independent risk factor for low eGFR (<60 mL/min/1.73 m2) (odds ratio [OR]=1.78 [1.22-2.61]). Low-density lipoprotein cholesterol (OR=2.90 [1.37-6.12]) and previous microalbuminuria (OR=6.42 [1.42-29.11]) were risk factors for transient macroalbuminuria. Interestingly, tacrolimus was a protective factor for macroalbuminuria (OR=0.12 [0.06-0.26]). Six of 30 (20%) normoalbuminuric subjects at baseline progressed to microalbuminuria. No subject developed sustained macroalbuminuria. Surprisingly, overall eGFR remained stable during follow-up (before transplant: 74.0+/-2.0; during immunosuppressive therapy: 75.4+/-2.8; and after withdrawal: 76.3+/-5.3 mL/min/1.73 m2; P>0.05). Even subjects with low eGFR and microalbuminuria at baseline (n=10) maintained stable values posttransplantation (61.13+/-3.25 mL/min/1.73 m2 vs. 63.32+/-4.36 mL/min/1.73 m2, P=0.500). CONCLUSIONS: Kidney function remained stable after islet transplantation alone. The unchanged kidney function found in this sample may be attributed to healthier kidney status at baseline and possibly to prompt treatment of modifiable risk factors. Aggressive treatment of risk factors for nephropathy, such as blood pressure, low-density lipoprotein cholesterol, and careful tacrolimus levels monitorization, should be part of islet transplant recipient care.

Early metabolic markers of islet allograft dysfunction.

BACKGROUND: Islet transplantation can restore normoglycemia to patients with unstable type 1 diabetes mellitus, but long-term insulin independence is usually not sustained. Identification of predictor(s) of islet allograft dysfunction (IGD) might allow for early intervention(s) to preserve functional islet mass. METHODS: Fourteen islet transplantation recipients with long-term history of type 1 diabetes mellitus underwent metabolic testing by mixed meal tolerance test, intravenous glucose tolerance test, and arginine stimulation test every 3 months postislet transplant completion. Metabolic responses were compared between subjects who maintained insulin independence at 18 months (group 1; n=5) and those who restarted insulin within 18 months (group 2; n=9). Data were analyzed before development of islet graft dysfunction and while insulin independent. RESULTS: The 90-min glucose, time-to-peak C-peptide, and area under the curve for glucose were consistently higher in group 2 and increased as a function of time. At 12 months, acute insulin release to glucose in group 2 was markedly reduced as compared with baseline (5.62+/-1.21 microIU/mL, n=4 vs. 16.14+/-3.69 microIU/mL, n=8), whereas it remained stable in group 1 (22.36+/-4.98 microIU/mL, n=5 vs. 27.70+/-2.83 microIU/mL, n=5). Acute insulin release to glucose, acute C-peptide release to glucose (ACpRg), and mixed meal stimulation index were significantly decreased and time-to-peak C-peptide, 90-min glucose, and area under the curve for glucose were significantly increased when measured at time points preceding intervals where IGD occurred compared with intervals where there was no IGD. CONCLUSIONS: The intravenous glucose tolerance test and mixed meal tolerance test may be useful in the prediction of IGD and should be essential components of the metabolic testing of islet transplant recipients.

Long-term insulin independence and improvement in insulin secretion after supplemental islet infusion under exenatide and etanercept.

BACKGROUND: Progressive graft dysfunction (GDF) and loss of insulin independence (II) have been invariably observed in islet transplant recipients under the "Edmonton protocol." To reestablish II, we performed supplemental islet infusions (SI) in recipients of allogeneic islet transplant alone, displaying GDF. To improve the engraftment and long-term graft function of SI, exenatide (EXN) and etanercept treatment at islet infusion, and long-term EXN treatment were tested in a non-randomized pilot clinical trial. METHODS: Patients with GDF received SI under Edmonton-like immunosuppression with daclizumab induction, either without interventions (SI-control; n=5) or with EXN and etanercept treatment (SI-EXN; n=4). Clinical and metabolic profiles were assessed during 18-month follow-up. RESULTS: Long-term II (18 months) was observed in 100% of SI-EXN and in 20% of SI-control (P=0.04). SI-EXN subjects demonstrated restoration of function better than that seen after initial islet infusions. Comparison of SI-EXN and SI-control groups demonstrated better responses in SI-EXN subjects at 3 months post-SI. During the 18 months of follow-up, function was sustained in the SI-EXN subjects better than in SI-controls. Acute effects of EXN during mixed meal tolerance test and intravenous glucose tolerance test results in improved first and second phase insulin release in response to intravenous glucose tolerance test and suppressed postprandial hyperglucagonemia after mixed meal tolerance test. CONCLUSION: These results suggest that the combination of EXN and etanercept improve engraftment and long-term islet survival and function in subjects undergoing SI. This data, however, must be interpreted with some caution because of small sample size, lack of randomization, and sequential comparison with historical controls.

Islet transplantation with alemtuzumab induction and calcineurin-free maintenance immunosuppression results in improved short- and long-term outcomes.

BACKGROUND: Only a minority of islet transplant recipients maintain insulin independence at 5 years under the Edmonton protocol of immunosuppression. New immunosuppressive strategies are required to improve long-term outcomes. MATERIALS AND METHODS: Three subjects with unstable type 1 diabetes mellitus underwent islet transplantation with alemtuzumab induction and sirolimus-tacrolimus maintenance for 3 months and then sirolimus-mycophenolic acid maintenance thereafter. Follow-up was more than 2 years. Comparison was with 16 historical subjects transplanted under the Miami version of the Edmonton protocol. RESULTS: Insulin independence was achieved in 2 of 3 alemtuzumab and 14 of 16 historical subjects. Those who did not achieve insulin independence only received a single islet infusion. Insulin-independence rates remained unchanged in the alemtuzumab group, but decreased from 14 of 16 (88%) to 6 of 16 (38%) in the historical group over 2 years. Insulin requirements increased in the historical group while remaining stable in the alemtuzumab group. Comparison of functional measures at 3 months suggested better engraftment with alemtuzumab (P=NS). Further comparison of alemtuzumab versus historical groups, up to 24 months, demonstrated significantly better: Mixed meal stimulation index (24 months, 1.0+/-0.08 [n=3] vs. 0.5+/-0.06 pmol/mL [n=6], P<0.01), mixed meal peak C-peptide (24 months, 5.0+/-0.5 [n=3] vs. 3.1+/-0.3 nmol/mL [n=6], P<0.05), HbA1c (24 months, 5.4+/-0.15 [n=3] vs. 6.3+/-0.12 pmol/mL [n=10], P<0.01). Administration of alemtuzumab was well tolerated. There was no increased incidence of infections in alemtuzumab subjects despite profound, prolonged lymphocyte depletion. CONCLUSIONS: Islet transplantation with alemtuzumab induction was well tolerated and resulted in improved short- and long-term outcomes. Further investigation is underway for validation.

Improved long-term health-related quality of life after islet transplantation.

BACKGROUND: Health related quality of life (HRQoL) is one of the most important outcomes to measure effectiveness of an intervention, especially for islet transplantation in which benefits should outweigh risks of long-term immunosuppression. This study aimed to evaluate long-term effects of islet transplantation and to outline possible influential factors. METHODS: Forty islet transplant recipients who completed 344 Health Status Questionnaires (HSQ 2.0) and 384 Diabetes Quality of Life Questionnaires (DQoL) between 2000 and 2007 were retrospectively reviewed. Assessments were analyzed in pretransplantation period, then every 3 months after the first infusion for 18 months and every 6 months thereafter. The mean follow-up posttransplantation was 40.8+/-21.9 months (9-72 months). RESULTS: Sustained improvement in DQoL-impact score was observed at all time-points posttransplantation. Similarly, worry and satisfaction scales were significantly better than pretransplant evaluation for most time-points. Four of eight HSQ 2.0 scales demonstrated a significant improvement at some time-points. Longitudinal analysis, after adjustments for potential confounding factors, showed significantly sustained improvement in impact scale up to 72 months. Longer diabetes duration, higher insulin dosage, and occurrence of adverse events had negative effects on HRQoL. Single islet infusion or islet after kidney transplant recipients showed the lowest values in HSQ 2.0. In contrast, subjects on exenatide therapy had significantly higher HSQ 2.0 scores. CONCLUSIONS: Islet transplantation is associated with long-term improvement in HRQoL. Exenatide usage had a positive effect whereas single islet infusion, islet after kidney transplantation, longer diabetes duration, higher insulin dosage, and adverse events had a negative impact on HRQoL scores.

The use of exenatide in islet transplant recipients with chronic allograft dysfunction: safety, efficacy, and metabolic effects.

BACKGROUND: A current limitation of islet transplantation is reduced long-term graft function. The glucagon-like peptide-1 receptor agonist, exenatide (Byetta, Amylin Pharmaceuticals, CA) has properties that could improve existing islet function, prevent further loss of islet mass and possibly even stimulate islet regeneration. METHODS: This prospective study evaluated the safety, efficacy, and metabolic effects of exenatide in subjects with type 1 diabetes mellitus and islet allograft dysfunction requiring exogenous insulin. RESULTS: Sixteen subjects commenced exenatide, 12 continue (follow-up 214+/-57 days; range 108-287), four (25%) discontinued medication because of side effects. At 6 months, exogenous insulin was significantly reduced with stable glycemic control (0.15+/-0.02 vs. 0.11+/-0.025 U/kg per day; P<0.0001); three subjects discontinued insulin from 4, 5, and 9 U/day, respectively, two sustained insulin independence with A1c reduction below graft dysfunction criteria. Postprandial capillary blood glucose was significantly decreased (129.4+/-3.8 vs. 118.7+/-4.6 mg/dL; P<0.001), C-peptide and C-peptide-to-glucose ratio increased significantly by 5th and 6th months of treatment (ratio, 1.09+/-0.15 vs. 1.52+/-0.18; P<0.05). Weight loss more than 3 kg occurred in 8 of 12 (67%) subjects. Stimulation testing demonstrated improved glucose disposal and C-peptide secretion (glucose area under the curve 52,332+/-3,219 vs. 42,072+/-1,965; P=0.002 mg x min x dL, mixed meal stimulation index 0.50+/-0.06 vs. 0.66+/-0.09; P=0.03 pmol x mL), with marked suppression of glucagon secretion and progressive increase in amylin secretion. Side effects were more frequent and severe compared with published reports in type 2 diabetes, tolerated doses were lower. CONCLUSIONS: Exenatide was tolerated in this patient population after appropriate dose titration and there appeared to be gradual but sustained positive effects on glycemic control and islet graft function.

Improved metabolic control and quality of life in seven patients with type 1 diabetes following islet after kidney transplantation.

BACKGROUND: The beneficial effects of glycemic control on both survival and function of transplanted kidneys in patients with type 1 diabetes mellitus (T1DM) and end-stage renal disease (ESRD) have been recognized. METHODS: Herein, we present the clinical outcome of a single-center pilot trial of islet after kidney (IAK) transplantation in seven patients with T1DM. The immunosuppression protocol for the kidney graft was converted to sirolimus+tacrolimus regimen 6 months before islet transplantation to exclude negative effects on kidney graft function. Primary endpoint was achievement of insulin independence after transplantation. Clinical outcome, metabolic control, severe hypoglycemia, kidney function, Quality of Life (QOL) psychometric measures, and adverse events were monitored. RESULTS: Seven patients showed graft function with improved metabolic control (A1c, fasting glycemia, and metabolic tests) after IAK (14,779+/-3,800 IEQ/kg). One-year insulin independence was 30% with persistent graft function in 86% (C-peptide-positive). A1c reduction was 1.95+/-0.31% from baseline (P<0.0001). No episodes of severe hypoglycemia were observed, even after resuming insulin. The direct consequence of these benefits was a significant improvement in diabetes QOL. Adverse events included procedure-related pleural effusion (n=2), cholecystitis (n=1), and additional immunosuppression-related, all resolved without sequelae. Kidney function (by estimated glomerular filtration rate) remained stable during follow-up in six of seven patients. CONCLUSIONS: Islet transplantation represents a feasible therapeutic option for patients with T1DM bearing a stable kidney allograft. Insulin independence at 1 year is lower than what reported in islet transplant alone. Nevertheless, clear benefits in terms of optimal metabolic control and absence of severe hypoglycemia are invariably present.

Nutritional status and behavior in subjects with type 1 diabetes, before and after islet transplantation.

BACKGROUND: To investigate whether changes of nutritional status and behavior are associated with islet transplantation (ITx) and to assess their possible mechanisms. METHODS: In this observational study, 52 subjects with type 1 diabetes, 30 of whom received ITx, underwent nutritional assessments. The study consisted of questionnaires complemented by a dietary intake recording, anthropometric measurements, and body composition analysis. Laboratory tests were also reviewed as part of the follow up. RESULTS: After ITx, significant reductions in body weight (3.7 kg; P<0.0001), body mass index (1.39 kg/m2; P<0.0001), waist circumference (3.96 cm; P=0.006), and fat weight (3.28 kg; P<0.01) were observed. The average consumption of carbohydrate and protein were also lower than pretransplant, together with some micronutrients (vitamins B12 and B6, zinc, and phosphorus). Insulin administration and changes in A1C were not associated with a significant change in anthropometric measurements. Subjects on exenatide after ITx showed significantly lower weight and body mass index than those not taking exenatide. CONCLUSIONS: ITx is associated with modifications in nutritional behavior and status. Drugs and health conditions are likely to be at least in part responsible for these changes, but a voluntary modification of eating habits by the patients also plays a role. Strict monitoring of nutritional parameters, counseling by experts in nutrition, and multivitamin/mineral supplement after ITx could be of benefit to the patients.