Medical Policy: 07.03.01
Original Effective Date: October 2004
Reviewed: October 2018
Revised: October 2018
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Autologous islet cell transplantation performed in conjunction with pancreatectomy, is proposed to reduce the likelihood of insulin-dependent diabetes. Allogeneic islet cell transplantation is being investigated as a treatment or cure for patients with type 1 diabetes.
The islet cells come from the patient (autologous transplant) or from a cadaveric donor (allogeneic transplant). Islet cell transplantation may benefit an individual who is without a functioning pancreas. Currently, only individuals with either chronic pancreatitis or type 1 diabetes mellitus have been subject to clinical investigations.
Autologous islet cell transplantation is generally performed during the pancreatectomy procedure, and the islet cells are isolated from the resected pancreas using enzymes, and a suspension of the cells is injected into the portal vein of the patient’s liver. Once implanted, the beta cells in these islets begin to make and release insulin. Because the body recognizes these islet cells as its own, there is no rejection of these cells by the patient’s body.
Allogeneic islet transplantation potentially offers an alternative to whole-organ pancreas transplantation. In the case of allogeneic islet cell transplantation, cells are harvested from a deceased donor’s pancreas, processed, and injected into the recipient’s portal vein. Up to 3 donor pancreas transplants may be required to achieve insulin dependence. However, a limitation of islet transplantation is that 2 or more donor organs are usually required for a successful transplantation, although experimentation with single-donor transplantation is occurring. A pancreas that is rejected for whole organ transplant is typically used for allogeneic islet transplantation. Therefore, allogeneic islet transplantation has generally been reserved for patients with frequent and severe metabolic complications who have consistently failed to achieve control with insulin based management. A modified immunosuppression regimen has increased the success of allogeneic islet transplantation, this regimen is known as the “Edmonton protocol” (sirolimus, tacrolimus and monoclonal antibody daclizumab).
Chronic pancreatitis is inflammation of the pancreas that does not heal or improve, it gets worse over time and leads to permanent damage. Chronic pancreatitis eventually impairs an individual’s ability to digest food and make pancreatic hormones. Individuals with chronic pancreatitis can experience intractable pain that can only be relieved with a total or near total pancreatectomy. However, the pain relief must be balanced against the certainty that the individual will be rendered an insulin-dependent diabetic.
The purpose of autologous pancreas islet transplantation for patients with chronic pancreatitis who are undergoing total or near total pancreatectomy is to provide a treatment option that is an alternative to or an improvement on existing therapies. Outcomes of interest include overall survival, insulin independence, change in disease status, medication use, resource utilization and treatment-related morbidity. Short-term follow-up is required to monitor for treatment related complications and long-term follow- up is required to establish durability of glucose control. Islet transplantation is provided in a hospital setting with specialized staff who are equipped to perform the interventional radiology procedure and manage post-transplant care.
There are several systematic reviews of the literature on chronic pancreatitis patients.
Dong et. al. (2011) published a systematic review and meta-analysis of studies on islet auto-transplantation after pancreatectomy for minimizing diabetes. Fifteen observational studies were eligible (11 islet autologous transplant (IAT) post total pancreatectomy (TP), two post-partial pancreatectomy (PP) and two including both). The insulin independence (II) rates for IAT post-TP at last follow-up and transiently during the study were 4·62 per 100 person-years (95% CI: 1·53-7·72) and 8·34 per 100 person-years (95% CI: 3·32-13·37), respectively. In the later group, patients achieved transient insulin independence (II) lasting 15·57 months (95% CI: 10·35-20·79). The insulin-independence (II) rate at last follow-up for IAT post-PP was 24·28 per 100 person-years (95% CI: 0·00-48·96). Whereas the 30-day mortality for IAT post-TP and post-PP was 5% (95% CI: 2-10%) and 0, respectively, the long-term mortality was 1·38 per 100 person-years (95% CI: 0·66-2·11) and 0·70 per 100 person-years (95% CI: 0·00-1·80) respectively. The authors concluded islet autologous transplantation (IAT) post pancreatectomy offers some patients a chance for insulin independence. Better data reporting are essential to establish the risks and benefits of IAT after pancreatic surgery.
In 2015, Wu et. al. published a systematic review and meta-analysis of studies on islet transplantation after total pancreatectomy (TP) for chronic pancreatitis (CP). Twelve studies reporting the outcomes of 677 patients were included in this review. The insulin independent rate for islet autologous transplant (IAT) after total pancreatectomy (TP) at last follow-up was 3.72 per 100 person-years (95% CI: 1.00-6.44). The 30-day mortality was 2.1% (95% CI: 1.2-3.8%). The mortality at last follow-up was 1.09 per 100 person-years (95% CI: 0.21-1.97). Factors associated with incidence density of insulin independence in univariate meta-regression analyses included islet equivalents per kg body weight (IEQ/kgBW) (P=0.026). Our systematic review suggests that IAT is a safe modality for patients with CP need to undergo TP. A significant number of patients will achieve insulin independence for a long time after receiving enough IEQ/kgBW.
Sutherland et. al. (2012) reported on 409 patients (including 53 children, 5 to 18 years) with chronic pancreatitis (CP) who underwent total pancreatectomy (TP) and islet autologous transplantation (IAT) at a single center. Islet function was classified as insulin independent for those on no insulin; partial, if known C-peptide positive or euglycemic on once-daily insulin; and insulin dependent if on standard basal-bolus diabetic regimen. A 36-item Short Form (SF-36) survey for quality of life was completed by patients before and in serial follow-up since 2007, with an integrated survey that was added in 2008.
Actuarial patient survival post TP-IAT was 96% in adults and 98% in children (1 year) and 89% and 98% (5 years). Complications requiring relaparotomy occurred in 15.9% and bleeding (9.5%) was the most common complication. IAT function was achieved in 90% (C-peptide >0.6 ng/mL). At 3 years, 30% were insulin independent (25% in adults, 55% in children) and 33% had partial function. Mean hemoglobin A1c was <7.0% in 82%. Earlier pancreas surgery lowered islet yield (2,712 vs 4,077/kg; p = 0.003). Islet yield (<2,500/kg [36%]; 2,501 to 5,000/kg [39%]; >5,000/kg [24%]) correlated with degree of function with insulin-independent rates at 3 years of 12%, 22%, and 72%, and rates of partial function 33%, 62%, and 24%. All patients had pain before TP-IAT and nearly all were on daily narcotics. After TP-IAT, 85% had pain improvement. By 2 years, 59% had ceased narcotics. All children were on narcotics before, 39% at follow-up; pain improved in 94%; and 67% became pain-free. In the SF-36 survey, there was significant improvement from baseline in all dimensions, including the Physical and Mental Component Summaries (p < 0.01), whether on narcotics or not. The authors concluded, total pancreatectomy (TP) can ameliorate pain and improve quality of life in otherwise refractory chronic pancreatitis (CP) patients, even if narcotic withdrawal is delayed or incomplete because of earlier long-term use. Islet autologous transplantation (IAT) preserves meaningful islet function in most patients and substantial islet function in more than two thirds of patients, with insulin independence occurring in one quarter of adults and half the children.
In 2014, Wilson et. al. reported on 166 patients with chronic pancreatitis (CP) who underwent total pancreatectomy and islet autologous transplantation at a single center. Actuarial survival rate at 5 years was 94.6%. Five or more years of data were available for 112 (67%) patients. At 1 year, 38% of patients were insulin independent and that declined to 27% at the 5-year follow-up. Daily insulin requirement, however, remained stable over the 5 years. Fifty-five percent of patients were independent of opioid analgesics at 1 year and improved to 73% at 5 years.
Chinnakotla et. al. (2014) reviewed a prospectively maintained database of 484 patients with chronic pancreatitis who underwent a total pancreatectomy (TP) and immediate islet autologous transplantation (IAT) at a single center. The outcomes (e.g., pain relief, narcotic use, β-cell function, health-related quality of life measures) of patients who received TP-IAT for hereditary/genetic pancreatitis (HGP) (protease trypsin 1, n = 38; serine protease inhibitor Kazal type 1, n = 9; cystic fibrosis transmembrane conductance regulator, n = 14; and familial, n = 19) were evaluated and compared with those with non-hereditary/nongenetic causes. All 80 patients with HGP were narcotic dependent and failed endoscopic management or direct pancreatic surgery. Post TP-IAT, 90% of the patients were pancreatitis pain free with sustained pain relief; >65% had partial or full β-cell function. Compared with nonhereditary causes, HGP patients were younger (22 years old vs 38 years old; p ≤ 0.001), had pancreatitis pain of longer duration (11.6 ± 1.1 years vs 9.0 ± 0.4 years; p = 0.016), had a higher pancreas fibrosis score (7 ± 0.2 vs 4.8 ± 0.1; p ≤ 0.001), and trended toward lower islet yield (3,435 ± 361 islet cell equivalent vs 3,850 ± 128 islet cell equivalent; p = 0.28). Using multivariate logistic regression, patients with non-HGP causes (p = 0.019); lower severity of pancreas fibrosis (p < 0.001); shorter duration of years with pancreatitis (p = 0.008); and higher transplant islet cell equivalent per kilogram body weight (p ≤ 0.001) were more likely to achieve insulin independence (p < 0.001). There was a significant improvement in health-related quality of life from baseline by RAND 36-Item Short Form Health Survey and in physical and mental component health-related quality of life scores (p < 0.001). None of the patients in the entire cohort had cancer of pancreatic origin in the liver or elsewhere develop during 2,936 person-years of follow-up. The authors concluded, total pancreatectomy and islet autologous transplantation in patients with chronic pancreatitis due to hereditary/genetic pancreatitis (HGP) cause provide long-term pain relief (90%) and preservation of β-cell function. Patients with chronic painful pancreatitis due to HGP with a high lifetime risk of pancreatic cancer should be considered earlier for total pancreatectomy (TP) and islet autologous transplantation (IAT) before pancreatic inflammation results in a higher degree of pancreatic fibrosis and islet function loss.
Autologous islet transplantation is frequently performed as an adjunct to total or near total pancreatectomies for chronic pancreatitis. Evidence from nonrandomized studies and systematic reviews has demonstrated that autologous islet transplantation decreases the incidence of diabetes in the setting of pancreatectomies for the treatment of chronic pancreatitis.
Glucose control is a challenge for individual with type I diabetes. Failure to prevent disease progression can lead to long-term complications such as retinopathy, neuropathy, nephropathy, and cardiovascular disease.
The purpose of allogeneic pancreas islet transplantation for patient who have type I diabetes is to provide a treatment option that is an alternative to or an improvement on existing therapies. General outcomes of interest are overall survival, insulin independence, change in disease status, medication use, resource utilization, and treatment-related morbidity.
According to U.S. Food and Drug Administration industry guidance on evaluating allogeneic pancreatic islet cell products, single-arm trials with historical controls may be acceptable alternatives to randomized controlled trials (RCTs) for evaluating the safety and efficacy of islet cell products in patients with metabolically unstable type I diabetes. Attainment of a normal hemoglobin A1C (HbA1C) range (i.e. < 6.5%) and elimination of hypoglycemia are acceptable primary end points. To assess the durability of the islet cell procedure, primary end points should be measured at 12 months after the final infusion. Other key clinical outcomes include insulin independence, measures of glucose metabolic control such as fasting plasma glucose levels and loss of hypoglycemia unawareness.
Short-term follow-up is required to monitor for transplant related complications, the long-term follow-up to assess the durability of glucose control and monitor immunosuppression is lifelong. Islet transplantation is provided in a hospital setting with specialized staff who are equipped to performed the interventional radiology procedure and manage post-transplant care.
A systematic review by Health Quality Ontario (2015) reported on allogeneic islet transplantation for patients with type I diabetes. The search yielded 1,354 citations. One health technology assessment, 11 additional observational studies to update the health technology assessment, one registry report, and four guidelines were included; the observational studies examined islet transplantation alone, islet-after-kidney transplantation, and simultaneous islet-kidney transplantation. In general, low to very low quality of evidence exists for islet transplantation in patients with type 1 diabetes with difficult-to-control blood glucose levels, with or without kidney disease, for these outcomes: health-related quality of life, secondary complications of diabetes, glycemic control, and adverse events. However, high quality of evidence exists for the specific glycemic control outcome of insulin independence compared with intensive insulin therapy. For patients without kidney disease, islet transplantation improves glycemic control and diabetic complications for patients with type 1 diabetes when compared with intensive insulin therapy. However, results for health-related quality of life outcomes were mixed, and adverse events were increased compared with intensive insulin therapy. For patients with type 1 diabetes with kidney disease, islet-after-kidney transplantation or simultaneous islet-kidney transplantation also improved glycemic control and secondary diabetic complications, although the evidence was more limited for this patient group. Compared with intensive insulin therapy, adverse events for islet-after-kidney transplantation or simultaneous islet-kidney transplantation were increased, but were in general less severe than with whole pancreas transplantation. The authors concluded, for patients with type 1 diabetes with difficult-to-control blood glucose levels, islet transplantation may be a beneficial β-cell replacement therapy to improve glycemic control and secondary complications of diabetes. However, there is uncertainty in the estimates of effectiveness because of the generally low to very low quality of evidence for all outcomes of interest. Additional long-term comparative studies are required for better understanding of continuing effects of transplanted islets and the immunosuppression protocols used.
In 2018, Leblanche et. al. published a multicenter, open-label, randomized controlled trial (TRIMECO trial) evaluating patients with type I diabetes with severe hypoglycemia or poorly controlled glycaemia after kidney transplantation. Patients with type I diabetes were randomly assigned (1:1) at 15 university hospital to receive immediate allogeneic islet transplantation or intensive insulin therapy (followed by delayed islet transplantation). Eligible patients were aged 18-65 years and had severe hypoglycemia or hypoglycemia unawareness, or kidney grafts with poor glycaemic control. We used computer-generated randomization, stratified by center and type of patient. Islet recipients were scheduled to receive 11,000 islet equivalents per kg bodyweight in one to three infusions. The primary outcome was proportion of patients with a modified β-score (in which an overall score of 0 was not allocated when stimulated C-peptide was negative) of 6 or higher at 6 months after first islet infusion in the immediate transplantation group or 6 months after randomization in the insulin group. The primary analysis included all patients who received the allocated intervention; safety was assessed in all patients who received islet infusions. This trial is registered with ClinicalTrials.gov, number NCT01148680, and is completed. Between July 8, 2010, and July 29, 2013, 50 patients were randomly assigned to immediate islet transplantation (n=26) or insulin treatment (n=24), of whom three (one in the immediate islet transplantation group and two in the insulin therapy group) did not receive the allocated intervention. Median follow-up was 184 days (IQR 181-186) in the immediate transplantation group and 185 days (172-201) in the insulin therapy group. At 6 months, 16 (64% [95% CI 43-82]) of 25 patients in the immediate islet transplantation group had a modified β-score of 6 or higher versus none (0% [0-15]) of the 22 patients in the insulin group (p<0·0001). At 12 months after first infusion, bleeding complications had occurred in four (7% [2-18]) of 55 infusions, and a decrease in median glomerular filtration rate from 90·5 mL/min (IQR 76·6-94·0) to 71·8 mL/min (59·0-89·0) was observed in islet recipients who had not previously received a kidney graft and from 63·0 mL/min (55·0-71·0) to 57·0 mL/min (45·5-65·1) in islet recipients who had previously received a kidney graft. Trial limitations include possible bias from open-label design as well as an inadequate follow-up period to demonstrate transplant durability. The authors concluded for the indications assessed in this study, islet transplantation effectively improves metabolic outcomes. Although studies with longer-term follow-up are needed, islet transplantation seems to be a valid option for patients with severe, unstable type 1 diabetes who are not responding to intensive medical treatments. However, immunosuppression can affect kidney function, necessitating careful selection of patients.
Thompson et. al. (2011) published findings from a prospective, crossover, cohort study comparing allogeneic islet cell transplantation (ICT) with intensive medical therapy on the progression of diabetic neuropathy, retinopathy, and neuropathy. The study included 45 patients; at the time of data analysis, 32 had receive islet cell transplants. Median follow-up was 47 months pretransplant and 66 months post-transplant. The overall HbA1C level was 7.8% pretransplant and 6.7% post-transplant (p<0.001). In the 16 patients for whom sufficient pre and post-transplant data were available on renal outcomes, the median decline in glomerular filtration rate was -6.7 mL/min/1.73 m2/y pretransplant and -1.3 mL/min/1.73 m2/y posttransplant (p=0.01). Retinopathy was assessed using a scale that categorized nonproliferative diabetic retinopathy as mild, moderate, or severe. Retinopathy progressed in 10 (12%) of 82 eyes pretransplant versus 0 of 51 post-transplant (p<0.01). The authors concluded, the rate of decline in glomerular filtration rate is slower after ICT than on medical therapy. There was significantly more progression of retinopathy in medically treated patients than post ICT. There was a nonsignificant trend for improved nerve condition velocity post ICT. Islet cell transplantation is associated with less progression of microvascular complications than intensive medical therapy which might have been due in part to the choice of maintenance immunosuppression. The study used a combination of tacrolimus and mycophenolate mofetil. Multicenter randomized trials are needed to further study the role of ICT in slowing the progression of diabetic complications.
Barton et. al. (2012) updated the Collaborative Islet Transplantation Registry (CITR) report, which focused on changes in outcomes over time. A total of 677 allogeneic islet transplant-alone or islet-after-kidney recipients with type I diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999-2002), mid (2003-2006), or recent (2007-2010) transplant era based on annual follow-up to 5 years. Insulin independence at 3 years after transplant improved from 27% in the early era (1999-2002, n = 214) to 37% in the mid (2003-2006, n = 255) and to 44% in the most recent era (2007-2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA(1c) and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007-2010 vs. 60-65% in 1999-2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001). The authors concluded the CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007-2010 compared with those in 1999-2006, with fewer islet infusions and adverse events per recipient.
Other small case series have reported some success and also adverse events. For example, O’Connell et. al. (2013) reported on 17 patients with type I diabetes with severe hypoglycemia who underwent allogeneic islet transplantation. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥ 12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation. Most adverse events were related to immunosuppression. Seven (41%) of the 17 patients developed mild lymphopenia and 1 developed colistridium difficile colitis; all responded to treatment. Eight patient developed anemia shortly after transplant and one required a blood transfusion. Procedure-related complications included 1 portal vein thrombosis and 3 postoperative bleeds; 2 of the bleeds required transfusion.
Allogeneic islet transplantation has been investigated in the treatment of type I diabetes. One randomized controlled trial (RCT) found the quality of life was significantly improved after islet transplantation; however, the short length of follow-up limits these conclusions. Evidence from registry studies and systematic reviews has demonstrated varying ranges of insulin independence post-transplantation. There is conflicting evidence that allogeneic islet transplantation reduces long-term diabetic complications. Long term comparative studies are needed to determine the effects of allogeneic islet transplantation in type 1 diabetic and post-transplant immunosuppression.
For individual with chronic pancreatitis undergoing total or new total pancreatectomy who receive autologous pancreas islet transplantation, the evidence includes nonrandomized studies and systematic reviews. Autologous islet transplants are performed in the context of total or new total pancreatectomy to treat intractable pain from chronic pancreatitis. The autologous islet transplant appears to decrease significantly the incidence of diabetes after total or new total pancreatectomy in patients with chronic pancreatitis. Also, the autologous islet cell transplant procedure is not associated with serious complications itself and is performed in patients who are already undergoing a pancreatectomy procedure. The evidence is insufficient to determine autologous islet cell transplantation results in a meaningful improvement in net health outcomes.
For individuals with type I diabetes who receive allogeneic pancreas islet transplantation, the evidence includes a randomized controlled trial (RCT), a systematic review and registry studies. Results of the 2018 randomized trial have suggested some reduction in the number of severe hypoglycemic incidence annually, but limited follow-up and other trial limitations reduce the certainty in conclusions drawn. A wide range of insulin dependence has been reported in the registry studies. There is conflicting evidence whether allogeneic islet transplantation reduces long-term diabetic complications. Long term comparative studies are required to determine the effects of allogeneic islet transplantation in type I diabetics.
The evidence is insufficient to determine the effects of allogeneic pancreatic islet transplantation on net health outcomes.
In 2014, the American Diabetes Association issued a position statement on type 1 diabetes through the life span, which included the following recommendation:
In 2008 the National Institute for Health and Clinical Excellence (NICE) issued guidance on allogeneic pancreatic islet cell transplantation for type I diabetes mellitus which states: The evidence on allogeneic pancreatic islet cell transplantation for type I diabetes mellitus shows short-term efficacy with some evidence of long-term efficacy. The evidence on safety shows that serious complications may occur as a result of this procedure. The long-term immunosuppression required is also associated with a risk of adverse events.
During consent, clinicians should ensure that patients understand the potential complications of the procedure and uncertainty about is efficacy in the long term.
Further audit and research should address the effect of the procedure on quality of life and its long term efficacy, particularly in relation to the complications of diabetes.
In 2008 the National Institute for Health and Clinical Excellence (NICE) issued guidance on autologous pancreatic islet cell transplantation for improved glycemic control after pancreatectomy which states: The current evidence on autologous pancreatic islet cell transplantation for improved glycemic control after pancreatectomy shows some short term efficacy, although most patients require insulin therapy in the long term. The reported complications result mainly from the major surgery involved in the pancreatectomy (rather than from the islet cell transplantation).
During consent, clinicians should ensure that patients understand that they may require insulin therapy in the long term.
In 2018 the following is the allocation policy of the Organ Procurement and Transplant Network (OPTN) for the allocation of islet cells.
A transplant hospital may register an islet candidate on the waiting list with an active status if the candidate meets either of the following requirements:
The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation title 21, parts 1270 and 1271. Allogeneic islet cells are included in these regulations.
See medical policy 07.03.09 Pancreas Transplants (including simultaneous pancreas-kidney, pancreas alone, and pancreas after kidney)
Autologous pancreas islet cell transplantation may be considered medically necessary as an adjunct to a total or near-total pancreatectomy in patients with chronic pancreatitis.
Autologous pancreas islet cell transplantation is considered investigational when the above criteria is not met and for all other indications because the safety and/or effectiveness of this procedure for all other indications can not be established based on available peer reviewed literature.
Allogeneic pancreas islet cell transplantation is considered investigational for all indications including the treatment of type 1 diabetes.
Based on review of the peer reviewed medical literature results of the 2018 randomized controlled trial (RCT) have suggested some reduction in the number of severe hypoglycemic incidence annually, but limited follow-up and other trial limitation reduce the certainty in conclusions drawn. There is conflicting evidence whether allogeneic islet transplantation reduces long-term diabetic complications. Long term comparative studies are required to determine the effects of allogeneic islet transplantation. The evidence is insufficient to determine the effects of allogeneic pancreatic islet transplantation on net health outcomes.
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