Regulatory considerations of delayed autologous islet infusion in a 4‐year‐old child undergoing total pancreatectomy for chronic pancreatitis

In patients undergoing total pancreatectomy for chronic pancreatitis, isolation, and infusion of autologous islets must comply with Good Manufacturing Practices standards established by the Food and Drug Administration (FDA) but does not standardly require an Investigational New Drug (IND) status. We report a case of a 4‐year‐old child with severe hereditary pancreatitis who developed clinical sepsis during total pancreatectomy (TP) surgery; subsequent pancreas, islet, and blood cultures were positive for Enterococcus. Because of clinical deterioration, planned islet infusion was aborted and islets were kept viable in a culture period while the patient was stabilized. Two days later, 38 000 islet equivalents (IEQ, 2808 IEQ/kg) were infused in a second procedure. Because maintaining the islets in culture met the FDA standard for “more than minimal” tissue manipulation, an emergency IND was obtained from the FDA to permit delayed infusion. The patient tolerated islet infusion well, and subsequently has partial islet graft function with normal glucoses and minimal insulin needs. This case highlights the possibility to delay islet infusion in an emergency, the potential for success with few islets in a young child, and the need to consider regulatory complexities of islet transplant in this situation.     

Total pancreatectomy with islet cell autotransplantation in a 2-year-old child with hereditary pancreatitis due to a PRSS1 mutation

Acute recurrent and chronic pancreatitis in children carries high morbidity and burden. Compared to adults, ~75% of the cases of chronic pancreatitis in children are associated with underlying genetic mutations. The decision to intervene and the optimal timing poses unique challenges. Total pancreatectomy and islet cell autotransplantation (TPIAT) provides definitive therapy to relieve pain and improve quality of life while minimizing the risk of pancreatogenic diabetes. Substantial clinical data are available for adults; however, information on clinical outcomes in children remains scarce, particularly for very young children. Herein, we present an unusual, complex case of a 2-year-old child that underwent a successful TPIAT due to hereditary pancreatitis with an underlying mutation in PRSS1 gene, complicated by unremitting pancreatic ascites, hemorrhage, and sepsis. This is the youngest case to be reported in the literature. We provide a comprehensive report of the course and procedures implemented in this patient to guide other teams when considering these extraordinary measures in similar cases.     

In‐hospital and 90‐day outcomes after total pancreatectomy with islet autotransplantation for pediatric chronic and acute recurrent pancreatitis

Total pancreatectomy with islet autotransplantation (TPIAT) is used to treat debilitating chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP) that has failed medical and endoscopic therapy. We performed a retrospective review of TPIAT patients at a free‐standing children's hospital to evaluate perioperative outcomes. Twenty patients (median age 13, 65% female) underwent TPIAT (2015 through 2017). Of the 20 patients, 95% had CP and 1 patient (5%) had ARP alone. Seventy‐five percent of the patients had a pancreatitis‐associated genetic mutation; 40% had pancreas divisum. The median surgical time was 757 (IQR 657 to 835) minutes. Median islet equivalents per kg of body weight (IEQ/kg) were 6404 (IQR 5018 to 7554). At 90 days postoperatively vs preoperatively, significantly fewer patients were receiving parenteral nutrition (0% vs 25%, P = .006) and opioids (45% vs 75%, P = .01). Short Form 36‐Item Health Survey (SF‐36) physical health module scores and total scores improved (34.0 preoperatively vs 54.6 at 90 days, P = .008, and 47.1 vs 65.3, P = .007, respectively); SF‐10 physical health scores also improved (13.4 vs 33.1, P = .02). Insulin requirement decreased from 0.5 unit/kg/day to 0.4 unit/kg/day between discharge and 90 days (P = .02). TPIAT is an effective option when debilitating disease persists despite maximal medical and endoscopic therapy. Opioid, parenteral nutrition, and exogenous insulin use can successfully be weaned within 90 days after TPIAT, with gains in health‐related quality of life.     

Metabolic measures before surgery and long-term diabetes outcomes in recipients of total pancreatectomy and islet autotransplantation

In this single-center, retrospective cohort study, we aimed to elucidate simple metabolic markers or surrogate indices of β-cell function that best predict long-term insulin independence and goal glycemic HbA1c control (HbA1c ≤ 6.5%) after total pancreatectomy with islet autotransplantation (TP-IAT). Patients who underwent TP-IAT (n = 371) were reviewed for metabolic measures before TP-IAT and for insulin independence and glycemic control at 1, 3, and 5 years after TP-IAT. Insulin independence and goal glycemic control were achieved in 33% and 68% at 1 year, respectively. Although the groups who were insulin independent and dependent overlap substantially on baseline measures, an individual who has abnormal glycemia (prediabetes HbA1c or fasting glucose) or estimated IEQs/kg < 2500 has a very high likelihood of remaining insulin dependent after surgery. In multivariate logistic regression modelling, metabolic measures correctly predicted insulin independence in about 70% of patients at 1, 3, and 5 years after TP-IAT. In conclusion, metabolic testing measures before surgery are highly associated with diabetes outcomes after TP-IAT at a population level and correctly predict outcomes in approximately two out of three patients. These findings may aid in prognostic counseling for chronic pancreatitis patients who are likely to eventually need TP-IAT.     

慢性胰腺炎胰腺切除术后自体胰岛移植现状

目前,胰腺切除后自体胰岛移植（IAT）主要用于治疗伴有顽固性疼痛的慢性胰腺炎。IAT可以防止或者减少由胰腺切除引起的外科糖尿病的发生,最大程度地保留胰腺内分泌功能。随着胰岛制备技术的不断提高,IAT的效果逐渐得到改善,且具有手术安全、术后不需免疫抑制剂、可有效防止糖尿病发生、改善预后等优点,应于国内推广开展。     

Utility of arginine stimulation testing in preoperative assessment of children undergoing total pancreatectomy with islet autotransplantation

Metabolic outcomes after total pancreatectomy with islet autotransplantation (TPIAT) are influenced by the islet mass transplanted. Preclinical and clinical studies indicate that insulin and C‐peptide levels measured after intravenous administration of the beta cell secretagogue arginine can be used to estimate the available islet mass. We sought to determine if preoperative arginine stimulation test (AST) results predicted transplanted islet mass and metabolic outcomes in pediatric patients undergoing TPIAT. We evaluated the association of preoperative C‐peptide and insulin responses to AST with islet isolation metrics using linear regression, and with postoperative insulin independence using logistic regression. Twenty‐six TPIAT patients underwent preoperative AST from 2015 to 2018. The acute C‐peptide response to arginine (ACRarg) was correlated with isolated islet equivalents (IEQ; r = 0.59, P = 0.002) and islet number (IPN; r = 0.48, P = 0.013). The acute insulin response to arginine (AIRarg) was not significantly correlated with IEQ (r = 0.38, P = 0.095) or IPN (r = 0.41, P = 0.071). Neither ACRarg nor AIRarg was associated with insulin use at 6 months postoperatively. Preoperative C‐peptide response to arginine correlates with islet mass available for transplant in pediatric TPIAT patients. AST represents an additional tool before autotransplant to provide counseling on likely islet mass and to inform quality improvements of islet isolation techniques.     

Variability in endocrine cell identity in patients with chronic pancreatitis undergoing islet autotransplantation

Beta‐cell dedifferentiation as shown by cellular colocalization of insulin with glucagon and/or vimentin, and decreased expression of MAFA and/or urocortin3 has been suggested to contribute to metabolic decompensation in type 2 diabetes, and was recently described postimplantation in islet allotransplant patients. Dysglycaemia and diabetes mellitus are often encountered preoperatively in patients undergoing pancreatectomy and islet autotransplantation (PIAT). In this series of case reports, we document variation in islet phenotypic identity in three patients with chronic pancreatitis (CP) without diabetes or significant insulin resistance who subsequently underwent PIAT. Pancreas histology was examined using colocalization of endocrine hormones, mesenchymal and pan‐endocrine markers in islets, and the relative expression of MAFA and urocortin3 in insulin‐expressing cells as compared to that of nondiabetic and type 2 diabetic donors. We present results of pre‐ and posttransplant clinical metabolic testing. Varying degrees of islet‐cell dedifferentiation are identified in nondiabetic patients with CP at the time of PIAT, and may need further investigation.     

Islet damage during isolation as assessed by miRNAs and the correlation of miRNA levels with posttransplantation outcome in islet autotransplantation

High‐quality pancreatic islets are essential for better posttransplantation endocrine function in total pancreatectomy with islet autotransplantation (TPIAT), yet stress during the isolation process affects quality and yield. We analyzed islet‐enriched microRNAs (miRNAs) ‐375 and ‐200c released during isolation to assess damage and correlated the data with posttransplantation endocrine function. The absolute concentration of miR‐375, miR‐200c, and C‐peptide was measured in various islet isolation steps, including digestion, dilution, recombination, purification, and bagging, in 12 cases of TPIAT. Posttransplantation glycemic control was monitored through C‐peptide, hemoglobin A_1c, insulin requirement, and SUITO index. The amount of miR‐375 released was significantly higher during enzymatic digestion followed by the islet bagging (P < .001). Mir‐200c mirrored these changes, albeit at lower concentrations. In contrast, the C‐peptide amount was significantly higher in the purification and bagging steps (P < .001). Lower amounts of miR‐375 were associated with a lower 6‐month insulin requirement (P = .01) and lower hemoglobin A_1c (P = .04). Measurement of the absolute quantity of miRNA‐375 and ‐200c released during islet isolation is a useful tool to assess islet damage. The quantity of released miRNA is indicative of posttransplantation endocrine function in TPIAT patients.     

Pancreatic islet autotransplantation with total pancreatectomy for chronic pancreatitis

Achieving pain relief and improving the quality of life are the main targets of treatment for patients with chronic pancreatitis. The use of total pancreatectomy to treat chronic pancreatitis is a radical and in some ways ideal strategy. However, total pancreatectomy is associated with severe diabetic control problems. Total pancreatectomy with islet autotransplantation can relieve severe pain and prevent the development of postsurgical diabetes. With islet autotransplantation, patients with chronic pancreatitis receive their own islet cells and therefore do not require immunosuppressive therapy. In the future, total pancreatectomy with islet autotransplantation may be considered a treatment option for chronic pancreatitis patients.     

Diabetes‐free survival after extended distal pancreatectomy and islet auto transplantation for benign or borderline/malignant lesions of the pancreas

Islet autotransplant is particularly attractive to prevent diabetes after extended pancreatectomy for benign or borderline/malignant pancreas disease. Between 2008 and 2018, 25 patients underwent left extended pancreatectomy (>60%) and islet autotransplant for a neoplasm located in the pancreatic neck or proximal body. Overall, disease‐free and diabetes‐free survivals were estimated and compared with those observed in 68 nondiabetic patients who underwent distal pancreatectomy for pancreatic neoplasms without islet autotransplant. Median follow‐up was 4 years. We observed no deaths and a low morbidity (nonserious procedure‐related complications in 2 of 25 patients). Patient and insulin‐independent survival rates at 4 years were 100% and 96%, respectively. Glucose homeostasis remained within a nondiabetic range at all times for 19 (73%) of 25 patients. Preoperative glycemic level and insulin resistance were major predictors of diabetes development in these patients. Patients undergoing islet autotransplant had a longer diabetes‐free survival than did patients without islet autotransplant (P = .04). In conclusion, islet autotransplant after extended pancreatic resection for neoplasms is a safe and successful procedure for preventing diabetes.     

The role of total pancreatectomy and islet autotransplantation for chronic pancreatitis

Total pancreatectomy and islet autotransplantation are done for chronic pancreatitis with intractable pain when other treatment measures have failed, allowing insulin secretory capacity to be preserved, minimizing or preventing diabetes, while at the same time removing the root cause of the pain. Since the first case in 1977, several series have been published. Pain relief is obtained in most patients, and insulin independence preserved long term in about a third, with another third having sufficient beta cell function so that the surgical diabetes is mild. Islet autotransplantation has been done with partial or total pancreatectomy for benign and premalignant conditions. Islet autotransplantation should be used more widely to preserve beta cell mass in major pancreatic resections.     

Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis

Background:

Total pancreatectomy and islet autotransplantation (TP/IAT) is a treatment option in a subset of patients with chronic pancreatitis. A systematic review of the literature was performed to evaluate the outcome of this procedure, with an attempt to ascertain when it is indicated.

Methods:

MEDLINE (1950 to present), Embase (1980 to present) and the Cochrane Library were searched to identify studies of outcomes in patients undergoing TP/IAT. Cohort studies that reported the outcomes following the procedure were included. The MOOSE guidelines were used as a basis for this review.

Results:

Five studies met the inclusion criteria. The techniques reported for pancreatectomy and islet cell isolation varied between studies. TP/IAT was successful in reducing pain in patients with chronic pancreatitis. Comparing morphine requirements before and after the procedure, two studies recorded significant reductions. Concurrent IAT reduced the insulin requirement after TP; the rate of insulin independence ranged from 46 per cent of patients at 5 years' mean follow‐up to 10 per cent at 8 years. The impact on quality of life was poorly reported. The studies reviewed did not provide evidence for optimal timing of TP/IAT in relation to the evolution of chronic pancreatitis.

Conclusion:

This systematic review showed that TP/IAT had favourable outcomes with regard to pain reduction. Concurrent IAT enabled a significant proportion of patients to remain independent of insulin supplementation. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.     

全胰腺切除术联合自体胰岛细胞移植治疗慢性胰腺炎的新进展

全胰腺切除术联合自体胰岛细胞移植(TP-IAT)治疗慢性胰腺炎可以较好地缓解慢性疼痛以减少对镇痛药物的依赖,同时又保持了一部分胰岛功能从而减少了胰岛素的使用。TP-IAT已逐渐成为了慢性胰腺炎的一种理想的治疗方式,尤其是对于终末期患者。笔者就近年来TP-IAT治疗慢性胰腺炎的研究进展进行综述。     

Total pancreaticoduodenectomy with autologous islet transplantation 14 years after liver‐contained composite visceral transplantation

Chronic pancreatitis (CP) is a severely disabling disorder with potential detrimental effects on quality of life, gut function, and glucose homeostasis. Disease progression often results in irreversible morphological and functional abnormalities with development of chronic pain, mechanical obstruction, and pancreatic insufficiency. Along with comprehensive medical management, the concept of total pancreatectomy and islet autotransplantation (TP‐AIT) was introduced 40 years ago for patients with intractable pain and preserved beta‐cell function. With anticipated technical difficulties, total excision of the inflamed‐disfigured gland is expected to alleviate the incapacitating visceral pain and correct other associated abdominal pathology. With retrieval of sufficient islet‐cell mass, the autologous transplant procedure has the potential to maintain an euglycemic state without exogenous insulin requirement. The reported herein case of CP‐induced recalcitrant pain and foregut obstruction is exceptional because of the technical challenges in performing native pancreaticoduodenectomy in close proximity to the composite visceral allograft with complex vascular and gut reconstructions. Equally novel is transplanting the auto‐islets in the liver‐contained visceral allograft. Despite intravenous nutrition shortly after birth, liver transplantation at age 13, retransplantation with liver‐contained visceral allograft at age 17 and TP‐AIT at age 31, the 38‐year‐old recipient is currently pain free with full nutritional autonomy and normal glucose homeostasis.     

The impact of islet mass,number of transplants,and time between transplants on graft function in a national islet transplant program

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3–8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12 months (p < .01). Despite 1.9-fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291–15 417] vs. 6442 [5156–7639] IEQ/kg; p < .0001), stimulated C-peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta ?0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function.     

Total or near total pancreatectomy and islet autotransplantation for treatment of chronic pancreatitis.

Total or near total pancreatectomy is the surest way to relieve the pain of chronic pancreatitis but is rarely applied because the metabolic consequences are so severe. For most patients drainage procedures are applicable, but pancreatectomy may be the only alternative for small duct disease or where procedures to improve duct drainage have failed. Preservation of endocrine function is a major problem in patients who require pancreatectomy. Experiments in pancreatectomized dogs have shown that intrasplenic or intraportal transplantation of unpurified pancreatic islet tissue dispersed by collagenase digestion can prevent diabetes. We have applied this technique to ten patients with chronic pancreatitis, small ducts, and intractable pain. The entire pancreas of > 95% of the pancrease was excised, minced, dispersed by collagenase digestion and infused into the portal vein < 2 1/2 hours after removal. Mean (+/- SD) rise in portal pressure was 17 +/- 8 cm of water. Liver function tests were altered minimally. All patients were relieved of pain. One patient died of a complication not related to the islet autotransplant; viable islets were identified in the liver at autopsy. Of the remaining nine patients, three have been insulin independent for 1, 9, and 38 months. One patient was insulin indpendent for 15 months and now takes 12 units of insulin daily. Three have nonketosis prone diabetes (tested by insulin withdrawal) and take 15--30 units of insulin per day. C-peptide studies in these patients show that functioning islets are present. Two patients are diabetic and require 35 and 60 units of insulin per day. In eight of nine patients tested serum insulin concentrations fell to undetectable levels during the interval between pancreatectomy and islet transplantation. Serum insulin levels during the first few hours after islet transplantation predicted success. In the insulin independent or in the patients with mild diabetes, insulin levels were persistently greater than or equal to 6 microU/ml. In the other two patients, the increase in insulin concentration was not sustained. Islet tissue preparation from a diseased pancreas is difficult. The surgeon and the patient must still be willing to accept diabetes for relief of pain when performing this operation. In some patients, however, islet autotransplantation can prevent or partially ameliorate diabetes after pancreatectomy, and preservation of endocrine function is worthwhile.     

Islet alloautotransplantation: Allogeneic pancreas transplantation followed by transplant pancreatectomy and islet transplantation

Simultaneous pancreas–kidney (SPK) transplantation is an important treatment option for patients with type 1 diabetes (T1D) and end‐stage renal disease (ESRD). Due to complications, in up to 10% of patients, allograft pancreatectomy is necessary shortly after transplantation. Usually the donor pancreas is discarded. Here, we report on a novel procedure to rescue endocrine tissue after allograft pancreatectomy. A 39‐year‐old woman with T1D and ESRD who had undergone SPK transplantation required emergency allograft pancreatectomy due to bleeding at the vascular anastomosis. Islets were isolated from the removed pancreas allograft, and almost 480 000 islet equivalents were infused into the portal vein. The patient recovered fully. After 3 months, near‐normal mixed meal test (fasting glucose 7.0 mmol/L, 2‐hour glucose 7.5 mmol/L, maximal stimulated C‐peptide 3.25 nmol/L, without insulin use in the preceding 36 hours) was achieved. Glycated hemoglobin while taking a low dose of long‐acting insulin was 32.7 mmol/mol hemoglobin (5.3%). When a donor pancreas is lost after transplantation, rescue β cell therapy by islet alloautotransplantation enables optimal use of scarce donor pancreata to optimize glycemic control without additional HLA alloantigen exposure.     

Purity of islet preparations and 5‐year metabolic outcome of allogenic islet transplantation

In allogenic islet transplantation (IT), high purity of islet preparations and low contamination by nonislet cells are generally favored. The aim of the present study was to analyze the relation between the purity of transplanted preparations and graft function during 5 years post‐IT. Twenty‐four patients with type 1 diabetes, followed for 5 years after IT, were enrolled. Metabolic parameters and daily insulin requirements were compared between patients who received islet preparations with a mean purity <50% (LOW purity) or ≥50% (HIGH purity). We also analyzed blood levels of carbohydrate antigen 19‐9 (CA 19‐9)—a biomarker of pancreatic ductal cells—and glucagon, before and after IT. At 5 years, mean hemoglobin A1c (HbA1c levels) (P = .01) and daily insulin requirements (P = .03) were lower in the LOW purity group. Insulin independence was more frequent in the LOW purity group (P < .05). CA19‐9 and glucagon levels increased post‐IT (P < .0001) and were inversely correlated with the degree of purity. Overall, our results suggest that nonislet cells have a beneficial effect on long‐term islet graft function, possibly through ductal‐to‐endocrine cell differentiation. ClinicalTrial.gov NCT00446264 and NCT01123187.