Preoperative ERCP has no impact on islet yield following total pancreatectomy and islet autotransplantation (TPIAT): Results from the Prospective Observational Study of TPIAT (POST) cohort

Background and aimsMany patients undergoing total pancreatectomy with islet autotransplant (TPIAT) for severe, refractory chronic pancreatitis or recurrent acute pancreatitis have a history of endoscopic retrograde cholangiopancreatography (ERCP). Using data from the multicenter POST (Prospective Observational Study of TPIAT) cohort, we aimed to determine clinical characteristics associated with ERCP and the effect of ERCP on islet yield.MethodsUsing data from 230 participants (11 centers), demographics, pancreatitis history, and imaging features were tested for association with ERCP procedures. Logistic and linear regression were used to assess association of islet yield measures with having any pre-operative ERCPs and with the number of ERCPs, adjusting for confounders.Results175 (76%) underwent ERCPs [median number of ERCPs (IQR) 2 (1-4). ERCP was more common in those with obstructed pancreatic duct (p = 0.0009), pancreas divisum (p = 0.0009), prior pancreatic surgery (p = 0.005), and longer disease duration (p = 0.004). A greater number of ERCPs was associated with disease duration (p < 0.0001), obstructed pancreatic duct (p = 0.006), and prior pancreatic surgery (p = 0.006) and increased risk for positive islet culture (p < 0.0001). Mean total IEQ/kg with vs. without prior ERCP were 4145 (95% CI 3621-4669) vs. 3476 (95% CI 2521-4431) respectively (p = 0.23). Adjusting for confounders, islet yield was not significantly associated with prior ERCP, number of ERCPs, biliary or pancreatic sphincterotomy or stent placement.ConclusionsERCP did not appear to adversely impact islet yield. When indicated, ERCP need not be withheld to optimize islet yield but the risk-benefit ratio of ERCP should be considered given its potential harms, including risk for excessive delay in TPIAT.     

Reduced bone mineral density in the first year after total pancreatectomy with islet autotransplantation (TPIAT)

Background/objectivesThe effect of total pancreatectomy with islet autotransplantation (TPIAT) on bone mineral density (BMD) in patients with CP is unknown. We aimed to assess bone health in patients with CP after TPIAT.MethodsWe measured BMD, BMD Z-score, and bone mineral content (BMC) for total body, lumbar spine, right and left hip in 78 patients before and after TPIAT using dual-energy X-ray absorptiometry (DXA, n = 78 pre-TPIAT, n = 65 paired pre- and 12 months post-TPIAT, n = 33 paired 12 and 18 months post-TPIAT), and tested for association with clinical history including age, smoking status, and medications using paired and two-sample t-tests, linear regression, and Fisher's exact test. Laboratory measures related to bone health were also assessed.ResultsIn the patients with pre-TPIAT DXA, 12% had low BMD (Z-score ≤ −2). BMD, BMD Z-score, and BMC all decreased from pre-to 12 months post-TPIAT. BMD declined by 1.7%–4.1% with the greatest change at the hips. Adjusted for change in lean and fat body mass, DXA changes remained significant for total body and hip. Serum carboxy-terminal collagen crosslinks telopeptide and alkaline phosphatase increased at 12 months post-TPIAT, suggesting possible increased bone remodeling. BMD, BMD Z-score, and BMC did not change between 12 months and 18 months in any of the four regions (p > 0.6).ConclusionsTPIAT is associated with decreases in BMD in the body, lumbar, and hip regions of patients with CP in the first year after TPIAT but these appear to stabilize between 12 and 18 months after TPIAT.     

Short- and long-term surgical outcomes of total pancreatectomy with islet autotransplantation: A comparative analysis of surgical technique and intraoperative heparin dosing to optimize outcomes

BackgroundTotal pancreatectomy with islet autotransplantation (TP-IAT) is an uncommon surgical procedure with unique perioperative management. We evaluated the short- and long-term morbidity and mortality of TP-IAT to optimize surgical technique and heparin dosing during islet autotransplantation.MethodsEighty patients with chronic pancreatitis undergoing TP-IAT were reviewed. Primary outcome was to evaluate morbidity and mortality based on operative technique: classic (resection of antrum) vs pylorus-preserving. Secondary outcome was to evaluate the effect of heparin dosing (<60 vs ≥ 60 units/kg) during islet autotransplantation on postoperative hemorrhage and portal vein thrombosis (PVT) rates.ResultsThere was no 90-day mortality, and median length of stay was 9 days. All patients underwent an open operation with 53 (66%) pylorus-preserving resections. The 30-day morbidity rate was 39%, with no difference between operative technique (p = 0.82). The median dose was different for each heparin group (<60: 52 units/kg vs ≥ 60: 66 units/kg, p < 0.0001). No difference was observed in postoperative hemorrhage rates between heparin groups (<60: 9% vs ≥ 60: 9%, p = 0.97), with no known incidence of PVT. Median follow-up was 36 months (IQR, 14–71). Morbidity >30 days after TP-IAT was 43% with a higher rate in the pylorus-preserving group (55% vs 15%, p < 0.0001), mainly attributed to marginal ulcer formation (15% vs 0%, p = 0.03).ConclusionsA classic TP-IAT technique should be universally adopted to achieve optimal outcomes, particularly to prevent the formation of marginal ulcers. When considering PVT versus postoperative hemorrhage risk, a lower heparin dose nearing 50 units/kg is optimal. These findings highlight potential areas for future improvement.     

Surgical approach and short-term outcomes in adults and children undergoing total pancreatectomy with islet autotransplantation: A report from the Prospective Observational Study of TPIAT

BackgroundTotal pancreatectomy with islet autotransplantation (TPIAT) is a viable option for treating debilitating recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) in adults and children. No data is currently available regarding variation in approach to operation.MethodsWe evaluated surgical techniques, islet isolation and infusion approaches, and outcomes and complications, comparing children (n = 84) with adults (n = 195) enrolled between January 2017 and April 2020 by 11 centers in the United States in the Prospective Observational Study of TPIAT (POST), which was launched in 2017 to collect standard history and outcomes data from patients undergoing TPIAT for RAP or CP.ResultsChildren more commonly underwent splenectomy (100% versus 91%, p = 0.002), pylorus preservation (93% versus 67%; p < 0.0001), Roux-en-Y duodenojejunostomy reconstruction (92% versus 35%; p < 0.0001), and enteral feeding tube placement (93% versus 63%; p < 0.0001). Median islet equivalents/kg transplanted was higher in children (4577; IQR 2816-6517) than adults (2909; IQR 1555-4479; p < 0.0001), with COBE purification less common in children (4% versus 15%; p = 0.0068). Median length of hospital stay was higher in children (15 days; IQR 14–22 versus 11 days; IQR 8–14; p < 0.0001), but 30-day readmissions were lower in children (13% versus 26%, p = 0.018). Rate of portal vein thrombosis was significantly lower in children than in adults (2% versus 10%, p = 0.028). There were no mortalities in the first 90 days post-TPIAT.ConclusionsPancreatectomy techniques differ between children and adults, with islet yields higher in children. The rates of portal vein thrombosis and early readmission are lower in children.     

Imaging prediction of islet yield and post-operative insulin requirement in children undergoing total pancreatectomy with islet autotransplantation

BackgroundPredicting post-operative glycemic control in children undergoing total pancreatectomy with islet autotransplantation (TPIAT) remains difficult. The purpose of our study was to explore preoperative imaging as a marker for islet yield and insulin need in pediatric patients undergoing TPIAT.MethodsThis was a retrospective study of children (≤18 years) who had undergone TPIAT between April 2015 and December 2018 and had 6 or more months of post-TPIAT follow-up. Patient specific factors (height, weight, body mass index [BMI], body surface area [BSA]) and pancreas volume segmented from the most recent pre-operative cross-sectional imaging were explored as predictors of islet yield (total islet counts [TIC], total islet equivalents [TIE], islet equivalents per kilogram body weight [IEQ/kg]) and glycemic control (total daily dose of insulin per kilogram body weight [TDD/kg], insulin independence) using Pearson correlation and univariate and multiple regression.ResultsThirty-three patients, median age 13 years (IQR: 10–15 years), 64% female (21/33) met inclusion criteria. Nine patients (27%) achieved insulin independence at six months. Median TIE isolated was 310,000 (IQR: 200,000–460,000). Segmented pancreas volume was moderately associated with TIE (coefficient estimate = 0.34, p = 0.034). On multiple regression analysis, there was no significant predictor of insulin independence but number of attacks of pancreatitis (estimate = 0.024; p = 0.018) and segmented pancreas volume by body weight (estimate = ?0.71; p < 0.001) were significant predictors of insulin TDD/kg.ConclusionPancreas volume segmented from pre-TPIAT imaging has predictive performance for post-TPIAT insulin need in children.     

Diabetic control after total pancreatectomy

BACKGROUND: Diabetes after total pancreatectomy is commonly described as 'brittle' with most series reporting outcomes after resection for pancreatitis alone. The aim of this study was to determine glycaemic control in patients resected for benign and malignant disease. METHODS: A retrospective analysis of all patients undergoing total pancreatectomy (1989-2003) from a single institution was done. Data of diabetic control were obtained from case notes, general practitioners and telephonic consultation. Comparison was made against a matched type 1 diabetic population. RESULTS: Forty-seven patients with a median age of 59 years (range 17-85 years) and median follow-up of 50 months (range 5-136 months) were identified. Thirty-five underwent primary resection with 11 receiving completion procedures. Thirty were for malignancy (19 deceased) and 17 for benign/indeterminate histology (2 deceased). Thirty-three patients were available for detailed follow-up. There was no significant difference between median HbA(1c) of the study group and the control (8.2% versus 8.1%). The majority of patients reported diabetic control and daily performance as excellent or good. Resection for pancreatitis gave poorer subjective control (p < 0.05) than those resected for malignancy. Two patients required in-patient treatment for diabetic complications, with no deaths related to diabetes observed. CONCLUSION: Diabetes after total pancreatectomy is not necessarily associated with poor glycaemic control and in the majority results in equivalent biochemical control compared to a normal type 1 diabetic population.     

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.     

The prognostic significance of glutamic acid decarboxylase antibodies in patients with chronic pancreatitis undergoing total pancreatectomy with islet autotransplantation

AimIslet autotransplantation (IAT) is considered a ‘non-immune’ model of islet transplant, with no risk for autoimmune-mediated beta cell loss, but we have previously observed de novo type 1 diabetes in one total pancreatectomy with islet autotransplantation (TPIAT) recipient. We aimed to investigate the clinical significance of glutamic acid decarboxylase antibodies (GADA), as a sensitive marker for autoimmune diabetes mellitus (DM), in patients with chronic pancreatitis undergoing TPIAT.MethodsWe identified 9 patients undergoing TPIAT with elevated GADA pre-TPIAT (8 non-diabetic and 1 with C-peptide positive DM), otherwise demographically similar to GADA negative TPIAT recipients (n = 341). Metabolic and clinical measures related to islet cell function were recorded both before and after TPIAT.ResultsNone of the 9 TPIAT patients achieved insulin independence after surgery, vs. 33% of GADA negative patients (n = 318 with 1-yr follow-up). The two patients with the highest titters of GADA (> 250 IU/mL) both experienced islet graft failure, despite normoglycaemia pre-TPIAT and high islet mass transplanted (5276 and 9378 IEQ per kg), with elevated HbA1c levels post-TPIAT (8.3%, 9.6%). The remaining 7 seven were insulin dependent with partial graft function and HbA1c levels < 7%.ConclusionInsulin dependence was more frequent in 9 patients with elevated GADA prior to TPIAT than in GADA negative TPIAT recipients, with graft failure in 2 cases. We speculate that beta-cell autoimmunity may occur in a small subset of TPIAT recipients and that beta cell antibody testing prior to TPIAT may be warranted to identify individuals at higher risk for insulin dependence.     

The role of total pancreatectomy with islet autotransplantation in the treatment of chronic pancreatitis: A report from the International Consensus Guidelines in chronic pancreatitis

BackgroundAdvances in our understanding of total pancreatectomy with islet autotransplantation (TPIAT) have been made. We aimed to define indications and outcomes of TPIAT.MethodsExpert physician-scientists from North America, Asia, and Europe reviewed the literature to address six questions selected by the writing group as high priority topics. A consensus was reached by voting on statements generated from the review.ResultsConsensus statements were voted upon with strong agreement reached that (Q1) TPIAT may improve quality of life, reduce pain and opioid use, and potentially reduce medical utilization; that (Q3) TPIAT offers glycemic benefit over TP alone; that (Q4) the main indication for TPIAT is disabling pain, in the absence of certain medical and psychological contraindications; and that (Q6) islet mass transplanted and other disease features may impact diabetes mellitus outcomes. Conditional agreement was reached that (Q2) the role of TPIAT for all forms of CP is not yet identified and that head-to-head comparative studies are lacking, and that (Q5) early surgery is likely to improve outcomes as compared to late surgery.ConclusionsAgreement on TPIAT indications and outcomes has been reached through this working group. Further studies are needed to answer the long-term outcomes and maximize efforts to optimize patient selection.     

Residual total pancreatectomy: Short- and long-term outcomes

Background/objectivesBecause of limited numbers of patients, there are limited data available regarding outcomes after residual total pancreatectomy (R-TP). This study aimed to assess outcomes after the R-TP vs the one-stage total pancreatectomy (O-TP), especially focused on the pancreatic adenocarcinoma cases.MethodsFrom 2005 to 2014, all patients who underwent the R-TP (n = 8) and the O-TP (n = 12) for pancreatic primary malignancy were prospectively enrolled.ResultsThe median time from the initial operation to the R-TP was 30 months. Ten patients in the O-TP group and 8 in the R-TP had pancreatic adenocarcinoma. Postoperative complications occurred in two O-TP patients and one R-TP patient. There was no in-hospital mortality. At 12 months after surgery, the median insulin dose was 27 U/day after the O-TP and 24 U/day after the R-TP, the median hemoglobin A1c was 7.2% after the O-TP and 6.9% after the R-TP. There was a significantly larger reduction in body weight after the O-TP than after the R-TP. Postoperative fatty liver disease occurred in about half of the patients in each group. In patients with pancreatic adenocarcinoma, the 2-year overall survival rate was not significantly different (68.6% after the O-TP vs 71.4% after the R-TP).ConclusionsAlthough the postoperative morbidity and nutritional statuses should be improved, these favorable short- and long-term outcomes demonstrate that the R-TP is a feasible procedure for patients with malignant tumor in the remnant pancreas.     

Insulin deficiency with and without glucagon: A comparative study between total pancreatectomy and type 1 diabetes

Aims/Introduction

Patients with a total pancreatectomy and type 1 diabetes are similar in regard to absolute insulin deficiency, but different in regard to glucagon, providing a unique opportunity to study the contribution of glucagon to glucose metabolism in an insulin‐dependent state. The aim of the present study was to investigate the contribution of glucagon to glucose homeostasis in complete insulin deficiency in vivo.

Methods

A total of 38 individuals with a complete lack of endogenous insulin (fasting C‐peptide <0.0066 nmol/L) and whose glycemic control was optimized with an insulin pump during hospitalization were retrospectively studied. The basal insulin requirement, time‐to‐time adjustment of the basal insulin infusion rate, prandial insulin requirement and fasting plasma glucagon were compared between patients with a total pancreatectomy (n = 10) and those with type 1 diabetes (n = 28) after achievement of optimal glycemic control.

Results

Total daily insulin (P = 0.03) and basal insulin (P = 0.000006), but not prandial insulin requirements, were significantly lower in total pancreatectomy patients than in type 1 diabetes patients. The basal percentage (basal insulin/total daily insulin) was also significantly lower in total pancreatectomy patients than in type 1 diabetes patients (15.8 ± 7.8 vs 32.9 ± 10.1%, P = 0.00003). An increase in the insulin infusion rate early in the morning was not necessary in most patients with a pancreatectomy. The fasting plasma glucagon concentration was significantly lower in total pancreatectomy patients than in type 1 diabetes patients (P = 0.00007), and was positively correlated with the basal insulin requirement (P = 0.038).

Conclusions

The difference in insulin requirements between total pancreatectomy and type 1 diabetes patients suggests a contribution of glucagon to the basal insulin requirement and dawn phenomenon.     

Prospective characterization of incident hepatic steatosis in pediatric and adolescent patients after total pancreatectomy with islet autotransplantation

BackgroundHepatic steatosis has been described as a common finding in adults following total pancreatectomy with islet autotransplantation (TPIAT) but it is unknown if this occurs in children and adolescents.ObjectivesTo define the frequency of post-TPIAT hepatic steatosis in a sample of children and adolescents and to identify clinical predictors of incident steatosis post-TPIAT.MethodsIn this prospective study, consecutive participants at least 1-month post-TPIAT underwent a liver MRI with proton density fat fraction (PDFF) and blood draw at our pediatric academic medical center between April 2021 and January 2022. Comparison clinical pre-TPIAT liver MRI or ultrasound and insulin use and graft function data were extracted from the medical record. T-tests were used for the comparison of means across continuous variables between participants with and without post-TPIAT steatosis.ResultsA total of 20 participants (mean: 13 ± 4 years; 12 female) were evaluated. Mean liver PDFF at research MRI was 7.4 ± 6.2% (range: 2–25%). Seven participants (35%) had categorical hepatic steatosis (PDFF>5%) post-TPIAT, five of whom had pre-TPIAT steatosis, reflecting a 13% (2/15; 95% CI: 2–40%) incidence of post-TPIAT steatosis. Participant characteristics were not significantly different between subgroups with and without post-TPIAT steatosis. Mean PDFF at research MRI was not different between graft function subgroups (7.5% optimal/good vs. 7.3% marginal/failure; p = .96).ConclusionOur study shows a moderate prevalence but low incidence of hepatic steatosis in a small sample of children and adolescents post-TPIAT. This study raises questions about a causal relationship between TPIAT and hepatic steatosis.     

年龄对胰腺部分切除的小鼠胰岛细胞再生和凋亡的影响

目的 探讨年龄对胰岛细胞再生的影响,初步揭示胰岛再生的机制以及与老龄性糖尿病的关系.方法 对清洁级3月龄[n=12,体重（16.7±1.9）g]、6月龄[n=12,体重（25.4±2.3）g]、12月龄[n=12,体重（28.5±3.0）g]近交品系C57B6小鼠胰腺切除65%～70%,在饮用水中加入BrdU以标记增殖细胞,各组动物分别于1、2、4周处死取材,通过测量空腹血糖、静脉糖耐量并应用免疫组织化学的方法对胰岛细胞的再生以及胰岛细胞的凋亡进行全面的研究.所得数据通过Graphpad Prism 5.0软件的2-way ANOVA进行统计学处理.结果 在3月龄的年轻小鼠部分胰腺切除后,术后1、2、4周胰岛β细胞再生率分别为15.1%±10.0%、25.5%±8.1%、45.7%±14.6%;6月龄小鼠胰岛再生率分别为23.9%±8.7%、28.3%±7.6%和27.2%±5.7%;而对于12月龄老龄的小鼠,胰岛细胞再生率分别为4.4%±6.9%、6.1%±5.8%和5.1%±7.0%,用GraphPad Prism 5.0软件进行2-way ANOVA分析表明时间、年龄对胰岛再生均有影响（P＜0.0001,P＜0.05）,各组间差异有统计学意义.3月龄的小鼠1、2、4周胰岛β细胞凋亡率分别为2.7%±2.4%、3.7%±3.4%、3.1%±3.6%,12月龄的小鼠1、2、4周胰岛β细胞凋亡率分别为5.6%±1.4%、5.8%±4.3%、6.7%±2.6%,3月龄小鼠凋亡的β细胞数量明显少于12月龄的小鼠（P＜0.05）.结论 随着年龄的增长,小鼠胰岛β细胞的再生能力明显降低,并且更易发生凋亡.这可能是导致老龄人群糖尿病发病率升高的主要原因之一.     

Total pancreatectomy with islet cell transplantation vs intrathecal narcotic pump infusion for pain control in chronic pancreatitis

AIM: To evaluate pain control in chronic pancreatitis patients who underwent total pancreatectomy with islet cell transplantation or intrathecal narcotic pump infusion.METHODS: We recognized 13 patients who underwent intrathecal narcotic pump (ITNP) infusion and 57 patients who underwent total pancreatectomy with autologous islet cell transplantation (TP + ICT) for chronic pancreatitis (CP) pain control between 1998 and 2008 at Indiana University Hospital. All patients had already failed multiple other modalities for pain control and the decision to proceed with either intervention was made at the discretion of the patients and their treating physicians. All patients were evaluated retrospectively using a questionnaire inquiring about their pain control (using a 0-10 pain scale), daily narcotic dose usage, and hospital admission days for pain control before each intervention and during their last follow-up.RESULTS: All 13 ITNP patients and 30 available TP + ICT patients were evaluated. The mean age was approximately 40 years in both groups. The median duration of pain before intervention was 6 years and 7 years in the ITNP and TP + ICT groups, respectively. The median pain score dropped from 8 to 2.5 (on a scale of 0-10) in both groups on their last follow up. The median daily dose of narcotics also decreased from 393 mg equivalent of morphine sulfate to 8 mg in the ITNP group and from 300 mg to 40 mg in the TP + ICT group. No patient had diabetes mellitus (DM) before either procedure whereas 85% of those who underwent pancreatectomy were insulin dependent on their last evaluation despite ICT.CONCLUSION: ITNP and TP + ICT are comparable for pain control in patients with CP however with high incidence of DM among those who underwent TP + ICT. Prospective comparative studies and longer follow up are needed to better define treatment outcomes.     

Patient outcomes after total pancreatectomy: a single centre contemporary experience

Introduction:

Total pancreatectomy (TP) is associated with significant metabolic abnormalities leading to considerable morbidity. With the availability of modern pancreatic enzyme formulations and improvements in control of diabetes mellitus, the metabolic drawbacks of TP have diminished. As indications for TP have expanded, we examine our results in patients undergoing TP.

Materials and methods:

Retrospective study of 47 patients undergoing TP from January 2002 to January 2008 was performed. Patient data and clinical outcomes were collected and entered into a database. Disease-free survival and overall survival were estimated using the Kaplan–Meier method.

Results:

Fifteen males and 32 females with a median age of 70 years underwent TP for non-invasive intraductal papillary mucinous neoplasms (IPMN) (21), pancreatic adenocarcinoma (20), other neoplasm (3), chronic pancreatitis (2) and trauma (1). Median hospital stay and intensive care stay were 11 days and 1 day, respectively. Thirty-day major morbidity and mortality was 19% and 2%, respectively. With a median follow-up length of 23 months, 33 patients were alive at last follow-up. Estimated overall survival at 1, 2 and 3 years for the entire cohort was 80%, 72% and 65%, and for those with pancreatic adenocarcinoma was 63%, 43% and 34%, respectively. Median weight loss at 3, 6 and 12 months after surgery was 6.8 kg, 8.5 kg and 8.8 kg, respectively. Median HbA1c values at 6, 12 and 24 months after surgery were 7.3, 7.5 and 7.7, respectively. Over one-half of the patients required re-hospitalization within 12 months post-operatively.

Conclusion:

TP results in significant metabolic derangements and exocrine insufficiency, diabetic control and weight maintenance remain a challenge and readmission rates are high. Survival in those with malignant disease remains poor. However, the mortality appears to be decreasing and the morbidities associated with TP appear acceptable compared with the benefits of resection in selected patients.