Islet Cell Autotransplantation Research Articles

Prolonged magnesium sulfate infusion as adjuvant analgesia in postoperative transplant patients in the pediatric ICU: Preliminary results of a feasibility study

AbstractThe opioid crisis has emphasized identification of opioid‐sparing analgesics. This study was designed as a prospective trial with retrospective control group to determine feasibility for implementing a high‐dose prolonged magnesium sulfate infusion for adjuvant analgesia in the pediatric intensive care unit. Approval was granted for study of children receiving total pancreatectomy with islet cell autotransplantation and liver transplantation ages 3–18 years. Study exclusions were pregnancy, neuromuscular disease, hypersensitivity, preoperative creatinine >1.5 times upper limit normal, arrhythmia or pacemaker presence, and clinician concern. Eleven patients were enrolled between January 2020 and December 2022. Magnesium sulfate bolus (50 mg/kg) followed by intravenous infusion (15 mg/kg/h) was initiated in the operating room and extended postoperatively (maximum 48 h). Serum magnesium levels were monitored serially. To prioritize safety, infusion dose was decreased by 5 mg/kg/h for levels greater than 3.5 mg/dL. Clinical team otherwise followed standard multimodal pain practice. Primary outcome was oral morphine equivalent per kg per day during intensive care course (maximum 7 days). Secondary outcomes focused primarily on magnesium safety, including hemodynamic variables, electrolyte variables, respiratory support, and opioid‐related side effects. There were no serious adverse events. Treatment group trended toward slightly higher intravenous fluid requirement (~1 bolus), however no increase in blood product. Treatment and control groups were otherwise comparable in targeted outcomes and overall adverse event profile. Use of a high‐dose magnesium sulfate infusion protocol for analgesic postoperative use in select transplant recipients appears feasible for continued optimization of study in the PICU.

Medzinárodná autotransplantácia Langerhansových ostrovčekov do portálneho riečiska po totálnej pankreatektómii u pacienta s chronickou hereditárnou pankreatitídou – kazuistika a prehľad súčasnej literatúry

Summary: Chronic pancreatitis with repeated painful relapses is a severe multifactorial, fibroinflammatory syndrome that significantly affects the quality of life of patients, mainly in terms of pain, development of diabetes mellitus, and repeated attacks of acute pancreatitis. Autologous islet transplantation after total pancreatectomy is a potential option in selected patients with severe, recurrent painful episodes of chronic pancreatitis. In our case, we present a patient with severe recurrent chronic pancreatitis. The patient required frequent hospitalizations with repeated stenting of the pancreatic duct. After the confirmation of a genetic mutation, the members of the multidisciplinary session decided to perform a total pancreatectomy with islet autotransplantation. In this case, we present the first international islet cell autotransplantation of Langerhans islets in Slovakia after total pancreatectomy in a patient with chronic hereditary pancreatitis. Key words: hereditary pancreatitis – total pancreatectomy – autotransplantation of Langerhans islets

Perioperative Management of Patients Undergoing Total Pancreatectomy with/without Islet Cell Autotransplantation: A Single Center Experience.

Total pancreatectomy (TP) and islet cell autotransplantation (IAT) are complex operations that require intensive postoperative monitoring with standardized protocols. There are few studies detailing immediate perioperative management. The purpose of this study was to describe the perioperative management of post-pancreatectomy patients in the first week following surgery to guide clinicians in addressing salient points from different organ systems. This is a retrospective cohort review of prospectively collected data from September 2017 to September 2022 at a single institution, including patients 16 years and older who underwent TP or TPIAT for chronic pancreatitis. Patients were maintained on a heparin drip (TPIAT), insulin drip, and ketamine infusion. Primary outcomes were complications in the first 5 days following surgery and ICU length of stay (LOS). Secondary outcomes included overall LOS and mortality. Of 31 patients, 26 underwent TPIAT, and 5 underwent TP. Median ICU LOS was five days (IQR 4-6). The most common immediate postoperative complications were reintubation [n = 5 (16%)] and bleeding [n = 2 (6%)]. Median insulin drip use was 70 h (IQR 20-124). There was no mortality. Patients were extubated quickly and progressed well on the protocol. Immediate postoperative complications were generally minor and without long-term effects.

Follow-up of Patients After Total Pancreatectomy and Islet Cell Autotransplantation at Off-Site Islet Isolation Facility.

Total pancreatectomy with islet autotransplantation (TPIAT) is a definitive management for intractable pain in patients with chronic pancreatitis. Islet autotransplantation (IAT) allows for the preservation of beta-cells to prevent complications of long-term diabetes. Our study follows TPIAT recipients for up to 12 years to determine the procedure's efficacy completed with an off-site islet isolation facility. Patient demographics, mixed meal tolerance test measures, glycosylated hemoglobin, insulin requirements, and homeostatic model assessment for insulin resistance values were collected prior to surgery and at the most recent follow-up. Forty-four patients (median age, 46.0 years; range, 20-78 years) underwent TPIAT for CP. At an overall median follow-up time of 845.5 days (range, 195-4470 days) 8 patients were insulin independent and 36 patients were insulin dependent. At the most recent follow-up, islet yield per kilogram was the strongest indicator of insulin independence. Homeostatic model assessment for insulin resistance values were comparable between insulin independent and dependent cohorts. Our long-term follow-up data suggest that IAT can effectively reduce insulin requirements and improve post-operative glycemic control.

Total pancreatectomy and islet cell autotransplantation: a 10-year update on outcomes and assessment of long-term durability.

Total pancreatectomy and islet cell autotransplantation (TPIAT) offers an effective, lasting solution for the management of chronic pancreatitis up to 5-years post-operatively. Our aim was to assess durability of TPIAT at 10-years. Patients undergoing TPIAT for chronic pancreatitis eligible for 10-year follow-up were included. Primary outcomes, including endocrine function and narcotic requirements, were reported at 5-, 7.5-, and 10-years post-operatively. Of the 231 patients who underwent TPIAT, 142 met inclusion criteria. All patients underwent successful TPIAT with an average of 5680.3 islet equivalents per body weight. While insulin independence tended to decrease over time (25.7% vs. 16.0% vs. 10.9%, p=0.11) with an increase in HbA1C (7.6% vs. 8.2% vs. 8.4%, p=0.09), partial islet function persisted (64.9% vs. 68.0% vs. 67.4%, p=0.93). Opioid independence was achieved and remained durable in the majority (73.3% vs. 72.2% vs. 75.5%, p=0.93). Quality of life improvements persisted, with 85% reporting improvement from baseline at 10-years. Estimated median overall survival was 202.7 months. This study represents one of the largest series reporting on long-term outcomes after TPIAT, demonstrating excellent long-term pain control and durable improvements in quality of life. Islet cell function declines over time however stable glycemic control is maintained.

Predicting endocrine function after total pancreatectomy and islet cell autotransplantation: A novel approach utilizing computed tomography texture analysis

BackgroundIslet cell autotransplantation is an effective method to prevent morbidity associated with type IIIc diabetes after total pancreatectomy. However, there is no valid method to predict long-term endocrine function. Our aim was to assess computed tomography texture analysis as a strategy to predict long-term endocrine function after total pancreatectomy and islet cell autotransplantation. MethodsAll patients undergoing total pancreatectomy and islet cell autotransplantation from 2007 to 2020 who had high-quality preoperative computed tomography imaging available for texture analysis were included. The primary outcome was optimal long-term endocrine function, defined as stable glycemic control with <10 units of insulin/day. ResultsSixty-three patients met inclusion criteria. Median yield was 6,111 islet equivalent/kg body weight. At a median follow-up of 64.2 months, 12.7% (n = 8) of patients were insulin independent and 39.7% (n = 25) demonstrated optimal endocrine function. Neither total islet equivalent nor islet equivalent/kg body weight alone were associated with optimal endocrine function. To improve endocrine function prediction, computed tomography texture analysis parameters were analyzed, identifying an association between kurtosis (odds ratio, 2.32; 95% confidence interval, 1.08–4.80; P = .02) and optimal endocrine function. Sensitivity analysis discovered a cutoff for kurtosis = 0.60, with optimal endocrine function seen in 66.7% with kurtosis ≥0.60, compared with only 26.2% with kurtosis <0.60 (P < .01). On multivariate logistic regression including islet equivalent yield, only kurtosis ≥0.60 (odds ratio, 5.61; 95% confidence interval, 1.56–20.19; P = .01) and fewer small islet equivalent (odds ratio, 1.00; 95% confidence interval, 1.00–1.00; P = .02) were associated with optimal endocrine function, with the whole model demonstrating excellent prediction of long-term endocrine function (area under the curve, 0.775). ConclusionComputed tomography texture analysis can provide qualitative data, that when used in combination with quantitative islet equivalent yield, can accurately predict long-term endocrine function after total pancreatectomy and islet cell autotransplantation.

499-P: Optimizing Diabetes Education before Total Pancreatectomy with Islet Cell Autotransplantation (TPIAT)

Background: Caregivers of pediatric recipients of a TPIAT must receive extensive education prior to discharge home. Retrospective review found caregivers were often surprised by the amount of education required and were not prepared to learn while their child was recovering from surgery. Expectations of preparedness were not uniformly reinforced with caregivers, despite available resources. We aimed to provide caregivers with comprehensive education pre-surgery in line with programmatic goals to reduce the inpatient length of stay (LOS) post-TPIAT. Method: We reviewed education time and days for 17 pre-intervention patients (September 2019-August 2020) , and 20 post-intervention patients (August 2020-October 2021) . Diabetes education time was consistently documented in the chart and represented the largest proportion of education needed prior to discharge. Pre-intervention patients received a printed binder of diabetes education and met with diabetes educators at least once in the 6 months prior to surgery. Post-intervention patients received an email with digital links to the timeline and expectations of pre-surgery education, modules for education on diabetes, medication administration, and feeding tube care, and received follow-up phone calls. The intervention was developed using the Plan-Do-Study-Act (PDSA) model of improvement. Results: Prior to the intervention, patients averaged 7minutes of inpatient education spread over an average of 6.4 days. After implementation, patients averaged 575 minutes spread over 4.7 days. There was no cost associated with the development of the intervention. Conclusion: We created our intervention in response to the goal of reducing LOS and adapted it to the low-resource and staffing constraints of a pandemic. We generated a free, sustainable tool that used existing resources. Though our project is ongoing, we are encouraged that inpatient education has been reduced from 7to 575 minutes and from 6.4 to 4.7 days. Disclosure R.E.Ellison: Other Relationship; AbbVie Inc. S.E.Tellez: None.

Selection of parenchymal preserving or total pancreatectomy with/without islet cell autotransplantation surgery for patients with chronic pancreatitis

BackgroundThe selection of surgery between parenchymal preserving (PPS) and total pancreatectomy (TP) with/without islet cell autotransplantation (IAT) for chronic pancreatitis (CP) patients varies based on multiple factors with a scarcity in literature addressing both at the same time. The aim of this manuscript is to present an algorithm for the surgery selection based on dominant area of disease, ductal dilatation, and glycemic control and compare outcomes. MethodsFrom 2017 to 2021, CP patients offered surgery at a single institution were retrospectively evaluated. Results51 patients underwent surgery (20 [39.2%] TPIAT, 4 [7.8%] TP, and 27 [52.9%] PPS – 9 Whipple procedures, 15 distal pancreatectomies, and 3 duct drainage procedures). No significant difference was observed in baseline characteristics or perioperative outcomes except median length of stay (8 days [IQR 6–10] vs. 13 days [IQR 9–15.5], p < 0.001), attributed to insulin requirement and education for TPIAT group. No differences in postoperative complications, such as clinically significant leak and intrabdominal fluid collection (3 [11.1%] vs 2 [10%], p = 1.0), hemorrhage (0 vs. 2 [10.0%], p = 0.2), delayed feeding (1 [3.7%] vs. 5 [25.0%], p = 0.07), or wound infection (4 [14.8%] vs. 0, p = 0.1) between PPS and TPIAT groups, respectively, were observed nor requirement of long-acting insulin at discharge (2 [15.4%] vs. 7 [43.8%], p = 0.1) for pre-operatively non-diabetic patients. No significant difference in weaning off narcotics and no mortality observed. ConclusionThe most appropriate selection of surgery based on the algorithm yields good and comparable outcomes.

Total Pancreatectomy and Islet Cell Autotransplantation: A 10-Year Update on Outcomes and Assessment of Long-Term Durability

Introduction: Total pancreatectomy and islet cell autotransplantation (TPIAT) offers an effective, durable solution for the management of chronic pancreatitis, as previously reported by our group. The aim of this study was to assess the durability of TPIAT at 10-years post-operatively.

167-OR: Long-Term Follow-up after Total Pancreatectomy and Islet Cell Autotransplantation in Patients with Chronic Pancreatitis Utilizing Off-Site Islet Isolation

Context: Total pancreatectomy (TP) with islet-cell auto transplantation (IAT) is an option for pain management for patients with chronic pancreatitis (CP). IAT allows the preservation of beta cell function to reduce or prevent long-term diabetes. Objective: We performed a follow-up study up to 12 years after TPIAT surgery with an off-site isolation laboratory, to determine the efficacy and durability of the procedure. Methods: Data (August 2008 to August 2020) were obtained from a TPIAT database which included information from medical records, clinic visits, questionnaires, and follow-up telephone calls. Patient demographics were collected. Additionally, each patient was assessed with a 4-hour mixed meal tolerance test for metabolic measurements, serial glycosylated hemoglobin (HbA1c), and insulin requirements prior to surgery and during their most recent follow-up appointment. Results: Seventy-seven patients with a median age of 45.0 years underwent TP-IAT for CP due to different etiologies. At a median follow-up time of 422.5 days 12 patients were insulin independent and 65 patients were on at least one insulin injection a day. Post-operative C-peptide area under the curve (AUC) measurements (P=0.008) were a better indicator of procedure success compared to the number of islet cells transplanted (P=0.225). Patients who were insulin-dependent post-surgery demonstrated increased insulin resistance prior to surgery, by their median pre-surgery insulin AUC; insulin-independent, 626 (241, 3803); insulin-dependent, 1591 (325, 4803), HOMA-IR values 9.02. Conclusions: TPIAT improves intractable pain for patients with CP. IAT decrease insulin requirement and improve blood glucose control after TP. Insulin resistance prior to surgery may be a predictor for insulin-dependence. Intervention studies using insulin sensitizer prior surgery may be considered in evaluating long-term outcomes for these patients. Disclosure S. U. Lad: None. K. F. Ali: None. P. C. Johnston: None. V. San martin: None. Y. Lin: None. R. Bottino: None. M. Walsh: None. T. Stevens: Speaker’s Bureau; Self; AbbVie Inc. B. Hatipoglu: None.

Comparable Long-Term Glycemic Control and Insulin-Independent Rate at Less Cost By Using Intra-Operative vs. Islet Cell Laboratory Isolation for Total Pancreatectomy With Islet Auto-Transplantation

Total pancreatectomy with intraportal islet cell autotransplantation (TPIAT) allows for the islets to be isolated and subsequently re-infused to prevent the complications associated with post-pancreatectomy diabetes in patients with chronic or recurrent pancreatitis. TPIAT requires a complex islet isolation process of the explanted pancreas, and historically required a specialized lab to perform islet cell isolation. We report our unique 5-year experience comparing our new technique of intra-operative islet isolation to the prior use of off-site specialized islet lab, thereby making the isolation process simpler, faster, and more accessible. Method: We performed a retrospective, comparative effectiveness analysis of 50 adult patients who underwent TPIAT at our tertiary care center from 2012 to 2020 (excluding patients with partial- or completion pancreatectomy with IAT). From 2012–2015, isolation occurred at a remote location 130 miles away in which the pancreas was explanted at our center, transported to the islet isolation lab, and returned the same day to our center for portal system infusion. From 2015–2020, islet isolation was performed using the novel intra-operative technique at our institution without a specialized islet isolation lab. We measured the islet equivalents per body weight (IEQ/kg), monitored glycemic control, and compared insulin-independent rate for patients in each group yearly up to 5 years. Results: Twenty patients underwent TPIAT with remote isolation while thirty patients underwent intra-operative isolation of islet cells. Baseline characteristics were similar between these groups. Mean islet yields-IEQ/kg (4,294 remote group vs. 3,015 intra-op group, p=0.06) were not different between the groups. Post-operative mean c-peptide levels at 1 and 3 years were stable over time and were not different between the groups (1.51 and 1.65 ng/mL remote group vs. 0.91 and 0.98 ng/mL intra-operative group, p=0.1 and 0.15 respectively). Mean HbA1c levels at 1–5 years were 7.5–8.2% in the remote group vs. 7.1–7.4% intra-op group, p=0.67, which suggests reasonable and durable glycemic control in both groups. Insulin independent rate was also very similar (43% vs 41%, p=0.10) at 3 years after the surgery when both groups reached the same number of patients (n=20) for the comparison. Average cost of hospitalization was less in the intra-operative group ($104,398 remote vs $78,986 intra-op). Conclusion: Intra-operative islet isolation has similar effectiveness in regard to glycemic outcomes and insulin independent rates but at a lower cost when compared with the use of a dedicated islet cell isolation lab. This technique can allow many more centers without a dedicated islet cell lab to offer islet cell auto-transplantation, which in turn will help reduce the burden of difficult diabetes care post-pancreatectomy and improve quality of life for the appropriate patients.

Total pancreatectomy and salvage completion pancreatectomy-early and late outcomes without Islet cell auto-transplantation

Background: Total pancreatectomy was abandoned for decades because of high peri and post-operative morbidity and mortality. However, with better peri-operative outcome and post-operative management of exocrine and endocrine insufficiency, the hesitancy to perform total pancreatectomy has been disappearing. &#x0D; Objectives: This study aims to study exocrinal and endocrinal effects of total pancreatectomy without Islet cell auto-transplantation and compare quality of life index among total pancreatectomy with Whipple patients.&#x0D; Methodology: This is a prospectively conducted matched-pairs study. Group A underwent total or completion pancreatectomy after non-salvageable complications of Whipple operation. A matched-pairs analysis of quality of life index of these patients by using SF-36 questionnaire were compared with Group B who underwent Whipple operation during the same period of time, according to age, gender and pre-operative diagnosis. &#x0D; Results: In four years (from February 2016 to February 2020), 160 patients underwent Whipple operation. The mean age of the patients was 59.9 +/-14.3 years. A total of nine patients underwent total pancreatectomy, among which two had per-operative decision of total pancreatectomy and seven had completion pancreatectomy. Median post-operative hospital stay was 11 days with two mortalities. Median follow-up of 12 months and quality of life index of total pancreatectomy patients were comparable to Whipple patients, although a few single quality of life items were reduced. &#x0D; Conclusion: Exocrinal pancreatic supplements and long acting insulin have augmented control of diabetes despite of not using Islet cell auto-transplantation. Quality of life index of total pancreatectomy patients were comparable to that of Whipple patients. Hence, this study signifies the importance of completion pancreatectomy following non-salvageable complications after Whipple operation in order to save life.

Duodenal-preserving pancreatic head resection with limited distal pancreatectomy: A novel, tailored approach for chronic pancreatitis

Presenter: Thomas Maatman MD | Indiana University Background: Operative management of chronic pancreatitis (CP) must be tailored to individual patient’s anatomy to achieve durable symptom relief. Incomplete drainage of an atrophic pancreatic tail is a common cause of symptom recurrence in patients undergoing drainage procedures. We have selectively applied limited distal pancreatectomy (DP) with duodenal-preserving pancreatic head resection (DPPHR) to patients with appropriate anatomy and hypothesized that this novel procedure provides durable therapy. Methods: Ten patients underwent DPPHR combined with limited DP between 2013-2018. Patient demographics, comorbidities, perioperative outcomes, and long-term CP-specific outcomes were recorded. Measurements of the pathology specimen determined pancreas tail volume. Chronic pancreatitis specific outcomes included endocrine/exocrine insufficiency, pain relief, and nutritional status. The amount of opioid pain medication was reported as daily morphine equivalents. Body mass index (BMI) and albumin were reported as surrogates for nutritional status. Descriptive statistics were applied. Continuous data are reported as means ± standard error of the mean. Results: Ten patients (8 females; age 49 ± 3 years) had etiology of idiopathic (n = 4), alcohol (n = 2), sequelae of severe acute pancreatitis (n = 1), hereditary (n = 1), autoimmune (n = 1), and pancreas divisum (n = 1). Operation was 57 ± 14 months after CP diagnosis. Patients had 6 ± 1 endoscopic procedures prior to operation. Mean operative time was 215 ± 11 minutes; estimated blood loss was 110 ± 28 mL. On average, 6 ± 1 cm of pancreatic tail was resected. Splenic preservation was possible in 7 patients. Postoperative LOS was 13 ± 2 days. Postoperative morbidity occurred in two patients; one grade B postoperative pancreatic fistula and one perforated duodenal ulcer. Readmission occurred in 5/10 patients at median time of 36 days (range, 16-78 days) postoperatively. Causes included abdominal pain (n = 2), small bowel obstruction (n = 1), intraabdominal abscess requiring antibiotic therapy (n = 1), and failure to thrive (n = 1). No perioperative mortality occurred. Overall, analgesic requirements and nutrition (measured by albumin) improved substantially (Figure 1). In addition, improvement in BMI (preoperative, 23.5 ± 1 kg/m2) was sustained at one- (23.7 ± 1 kg/m2), three- (25.6 ± 1 kg/m2), and five-years postoperatively (24.2 ± 1 kg/m2). At operation, 20% of patients required insulin; at five-year follow up this number was 25%. Eighty percent of patients were prescribed exocrine replacement preoperatively; all patients were on exocrine replacement at five-year follow up. During follow up (mean, 38 ± 7 months), one patient with hereditary CP underwent salvage total pancreatectomy with islet cell auto-transplantation 13 months postoperatively. Conclusion: In select chronic pancreatitis patients, including limited distal pancreatectomy with duodenal-preserving pancreatic head resection provides durable, long-term pain relief and improves nutritional parameters with minimal effect on pancreatic endocrine and exocrine function. This operation should be considered in select patients with appropriate anatomy.

Hydroxyurea Pharmacokinetic Profiles in Children Treated for Extreme Thrombocytosis after Total Pancreatectomy with Islet Cell Autotransplant Demonstrate Poor Absorption

Background Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical treatment for chronic recurrent pancreatitis that involves splenectomy, pancreatectomy and creation of a Roux-en-Y, followed by re-injection of the pancreatic islets into the portal vein. Postoperatively, patients develop a sustained and extreme thrombocytosis (ExT) with platelets ≥1000 K/μL, a response more exaggerated than the typical post-splenectomy course (Gurria JP et al, Pancreas 2019). Empiric aspirin (antiplatelet effect) and hydroxyurea (cytoreduction) are initiated postoperatively per a standard protocol. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of hydroxyurea have not been studied in children other than young children with sickle cell disease; neither dose nor dose interval have been evaluated in TPIAT patients. Recently a population PK model was developed to support individualized hydroxyurea dosing in patients with sickle cell anemia (SCA; Dong M et al, Br J Clin Pharmacol 2016). In a prospective evaluation as part of the Therapeutic Response Evaluation and Adherence Trial (TREAT, McGann PT et al, Am J Hematol 2019), PK-guided individualized dosing resulted in better clinical and laboratory benefits than with conventional weight-based dosing. This study aimed to determine if a hydroxyurea PK model could be developed for non-SCA children dosed postoperatively for control of TPIAT-associated ExT, and if so, to compare it to previously published models for SCA. Methods A prospective single-site pilot study was performed in patients ages 0-21 years who underwent TPIAT between April 2018 and June 2019. Whole blood was collected via finger stick or venipuncture at 3 time points (20 minutes, 1 hour, 4 hours) after the initial hydroxyurea dose (15-20 mg/kg), given between postoperative day 5-7 (PK1). Plasma hydroxyurea was quantified by high performance liquid chromatography on 150-200 μL plasma. Testing was repeated once 2-6 months postoperatively (PK2) to determine whether PK profiles changed over time in relation to surgery. PK analyses and estimation of the area under the concentration-time curve (AUC) as a measure of exposure were performed using MW/Pharm (Mediware, Prague, Czech Republic). PK data from HUSTLE (NCT00305175) were used for comparison to SCA patients. Results Of 19 enrolled subjects, 15 had evaluable results: 7 had both PK collections while 8 had a single collection (5 only had PK1, 3 only had PK2). All 5 patients with only PK1 measurements had discontinued hydroxyurea by the time PK2 samples would have been collected, whereas those with only PK2 all had unsuccessful PK1 collection attempts. Mean age was 13.5 years [standard deviation (SD) 5] with mean weight-based dose 14 mg/kg (SD 3.4). Serum creatinine was normal for age in all patients. Hydroxyurea suspension was delivered via jejunal tube at PK1 while oral tablets were used at PK2 per surgical protocol. The AUC was 60.1 h*μg/ml at PK1 and 68.6 h*μg/ml at PK2. When compared to HUSTLE cohort (Figure 1), TPIAT subjects overall had lower drug exposure (AUC), worse for PK1 than PK2, especially when hydroxyurea concentration was normalized to dose. TPIAT patients also appear to have had slower absorption, evidenced by still-rising hydroxyurea concentrations after 1 hour, compared to 20-30 minute peak concentrations in HUSTLE. Conclusions TPIAT subjects treated empirically with hydroxyurea to modulate ExT have decreased absorption and overall lower concentrations and drug exposure relative to our SCA population. Lower bioavailability and/or altered absorption may in part be caused by differences in formulation (suspension versus tablet) and route of administration (oral versus jejunal) along with postoperative anatomic changes not present in the SCA cohort, since Roux-en-Y may alter drug absorption and metabolism (Rogers CC et al, Clin Transpl2008). It is unknown whether higher enteral hydroxyurea doses would increase exposure and effect. Additional evaluation of the absorption characteristics and PK/PD of hydroxyurea in TPIAT patients, as well as efficacy, are urgently needed. Figure 1 Disclosures Ware: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; Bristol Myers Squibb: Other: Research Drug Donation; Addmedica: Other: Research Drug Donation. OffLabel Disclosure: Hydroxyurea to reduce extreme thrombocytosis after splenectomy/pancreatic islet cell transplant in children

2360 Progression of Post-Islet Cell Transplantation Hepatic Steatosis to Cirrhosis: A Rare Complication of a Common Finding

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a growing cause of liver disease in the USA and throughout the rest of the world and is predicted to soon become the leading indication for liver transplantation. NAFLD exists on a spectrum from hepatic steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis. It is closely related to metabolic syndrome and insulin resistance. A lesser known cause of hepatic steatosis is islet cell allotransplantation and autotransplantation, which are experimental treatments for Type 1 Diabetes Mellitus and FDA- approved treatment for patients with chronic pancreatitis who have undergone pancreatectomy, respectively. In this case, we present the first case of post-islet cell transplantation hepatic steatosis progressing to cirrhosis. CASE DESCRIPTION/METHODS: The patient is a 27 year old female with a history of chronic pancreatitis secondary to cystic fibrosis, status-post total pancreatectomy and islet cell autotransplantation, complicated by development of non-alcoholic steatohepatitis. Her NASH was treated with probiotics and vitamin E supplementation. Eight years after her islet cell transplant, she was hospitalized for nausea, vomiting, and abdominal pain. A CT scan showed that she had developed severe, diffuse hepatic steatosis. Her ALP and AST were mildly elevated. ALT and total bilirubin were normal. She had facial and pedal edema, but no other stigmata of cirrhosis. She underwent a liver biopsy which showed bridging fibrosis and a small regenerative nodule with steatohepatitis. It was with these findings that she was diagnosed with cirrhosis. DISCUSSION: Hepatic steatosis has been reported with a prevalence of 20-40% of patients following islet cell transplantation. These reports have not been associated with any long term liver or graft survival outcomes. The usual onset of histological findings in one study was approximately 3 years after transplant, and some of these cases resolved over time. These reported cases did not have any changes in total bilirubin, ALP, AST, or ALT. Hepatic steatosis from islet transplantation is thought to develop due to the paracrine effect of localized hyperinsulinemia and fatty acid infiltration from the islet cells, which are inserted into the portal vein and taken to the liver during transplant. To our knowledge, this is the only reported case in which post-islet cell transplantation hepatic steatosis progressed to NASH cirrhosis along with abnormal liver biomarkers.

Chronic Pancreatitis and Nutrition Therapy.

Chronic pancreatitis is a complex and irreversible disease of the pancreas and is associated with significant morbidity and mortality. Nutrition deficiencies in chronic pancreatitis are common and can be atypical in nature. As such, the management of these deficiencies can be individualized for patients. The aim of this review is to discuss the components of nutrition deficiencies in chronic pancreatitis, their management, and the current areas of research that are being explored. The clinical guidelines of major national and international societies were analyzed for recommendations on the nutrition management of chronic pancreatitis. The etiology of nutrition deficiencies in chronic pancreatitis is multifactorial and includes aspects of exocrine and/or endocrine dysfunction, significant abdominal pain, often persistent alcohol consumption, and increased metabolic activity. A large number of patients with nutrition deficiencies are underrecognized and undertreated. Although the majority of these patients can be managed by oral and pancreatic enzyme supplementation, some patients may require enteral tube feeding and, in rare cases, parenteral feeding. Current areas of research include the accurate identification of patients at risk for nutrition deficiencies, optimization of feeding regimens, and research into islet cell autotransplantation.

Sa2049 ENDOSCOPY BURDEN OF PEDIATRIC PATIENTS WITH CHRONIC PANCREATITIS OR RECURRENT ACUTE PANCREATITIS: A 10-YEAR RETROSPECTIVE REVIEW

Chronic pancreatitis (CP) and recurrent acute pancreatitis (RAP) are associated with comorbidities and high medical cost. Patients may need endoscopy in addition to medical treatment during pancreatitis episodes. Endoscopy may also be performed to evaluate GI symptoms (ie: abdominal pain) that may or may not be related to CP or RAP. Patients with refractory CP or RAP may benefit from total pancreatectomy with islet cell auto-transplantation (TPIAT). We evaluated the endoscopy burden of pediatric patients with CP or RAP, and to see if patients who have undergone TPIAT experience a different endoscopy burden.

Efficacy of total pancreatectomy with islet autotransplantation on opioid and insulin requirement in painful chronic pancreatitis: A systematic review and meta-analysis

BackgroundThe rationale for total pancreatectomy in painful, treatment refractory, chronic pancreatitis is pain control. Concomitant islet cell autotransplantation can prevent the loss of islet cell function. This study aimed to systematically examine the impact of total pancreatectomy with islet cell autotransplantation on pain and quality of life. MethodsThis meta-analysis was conducted according the Meta-analyses of Observational Studies in Epidemiology guideline. The Cochrane Library, PubMed, and Embase were searched for the following terms (1990 through April 2018): total pancreatectomy and chronic pancreatitis. Studies were included when addressing total pancreatectomy with islet cell autotransplantation for chronic pancreatitis in adults. Studies that reported no data on pain, endocrine function, or quality of life were excluded. Quality was assessed using the Newcastle-Ottawa scale for evaluation of all studies. ResultsWe included 15 observational studies evaluating 1,255 patients, of whom 28% had had endoscopic and 23% operative therapy. One year after total pancreatectomy with islet cell autotransplantation, the opioid-free rate had improved from between 0% and 15% to 63% (95% CI 46–77), and the insulin-free rate had decreased from between 89.5% and 100% to 30% (95% CI 20–43). An alcoholic etiology was associated with a lesser insulin-free rate after total pancreatectomy with islet cell autotransplantation. Quality of life improved statistically after total pancreatectomy with islet cell autotransplantation. Publication bias was present for both opioid and insulin outcomes. ConclusionIn selected patients with painful, treatment refractory, chronic pancreatitis, evidence shows that total pancreatectomy with islet cell autotransplantation is effective for pain control in almost two-thirds of patients, whereas the insulin-free rate is relatively low.

Ductal Cell Reprogramming to Insulin-Producing Beta-Like Cells as a Potential Beta Cell Replacement Source for Chronic Pancreatitis.

Islet cell auto-transplantation is a novel strategy for maintaining blood glucose levels and improving the quality of life in patients with chronic pancreatitis (CP). Despite the many recent advances associated with this therapy, obtaining a good yield of islet infusate still remains a pressing challenge. Reprogramming technology, by making use of the pancreatic exocrine compartment, can open the possibility of generating novel insulin-producing cells. Several lineage-tracing studies present evidence that exocrine cells undergo dedifferentiation into a progenitor-like state from which they can be manipulated to form insulin-producing cells. This review will present an overview of recent reports that demonstrate the potential of utilizing pancreatic ductal cells (PDCs) for reprogramming into insulin- producing cells, focusing on the recent advances and the conflicting views. A large pool of ductal cells is released along with islets during the human islet isolation process, but these cells are separated from the pure islets during the purification process. By identifying and improving existing ductal cell culture methods and developing a better understanding of mechanisms by which these cells can be manipulated to form hormone-producing islet-like cells, PDCs could prove to be a strong clinical tool in providing an alternative beta cell source, thus helping CP patients maintain their long-term glucose levels.

How Durable Is Total Pancreatectomy and Intraportal Islet Cell Transplantation for Treatment of Chronic Pancreatitis?

A total pancreatectomy and intraportal islet cell autotransplant (TPIAT) is increasingly being offered to patients with chronic pancreatitis (CP). The benefits include removal of the root cause of pain and amelioration of diabetes. However, the long-term durability of this operation remains unclear. Of the 742 patients who have undergone a TPIAT at our center, 215 who did so between 1998 and 2008 now have at least 10 years of follow-up time and were eligible for this single-center observational study. Our outcomes measures included abdominal pain relief, narcotic use, islet graft function (subdivided into 3 groups: insulin independence; partial graft function, defined by C-peptide level > 0.6 mg/dL; and no function, defined by C-peptide level < 0.6 mg/dL), and health-related quality of life. The 10-year actuarial survival rate was 72%. A BMI > 30 kg/m2 (p= 0.04) predicted 10-year mortality. The rates of pain relief were 82% at 10 years and 90% at 15 years. Narcotic use declined with time: the rates were 50% at 5 years and 37% at 10 years. At 10 years, the rate of insulin independence was 20%; the rate of partial graft function, 32%. Transplantation of islet equivalents/kg > 4,000 was the strongest predictor of islet graft function at 10 years. Pediatric patients were more likely to have islet function than adults (p= 0.01). Health-related quality of life continued to improve at 10 years, even in patients on narcotics. This represents the first and largest series to examine long-term outcomes (10 years or more) in TPIAT patients. In our series, this dual procedure produced durable pain relief and sustained islet graft function, even past 10 years postoperatively.