Out with the pancreas, in with the islets-exploring endocrine, exocrine, and perioperative nutritional complexities of total pancreatectomy with islet autotransplantation.

Progress in individualizing autologous islet isolation techniques for pediatric islet autotransplantation after total pancreatectomy in children for chronic pancreatitis.

Islet cell autotransplantation and chronic pancreatitis – still options

Pancreatic arteriovenous malformation (AVM) is defined as a tumorous formation or vascular anomaly that builds up via an aberrant bypass anastomosis of the arterial and venous systems in the pancreas (Fig. 1A) (1). Most AVM cases have pancreatic bleeding due to portal hypertension and the rupture of abnormal vessels (2, 3), and AVM is thought to correlate with pancreatitis (2). AVM may be an indication for surgical therapy, including total pancreatectomy (TP). To prevent diabetes induced by TP, islet autotransplantation (IAT) can be an ideal choice.FIGURE 1: A, abdominal 3D (left, opacification; right, rarefaction) computed tomography imaging of an AVM patient. Conglomerations of small vessels were detected around and in the pancreas (arrow). B, blood glucose, HbA1c, serum C-peptide, and daily insulin use changes before and after TP with IAT in patients 1 and 3. The blood glucose levels were well controlled by a low-dose insulin injection in these patients. The blood glucose of the recipients was well maintained without hypoglycemia, and a substantial level of fasting C-peptide was observed under a low dose of daily insulin supplementation.Three male AVM patients underwent TP with IAT at our institute. Their ages were 39, 52, and 59 years. All had had one or more attacks of pancreatitis. Pancreatic pseudocysts were found in the body or tail of the pancreas in all three patients, and all of them had had episodes of bleeding in the pseudocyst. Patients 1 and 2 underwent emergency TP with IAT due to bleeding. We selected a two-step procedure for the TPs (distal pancreatectomy and pancreaticoduodenectomy), because TP for AVM presents a risk of massive bleeding. The warm ischemic times were within 10 min in all three patients, and the cold ischemia times were 33 (body/tail) and 74 min (head) in patient 1, 52 (body/tail) and 81 min (head) in patient 2, and 32 (body/tail) and 197 min (head) in patient 3. The numbers of isolated islets and total tissue volume were 355,270 islet equivalents (IEQ) and 5.7 mL (patient 1), 244,758 IEQ and 16.0 mL (patient 2), and 310,238 IEQ and 1.0 mL (patient 3). The percentages of purity were 30% to 60% (patient 1), 15% to 40% (patient 2), and 40% to 80% (patient 3). Many larger clusters derived from a cystic lesion were detected in patient 2. There was no increase or only a slight increase in the portal vein pressure and no adverse events during transplantation, except in patient 2 (it was significantly increased to 26 mm Hg). Thus, we had to stop patient 2's transplantation when half of the islets were transplanted, but severe hypoglycemia occurred during and after transplantation. No recurrence has been seen thus far at the transplanted site in any of the patients. Figure 1B shows the preoperative and postoperative courses of the patients. The blood glucose levels were well controlled using low-dose insulin injection in patients 1 and 3. The blood glucose of the recipients was well maintained without hypoglycemia, and a substantial level of fasting C-peptide was observed under a low dose of daily insulin supplementation. The secretory unit of islet in transplantation indexes, calculated as 250×(fasting C-peptide [nM])/(fasting blood glucose [nM]-3.43) (4), were 15 to 27 in patient 1 and 6 to 10 in patient 3. These two patients were free from severe and uncontrollable diabetes mellitus. Patient 2 had severe adverse events and poor control of blood glucose. He had total portal thrombus on day 1 after transplantation, and an emergency surgery was performed due to liver dysfunction caused by the portal thrombus. The portal vein thrombectomy was done, and then anticoagulant therapy by continuous injection of heparin and urokinase was performed. Finally, the blood flow in the portal vein recovered and the elevated hepatic enzymes were improved. He was discharged on 92 days after transplantation, but his blood glucose levels became unstable (they increased to >300 mg/dL). Based on our experience with patient 2, we learned that, for patients in a severe preoperative general condition, IAT should not be performed at the same time that a TP is performed. We also know that lower purity of the grafts might be a cause of portal thrombus, even in IAT. To perform TP with IAT as safe, preoperative inflammatory control is of great importance. If an emergency operation is needed for severe inflammation, TP and islet isolation should be done first. Then, cultured islets are transplanted after the patient has recovered from his or her severe general condition. A short culture of the grafts may be beneficial not only for the recipient but also for the islets per se due to mitigation of the inflammatory status. In addition, intramuscular islet transplantation can be an alternative and safe choice to prevent portal thrombus (5). In conclusion, AVM is appropriately treated with TP with IAT. We performed this treatment for three AVM patients and had good outcomes in two of the patients. Further optimizations based on a systematic evaluation of clinical experiences are needed to improve the outcome and safety of this promising approach. Naoaki Sakata 1 Masafumi Goto2,3,8 Fuyuhiko Motoi1 Hiroki Hayashi1 Kei Nakagawa1,4 Masamichi Mizuma1 Hideyuki Yamaya2 Yutaka Hasegawa5 Suguru Yamaguchi5 Shojiro Sawada5 Shigeru Ottomo1 Takaho Okada1 Koji Fukase1 Hiroshi Yoshida1 Tsuneo Ito6 Morihisa Hirota7 Yasushi Ishigaki5 Satoshi Sekiguchi2 Toshiki Rikiyama1 Yu Katayose1,4 Keisei Fujimori2 Shinichi Egawa1 Toru Shimosegawa7 Hideki Katagiri5 Susumu Satomi2 Michiaki Unno1 1 Division of Hepato-Biliary-Pancreatic Surgery Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan 2 Division of Advanced Surgical Science and Technology Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan 3 New Industry Creation Hatchery Center Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan 4 Division of Integrated Surgery and Oncology Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan 5 Division of Molecular Metabolism and Diabetes Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan 6 Translate Research Center Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan 7 Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan ACKNOWLEDGMENT The authors thank all the medical staff for contributing to this clinical study.

Total Pancreatectomy With Autologous Islet Cell Transplantation in Children: Making a Difference

Pancreatic Islet Autotransplantation After Completion Pancreatectomy for Pancreatic Fistula After Hemipancreatoduodenectomy for Carcinoma

Introduction: Islet auto-transplantation (IAT) is increasingly being performed to prevent brittle diabetes following pancreatic resection in patients with benign pancreatic diseases. While patients undergoing total or completion pancreatectomy clearly benefit from IAT, the glycemic benefit of IAT in patients undergoing partial pancreatic resection is not known. We aimed to determine if IAT improved glycemic outcomes in patients undergoing partial pancreatectomy for benign pancreatic diseases. Methods: We performed a multicenter, retrospective case-control study of patients who underwent partial pancreatic resection with IAT at two tertiary care centers. Case patients were compared to controls who underwent partial pancreatic resection without IAT at one center prior to offering IAT. The primary outcome was the mean change in pre vs. post-operative HgA1c following transplant as well as the development of new post-operative diabetes. Results: 9 patients requiring partial pancreatectomy for benign disease underwent IAT and were compared to 13 historical controls without IAT. Baseline characteristics were similar between groups including age, etiology of pancreatitis, the presence of diabetes and pre-operative HgA1c (5.7 vs. 5.2, p=0.448). With a median follow-up of 22 months, those who received an IAT had a smaller increase in their pre- vs. post-operative HgA1c (0.42 vs 2.83, p=0.004) and one case patient (14.3%) vs. three control patients (23.1%) developed new post-operative diabetes (p=0.581). Patients who underwent IAT had a shorter length of stay (6 days vs 11 days, p=0.039) compared to control patients. Conclusions: Patients undergoing partial pancreatic resection for benign pancreatic disease should be considered for IAT, as long-term glycemic outcomes are improved in those undergoing transplant. The shorter length of hospital stay is likely related to less brittle glucose control after the surgery with some endogenous insulin production by auto-islet graft function.

Introduction: Total pancreatectomy with islet auto-transplantation is a realistic therapeutic choice and an advanced surgical operation for individuals with chronic pancreatitis. The primary purpose of total pancreatectomy with islet auto-transplantation is to alleviate the debilitating pain caused by chronic pancreatitis and thereby significantly improve the quality of life of patients with chronic pancreatitis. Although the permanent loss of the function of the pancreatic endocrine occurs due to total pancreatectomy, it may be substituted by autologous transplantation of islets. Patients receiving total pancreatectomy and Islet Transplantation may be less dependent on insulin than patients receiving total pancreatectomy. This process, although not without some difficulties, has consistently demonstrated promising results in reducing pain, improving glycemic control, mitigating diabetic complications, and enhancing the overall quality of life in patients with chronic pancreatitis. In this article, we review the global experience with Total pancreatectomy with islet auto-transplantation and examine the prospects for its implementation in the Albanian health system. They can alleviate the burden of chronic pancreatitis, improve patients' prognosis, and enhance the country's healthcare system capacity. However, the introduction will also necessitate a strategic transformation of infrastructure, training, and health policy, which is discussed below. Conclusions: Total pancreatectomy with islet auto-transplantation is a novel, effective treatment option for patients with recurrent acute pancreatitis and those with chronic pancreatitis. Its implementation in Albania, while promising, necessitates strategic reforms in infrastructure, training, and health policy. However, if constructed as a secondary project with the aim of institutional support, these reforms can significantly increase the quality of care for patients with chronic pancreatitis in our country.

Describe the surgical technique, complications, and long-term outcomes of total pancreatectomy and islet autotransplantation (TP-IAT) in a large series of pediatric patients. Surgical management of childhood pancreatitis is not clear; partial resection or drainage procedures often provide transient pain relief, but long-term recurrence is common due to the diffuse involvement of the pancreas. Total pancreatectomy (TP) removes the source of the pain, whereas islet autotransplantation (IAT) potentially can prevent or minimize TP-related diabetes. Retrospective review of 75 children undergoing TP-IAT for chronic pancreatitis who had failed medical, endoscopic, or surgical treatment between 1989 and 2012. Pancreatitis pain and the severity of pain statistically improved in 90% of patients after TP-IAT (P < 0.001). The relief from narcotics was sustained. Of the 75 patients undergoing TP-IAT, 31 (41.3%) achieved insulin independence. Younger age (P = 0.032), lack of prior Puestow procedure (P = 0.018), lower body surface area (P = 0.048), higher islet equivalents (IEQ) per kilogram body weight (P = 0.001), and total IEQ (100,000) (P = 0.004) were associated with insulin independence. By multivariate analysis, 3 factors were associated with insulin independence after TP-IAT: (1) male sex, (2) lower body surface area, and (3) higher total IEQ per kilogram body weight. Total IEQ (100,000) was the single factor most strongly associated with insulin independence (odds ratio = 2.62; P < 0.001). Total pancreatectomy and islet autotransplantation provides sustained pain relief and improved quality of life. The β-cell function is dependent on islet yield. Total pancreatectomy and islet autotransplantation is an effective therapy for children with painful pancreatitis that failed medical and/or endoscopic management.

Pancreas and Islet Transplantation

To assess the safety and efficacy of islet autotransplantation (IAT) combined with total pancreatectomy (TP) to prevent diabetes. There have been recent concerns regarding the safety of TP and IAT. This is thought to be related to the infusion of large volumes of unpurified pancreatic digest into the portal vein. Minimizing the volume of islet tissue by purifying the pancreatic digest has not been previously evaluated in terms of the postoperative rate of death and complications, pain relief, and insulin independence. During a 54-month period, 24 patients underwent pancreas resection with IAT. Islets were isolated using collagenase and a semiautomated method of pancreas digestion. Where possible, islets were purified on a density gradient and COBE processor. Islets were embolized into the portal vein, within the spleen and portal vein, or within the spleen alone. The total median volume of digest was 9.9 mL. The median number of islets transplanted was 140,419 international islet equivalents per kilogram. The median increase in portal pressure was 8 mmHg. Early complications included duodenal ischemia, a wedge splenic infarct, partial portal vein thrombosis, and splenic vein thrombosis. Intraabdominal adhesions were the main source of long-term problems. Eight patients developed transient insulin independence. Three patients were insulin-independent as of this writing. Patients had significantly decreased insulin requirements and glycosylated hemoglobin levels compared with patients undergoing TP alone. Of the patients alive and well as of this writing, four had failed to gain relief of their abdominal pain and were still opiate-dependent. Combined TP and IAT can be a safe surgical procedure. Unfortunately, almost all patients were still insulin-dependent, but they had decreased daily insulin requirements and glycosylated hemoglobin levels compared with patients undergoing TP alone. A prospective randomized study is therefore needed to assess the long-term benefit of TP and IAT on diabetic complications.

Factors Associated With Morbidity Following Total Pancreatectomy and Islet Autotransplantation: A NSQIP Analysis

How Are Select Chronic Pancreatitis Patients Selected for Total Pancreatectomy with Islet Autotransplantation? Are There Psychometric Predictors?

We would like to congratulate Balzano et al1 on their randomized controlled bicenter PAN-IT trial wherein total pancreatectomy (TP) with islet-autotransplantation (IAT) was studied as an alternative for patients undergoing pancreatoduodenectomy (PD) with a high-risk for developing postoperative pancreatic fistula (POPF). However, we have some concerns regarding the authors’ final conclusions that TP-IAT may become the standard treatment in candidates for PD with a high risk for POPF. Our concerns center on (1) the primary endpoint of the PAN-IT trial, (2) the lack of assessment of patient-reported outcomes, and (3) the quality of diabetes control. First, it is questionable if postoperative morbidity is the optimal endpoint in a trial that aims to elucidate the role of TP(-IAT) as alternative to PD with a high risk for POPF. How much morbidity should be prevented to justify a lifelong apancreatic state? Indeed, TP-IAT improved the primary endpoint (ie, 90-day overall complication rate) by avoiding POPF, but the 90-day mortality did not differ statistically significant despite a clinically relevant difference (9.7% after PD vs 3.3% after TP-IAT), which is line with recent retrospective single-center series.2,3 However, the mortality after TP(-IAT) in the daily clinical practice may be substantially higher. A recent prospective European international multicenter study including 277 patients who underwent TP found a 90-day mortality rate of 7.6%, which increased to even 11.9% in centers performing less than 60 PDs per year.4 Moreover, the recent Dutch PORSCH trial demonstrated that postoperative mortality can be reduced after PD regardless of hospital volume due to the implementation of an algorithm for early detection and treatment of POPF.5 As a consequence, the vast majority of the clinically relevant POPF can be managed either conservatively or with minimally invasive interventions.5 Second, patient-reported outcomes including quality of life over time are highly relevant endpoints when determining the role of TP(-IAT) in our opinion. Surprisingly, quality of life was not evaluated over time, while the prospective nature of the PAN-IT trial offered a unique opportunity to investigate this properly. This should be included in future prospective studies. Although the interest in TP for this indication has been renewed in recent years by the improved morbidity and mortality after TP in high-volume centers4,6 and more adequate management of the associated metabolic insufficiencies, the related adverse events remain substantial.7 Quality of life on the middle- and long-term after TP is reduced in comparison to the general population.8,9 IAT after TP only (mostly temporarily) controls the endocrine insufficiency partially, whereas exocrine insufficiency remains a challenge. This is especially relevant for the currently studied indication of TP(-IAT) since patients with a high risk for POPF after PD often have long-term survival because of benign/ premalignant pancreatic diseases. Third, the quality of diabetes control and insulin independence obtained by TP-IAT. Already after 1 month, glycemic control as measured by hemoglobin A1c was worse in the TP-IAT group and at the end of follow-up (median follow-up of 388 days), only 6.7% of patients after TP-IAT were independent of insulin versus 80.6% of patients after high-risk PD. The authors argue that the absence of serious hypoglycemic events is explained by the remaining graft function. However, long-term results are missing, while these are highly important considering the likelihood that the graft function will further decrease over time. An alternative for or additive to IAT might be the bihormonal artificial pancreas, for which we recently demonstrating promising results.10 In summary, the PAN-IT is a high quality randomized trial that provides quite relevant insights, but in our opinion does not confirm that TP-IAT may become the standard treatment in patients with a high risk for POPF after PD. We question whether a 30% absolute risk reduction of short-term postoperative morbidity justifies a 73% absolute risk increase of lifelong insulin dependence and, most likely, decreased quality of life. Furthermore, early POPF recognition and step-wise minimally invasive management have an important role in the improvement of both morbidity and mortality after PD. Only future large, randomized studies with mortality and quality of life as primary outcome can answer this question.

Islet autotransplantation (IAT) may decrease the morbidity and mortality of postpancreatectomy diabetes mellitus. The current systematic review and meta-analysis examined the rate of insulin independence (II) and mortality after IAT post-total (TP) or partial pancreatectomy (PP). Ovid MEDLINE, EMBASE, Web of Science, SCOPUS and reference lists were searched until 31 January 2011. Eligible studies enrolled adult patients with IAT post-TP or PP, regardless of study design, sample size and language. Two investigators identified eligible studies and extracted data independently. From each study, 95% confidence intervals (CIs) were estimated and pooled using random effects meta-analysis. Fifteen observational studies were eligible (11 IAT post-TP, two post-PP and two including both). The 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 II lasting 15·57 months (95% CI: 10·35-20·79). The 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. IAT postpancreatectomy offers some patients a chance for insulin independence. Better data reporting are essential to establish the risks and benefits of IAT after pancreatic surgery.

Objective: Although many studies on islet autotransplantation for the treatment of chronic pancreatitis have so far been reported, there have only been a few reports regarding islet autotransplantation for the treatment of acute pancreatitis with severe inflammation. In patients demonstrating a severe inflammatory status, islet autotransplantation usually fails due to both an insufficient islet yield and an impaired islet quality. Therefore, it is important to both identify such cases and improve the treatment protocol in order to increase the success of this therapeutic approach. In the present study, we experienced three cases of islet autotransplantation who all had a severe inflammatory status due to a rupture of a pancreatic arteriovenous The Lessons Learned from Three Cases of Islet Autotransplantation with a Severe Inflammatory Status Due to a Rupture of a Pancreatic Arteriovenous Malformation malformation, and we established a novel graft protection protocol to more effectively treat such patients. Methods: Total pancreatectomy and islet autotransplantation were performed in 3 males diagnosed with a pancreatic arteriovenous malformation. An emergency operation was performed on 2 of these cases due to a rupture and bleeding from the mass. The pancreas weight was 54, 186, and 86 g, respectively. The pancreatic islets were isolated using a modified Ricordi method. The inhalation of isoflurane during islet infusion and continuous intensive insulin treatment combined with shortterm fasting/total parenteral nutrition during the avascular period of the grafts (10 days) were carried out in order to allow the islet grafts to rest. Results: The islet yield was 355,270, 244,758, and 310,238 islet equivalents, respectively, but only 229,538 islet equivalents were infused due to catheter trouble in the third case. The total tissue volume was 5.7, 16.0, and 1.0 ml, respectively. After certifying that no bacterial contamination existed, the islets were then transplanted via the portal vein. In the second case, a sudden increase in the portal vein pressure was seen during islet infusion, and then a portal embolism was observed over a wide range of the liver. As a result, a surgical embolectomy and embolytic therapy were performed. In the other 2 cases, the blood glucose of the recipients was well maintained with no sign of hypoglycemia, and a substantial level of fasting C-peptide was observed under a low dose of daily insulin supplementation. The SUIT index of the first case (15-27) was considerably higher than that of the third case (6-10), thus suggesting that the transplanted islet amount and/or the transplanted tissue amount may play an important role in the treatment outcome. Of particular note, no recurrence of the arteriovenous malformation in all the cases has so far been seen at the transplanted site. Conclusions: These data suggest that the above described refined islet isolation procedures combined with a novel graft protecting protocol could play an important role in achieving successful islet autotransplantation in patients with a severe inflammatory status. Furthermore, several modifications, including changes in the catheterization procedures, reducing the graft amount, and switching to either cultured-islet transplantation or intramascular islet transplantation make need to be performed when complications such as unexpected copious bleeding or a suture of the portal vein occurs.