Research
Original Investigation | PACIFIC COAST SURGICAL ASSOCIATION
Autologous Islet Transplantation With Remote Islet Isolation After Pancreas Resection for Chronic Pancreatitis Denise S. Tai, MD; Na Shen, MD; Gregory L. Szot, MS; Andrew Posselt, MD, PhD; Nicholas J. Feduska, MS; Andrew Habashy, BS; Barbara Clerkin, RN; Erin Core, RN; Ronald W. Busuttil, MD, PhD; O. Joe Hines, MD; Howard A. Reber, MD; Gerald S. Lipshutz, MD, MS
IMPORTANCE Autologous islet transplantation is an elegant and effective method for preserving euglycemia in patients undergoing near-total or total pancreatectomy for severe chronic pancreatitis. However, few centers worldwide perform this complex procedure, which requires interdisciplinary coordination and access to a sophisticated Food and Drug Administration–licensed islet-isolating facility. OBJECTIVE To investigate outcomes from a single institutional case series of near-total or total pancreatectomy and autologous islet transplantation using remote islet isolation. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study between March 1, 2007, and December 31, 2013, at tertiary academic referral centers among 9 patients (age range, 13-47 years) with chronic pancreatitis and reduced quality of life after failed medical management. INTERVENTIONS Pancreas resection, followed by transport to a remote facility for islet
isolation using a modified Ricordi technique, with immediate transplantation via portal vein infusion. MAIN OUTCOMES AND MEASURES Islet yield, pain assessment, insulin requirement, costs, and
transport time. RESULTS Eight of nine patients had successful islet isolation after near-total or total pancreatectomy. Four of six patients with total pancreatectomy had islet yields exceeding 5000 islet equivalents per kilogram of body weight. At 2 months after surgery, all 9 patients had significantly reduced pain or were pain free. Of these patients, 2 did not require insulin, and 1 required low doses. The mean transport cost was $16 527, and the mean transport time was 3½ hours. CONCLUSIONS AND RELEVANCE Pancreatic resection with autologous islet transplantation for severe chronic pancreatitis is a safe and effective final alternative to ameliorate debilitating pain and to help prevent the development of surgical diabetes. Because many centers lack access to an islet-isolating facility, we describe our experience using a regional 2-center collaboration as a successful model to remotely isolate cells, with outcomes similar to those of larger case series.
JAMA Surg. 2015;150(2):118-124. doi:10.1001/jamasurg.2014.932 Published online December 10, 2014. 118
Author Affiliations: Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles (Tai, Feduska, Habashy, Clerkin, Core, Busuttil, Hines, Reber, Lipshutz); Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles (Shen, Lipshutz); Department of Surgery, University of California, San Francisco (Szot, Posselt); UCLA Center for Pancreatic Diseases, University of California, Los Angeles (Clerkin, Hines, Reber, Lipshutz). Corresponding Author: Gerald S. Lipshutz, MD, MS, Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Room 77-120, Center for the Health Sciences, Los Angeles, CA 90095 (glipshutz @mednet.ucla.edu). (Reprinted) jamasurgery.com
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Purdue University User on 05/19/2015
Autologous Islet Transplantation for Pancreatitis
C
hronic pancreatitis (CP) is an inflammatory disease of the pancreas that over time leads to irreversible fibrosis and loss of function. Such repeated and progressive injury commonly manifests with intractable pain, malabsorption, and diabetes mellitus.1,2 During a period of decades, the risk of malignant conversion is up to 50 times greater in patients with CP than in the general population, particularly among those with a history of smoking or hereditary etiology.3 For many, the debilitating abdominal pain often leads to a diminished quality of life due to multiple hospitalizations, invasive interventions, and potential narcotic dependency. Although CP is a prevalent disorder, it can be difficult to diagnose because of its progressive nature and nonspecific symptoms that overlap with many conditions. Epidemiologic data are limited in the United States, but the economic burden of all pancreatitis cases was estimated at $3.7 billion in 2004, with CP-related discharges from hospitals estimated at 8.1 per 100 000 persons.4,5 Excessive alcohol consumption is the most common etiology in the United States; less common causes include hypertriglyceridemia, pancreas divisum, and autoimmune and familial pancreatitis, with known mutations in several genes, including the cystic fibrosis transmembrane receptor (CFTR) (OMIM 602421), trypsin inhibitor (SPINK1) (OMIM 167790), and trypsin 1 gene (PRSS1) (OMIM 276000). Chronic pain is often the most challenging symptom to treat, and its pathogenesis remains poorly defined. Evidence suggests that ductal obstruction via stricture or stones and the concomitant rise of intraductal pressure lead to parenchymal ischemia and neuronal injury that may contribute to pain in pancreatitis.1 Although medical management and pain control are the initial approaches to CP, a subset of patients develop intractable pain that requires more invasive intervention via endoscopy to relieve elevated ductal pressure.6 When such interventions fail, surgical management is often the next logical approach to management. Selecting the optimal surgical procedure depends largely on the extent and complication of disease, as well as ductal size. Options have traditionally included procedures to improve drainage such as lateral pancreaticojejunostomy, resection, or a combination of drainage and resection. Pancreatic resection with total pancreatectomy (TP) or pancreatoduodenectomy (Whipple procedure) has been shown to provide pain relief in up to 80% of patients. 7 However, pancreatectomy invariably produces brittle diabetes by removal of insulinsecreting beta cells that reside in the islets of Langerhans and by loss of glucagon counterregulation.2 Autologous islet transplantation (AIT) was first described in the 1970s as a method for preserving long-term euglycemia after near-total or TP for CP. 8 In a specialized isletisolating facility, islets are procured from the resected pancreas by enzymatic and mechanical digestion.9 After assessing for quality and quantity, the islet preparation is immediately transplanted to the patient via portal vein infusion. After a period of islet rest and engraftment, islets produce insulin that can reduce episodes of hypoglycemic unawareness and facilitate insulin independence. jamasurgery.com
Original Investigation Research
Despite the effective pain relief and insulin independence reported in many patients after pancreatectomy and AIT,10 few medical centers worldwide offer such treatment options for patients with CP. Possible reasons include the limited access to and cost of maintaining an islet-isolating facility, a lack of consensus regarding indications for and timing of surgical intervention, and the paucity of data on long-term outcomes. At the University of California, Los Angeles (UCLA), we have performed pancreatic resection and AIT on a series of pediatric and adult patients with CP during 7 years. To circumvent the limitation of direct access to an islet-isolating facility, we developed a unique regional collaboration to remotely process islets after pancreas resection. The objectives of this study were to report the results of our case series and collaborative experience and to contribute to the growing body of literature on TP and AIT as a promising strategy to treat patients with unremitting symptoms of pancreatitis.
Methods Patients and Data Collection This study was approved by the Committee for Human Research at UCLA. All patients were fully informed of the risks and uncertain efficacy of AIT and provided written consent. Between March 1, 2007, and December 31, 2013, nine patients with a diagnosis of CP were referred to the UCLA Center for Pancreatic Diseases for pancreatic resection and AIT. The diagnosis was made by a history of chronic abdominal pain requiring narcotics, recurrent episodes of acute pancreatitis, and radiographic or endoscopic findings consistent with CP. Medical records were retrospectively reviewed to collect preoperative, operative, posttransplantation, and financial data.
Preoperative Assessment Before surgery, patients were evaluated by a local endocrinologist or by the UCLA endocrinology service. Glycated hemoglobin level, fasting C-peptide level, and a metabolic panel were obtained. Patients were evaluated by teams from the UCLA Center for Pancreatic Diseases (B.C., O.J.H., H.A.R., and G.S.L.) and the UCLA transplantation services (G.S.L.). All patients were offered the option of a Whipple procedure or TP and possible AIT. All patients who decided to undergo a Whipple procedure also elected to receive AIT to preserve functional islet tissue.
Operative and Autologous Islet Transplantation Procedures Patients who underwent pancreatic resection received a duodenum-preserving pancreatoduodenectomy or TP with splenectomy by standard technique. Effort was made to maintain arterial perfusion and unimpeded venous outflow from the pancreas for as long as possible. The pancreas was removed from the operating table, and a biopsy specimen was obtained for frozen section analysis. The gastroduodenal artery and splenic artery were flushed, and the pancreas was packaged in 3 sterile layers and transported to the University of California, San Francisco, Islet Preparation Core for islet isola(Reprinted) JAMA Surgery February 2015 Volume 150, Number 2
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Purdue University User on 05/19/2015
119
Research Original Investigation
Autologous Islet Transplantation for Pancreatitis
Table 1. Patient Demographics Variable
Value
Age, mean (range), y
26.7 (13-47)
Body mass index, mean (range)a
21.9 (18.4-27.0)
Sex, No. Female
4
Male
5
Pancreatitis diagnosis, No. Alcohol induced
1
Hereditary
4
Idiopathic
3
Hypertriglyceridemia
1
Genetic mutation identified, No. PRSS1b
2
SPINK1
2
Preoperative intervention, No. c
Prior surgery
3
Endoscopic retrograde cholangiopancreatography
6
Stent
3
Operation, No. Pylorus-preserving Whipple procedure
3
Total pancreatectomy
6
a
Calculated as weight in kilograms divided by height in meters squared.
b
One patient with the PRSS1 mutation was also positive for the CFTR mutation.
c
Includes cholecystectomy, duodenojejunostomy with Roux-en-Y reconstruction, and gastrostomy.
tion. On return with the islets, heparin sodium was administered intravenously to the patient. A 14-gauge catheter was placed in the portal vein, and islets were infused at approximately 30-mL intervals, with serial portal venous pressures obtained. After completion of infusion, the catheter was removed, the abdomen was closed in the normal fashion, and the patient was taken to the intensive care unit for monitoring.
Transport to the Remote Islet-Isolating Facility After resection and perfusion with a cold storage preservation solution (Cold Storage/Purification Stock Solution; Mediatech, Inc), the pancreas was transported via helicopter from the UCLA to Van Nuys Airport, Van Nuys, California, where a regional plane transported the transplant team (D.S.T., N.J.F., E.C., and G.S.L.) and pancreas to San Francisco International Airport. Car service was used for transportation to the University of California, San Francisco, Islet Preparation Core. Return transport to the UCLA was identically used.
Autologous Islet-Isolating Procedures Autologous islet isolation was performed and modified from a standard allogeneic islet-isolating procedure as previously described.11-14 Briefly, after removal of excess tissue and duodenum, the pancreas was immersed in an antibiotic and antimycotic solution. The pancreatic duct was catheterized and infused with collagenase (NB 1 GMP grade) and neutral proteases (NB 1 GMP grade) (Serva/Nordmark). After distension, the pancreas was divided into 7 to 10 pieces and trans120
ferred to a 600-mL digestion chamber (Ricordi; Biorep Technologies, Inc) to allow closed circulation of the enzyme solution at 37°C.15 Samples of digested tissue were periodically obtained and monitored closely to prevent overdigestion. When most of the islets observed in the samples were free of exocrine tissue, the digestion was stopped with cold solution. Tissue digest containing liberated islets and non–islet (acinar) cells was washed, counted, and evaluated for viability, sterility, and endotoxin. The release criteria for infusion was a yield exceeding 10 000 islet equivalents (IE) total. The final pellet was resuspended in 200 mL of transplant media, transferred to an islet infusion bag, and supplemented with heparin sodium (10003000 U total) and ciprofloxacin hydrochloride for infusion.
Postoperative Insulin Management and Follow-up Following surgery, patients were placed on an intensive intravenous insulin infusion protocol managed by the UCLA endocrinology service. Blood glucose levels were maintained between 70 and 110 mg/dL for 10 to 14 days to optimize islet engraftment (to convert glucose level to millimoles per liter, multiply by 0.0555). After beginning oral nutrition, patients were placed on subcutaneous prandial short-acting analogue insulin and intravenous insulin. After a period of stable nutrition, patients transitioned to a basal and bolus subcutaneous insulin regimen, and fasting C-peptide levels were obtained. On postoperative day 1, patients underwent liver and portal venous Doppler ultrasonography to evaluate for thrombosis. Patients underwent anticoagulation with intravenous heparin for the first 7 to 10 days after surgery and then transitioned to subcutaneous fractionated heparin for an additional 1 to 2 weeks. For further insulin management after discharge, patients were followed up in the UCLA Endocrinology Clinic or with their local endocrinologist if they lived beyond the local Los Angeles County area.
Results Demographics Between 2007 and 2013, nine patients (5 male) with CP underwent a duodenum-preserving Whipple procedure (n = 3) or TP (n = 6), followed by immediate AIT. Their mean (SD) age was 26.7 (13.4 years), and their mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 21.9 (3.0). The CP etiologies included hereditary, alcohol induced, hypertriglyceridemia, and idiopathic. All 4 patients with hereditary pancreatitis were positive for SPINK1 or PRSS1 mutations, and one patient was positive for both PRSS1 and CFTR mutations. One pediatric patient with hereditary pancreatitis was also positive for type 1 diabetes mellitus autoantibodies (glutamic acid decarboxylase 65 [GAD65], microinsulin autoantibody [MIAA], and islet cell antibody [ICA] antibodies) (Table 1). Before consideration for surgical resection, all patients had multiple documented episodes of acute pancreatitis and had undergone interventional procedures, including endoscopic retrograde cholangiopancreatography with sphincterotomy,
JAMA Surgery February 2015 Volume 150, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Purdue University User on 05/19/2015
jamasurgery.com
Autologous Islet Transplantation for Pancreatitis
Original Investigation Research
Table 2. Individual Patient Demographics
Patient No./Sex/ Age, y
Body Mass Indexa Pancreatitis Diagnosis
Genetic Mutation Identified
1/M/17
24.0
Idiopathic
NA
Pyloruspreserving Whipple procedure
2/M/16
20.2
Hypertriglyceridemia
NA
3/M/47
22.7
Alcohol induced
4/M/36
27.0
5/F/13
Islet Equivalents per Kilogram of Body Weight
Glycated Hemoglobin Level, %
C-peptide Level, ng/mL
Postoperative Insulin Use
Preoperative
Postoperative
Preoperative
Postoperativeb
951
5.7
5.6
1.7
0.8
None
Pyloruspreserving Whipple procedure
93
5.0
4.3
0.2
0.2
None
NA
Pyloruspreserving Whipple procedure
0
6.5
NA
1.4
NA
Unknown
Hereditary
PRSS1, CFTR
TP, splenectomy
130
6.2
8.3
2.0
Original Investigation | PACIFIC COAST SURGICAL ASSOCIATION
Autologous Islet Transplantation With Remote Islet Isolation After Pancreas Resection for Chronic Pancreatitis Denise S. Tai, MD; Na Shen, MD; Gregory L. Szot, MS; Andrew Posselt, MD, PhD; Nicholas J. Feduska, MS; Andrew Habashy, BS; Barbara Clerkin, RN; Erin Core, RN; Ronald W. Busuttil, MD, PhD; O. Joe Hines, MD; Howard A. Reber, MD; Gerald S. Lipshutz, MD, MS
IMPORTANCE Autologous islet transplantation is an elegant and effective method for preserving euglycemia in patients undergoing near-total or total pancreatectomy for severe chronic pancreatitis. However, few centers worldwide perform this complex procedure, which requires interdisciplinary coordination and access to a sophisticated Food and Drug Administration–licensed islet-isolating facility. OBJECTIVE To investigate outcomes from a single institutional case series of near-total or total pancreatectomy and autologous islet transplantation using remote islet isolation. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study between March 1, 2007, and December 31, 2013, at tertiary academic referral centers among 9 patients (age range, 13-47 years) with chronic pancreatitis and reduced quality of life after failed medical management. INTERVENTIONS Pancreas resection, followed by transport to a remote facility for islet
isolation using a modified Ricordi technique, with immediate transplantation via portal vein infusion. MAIN OUTCOMES AND MEASURES Islet yield, pain assessment, insulin requirement, costs, and
transport time. RESULTS Eight of nine patients had successful islet isolation after near-total or total pancreatectomy. Four of six patients with total pancreatectomy had islet yields exceeding 5000 islet equivalents per kilogram of body weight. At 2 months after surgery, all 9 patients had significantly reduced pain or were pain free. Of these patients, 2 did not require insulin, and 1 required low doses. The mean transport cost was $16 527, and the mean transport time was 3½ hours. CONCLUSIONS AND RELEVANCE Pancreatic resection with autologous islet transplantation for severe chronic pancreatitis is a safe and effective final alternative to ameliorate debilitating pain and to help prevent the development of surgical diabetes. Because many centers lack access to an islet-isolating facility, we describe our experience using a regional 2-center collaboration as a successful model to remotely isolate cells, with outcomes similar to those of larger case series.
JAMA Surg. 2015;150(2):118-124. doi:10.1001/jamasurg.2014.932 Published online December 10, 2014. 118
Author Affiliations: Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles (Tai, Feduska, Habashy, Clerkin, Core, Busuttil, Hines, Reber, Lipshutz); Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles (Shen, Lipshutz); Department of Surgery, University of California, San Francisco (Szot, Posselt); UCLA Center for Pancreatic Diseases, University of California, Los Angeles (Clerkin, Hines, Reber, Lipshutz). Corresponding Author: Gerald S. Lipshutz, MD, MS, Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Room 77-120, Center for the Health Sciences, Los Angeles, CA 90095 (glipshutz @mednet.ucla.edu). (Reprinted) jamasurgery.com
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Purdue University User on 05/19/2015
Autologous Islet Transplantation for Pancreatitis
C
hronic pancreatitis (CP) is an inflammatory disease of the pancreas that over time leads to irreversible fibrosis and loss of function. Such repeated and progressive injury commonly manifests with intractable pain, malabsorption, and diabetes mellitus.1,2 During a period of decades, the risk of malignant conversion is up to 50 times greater in patients with CP than in the general population, particularly among those with a history of smoking or hereditary etiology.3 For many, the debilitating abdominal pain often leads to a diminished quality of life due to multiple hospitalizations, invasive interventions, and potential narcotic dependency. Although CP is a prevalent disorder, it can be difficult to diagnose because of its progressive nature and nonspecific symptoms that overlap with many conditions. Epidemiologic data are limited in the United States, but the economic burden of all pancreatitis cases was estimated at $3.7 billion in 2004, with CP-related discharges from hospitals estimated at 8.1 per 100 000 persons.4,5 Excessive alcohol consumption is the most common etiology in the United States; less common causes include hypertriglyceridemia, pancreas divisum, and autoimmune and familial pancreatitis, with known mutations in several genes, including the cystic fibrosis transmembrane receptor (CFTR) (OMIM 602421), trypsin inhibitor (SPINK1) (OMIM 167790), and trypsin 1 gene (PRSS1) (OMIM 276000). Chronic pain is often the most challenging symptom to treat, and its pathogenesis remains poorly defined. Evidence suggests that ductal obstruction via stricture or stones and the concomitant rise of intraductal pressure lead to parenchymal ischemia and neuronal injury that may contribute to pain in pancreatitis.1 Although medical management and pain control are the initial approaches to CP, a subset of patients develop intractable pain that requires more invasive intervention via endoscopy to relieve elevated ductal pressure.6 When such interventions fail, surgical management is often the next logical approach to management. Selecting the optimal surgical procedure depends largely on the extent and complication of disease, as well as ductal size. Options have traditionally included procedures to improve drainage such as lateral pancreaticojejunostomy, resection, or a combination of drainage and resection. Pancreatic resection with total pancreatectomy (TP) or pancreatoduodenectomy (Whipple procedure) has been shown to provide pain relief in up to 80% of patients. 7 However, pancreatectomy invariably produces brittle diabetes by removal of insulinsecreting beta cells that reside in the islets of Langerhans and by loss of glucagon counterregulation.2 Autologous islet transplantation (AIT) was first described in the 1970s as a method for preserving long-term euglycemia after near-total or TP for CP. 8 In a specialized isletisolating facility, islets are procured from the resected pancreas by enzymatic and mechanical digestion.9 After assessing for quality and quantity, the islet preparation is immediately transplanted to the patient via portal vein infusion. After a period of islet rest and engraftment, islets produce insulin that can reduce episodes of hypoglycemic unawareness and facilitate insulin independence. jamasurgery.com
Original Investigation Research
Despite the effective pain relief and insulin independence reported in many patients after pancreatectomy and AIT,10 few medical centers worldwide offer such treatment options for patients with CP. Possible reasons include the limited access to and cost of maintaining an islet-isolating facility, a lack of consensus regarding indications for and timing of surgical intervention, and the paucity of data on long-term outcomes. At the University of California, Los Angeles (UCLA), we have performed pancreatic resection and AIT on a series of pediatric and adult patients with CP during 7 years. To circumvent the limitation of direct access to an islet-isolating facility, we developed a unique regional collaboration to remotely process islets after pancreas resection. The objectives of this study were to report the results of our case series and collaborative experience and to contribute to the growing body of literature on TP and AIT as a promising strategy to treat patients with unremitting symptoms of pancreatitis.
Methods Patients and Data Collection This study was approved by the Committee for Human Research at UCLA. All patients were fully informed of the risks and uncertain efficacy of AIT and provided written consent. Between March 1, 2007, and December 31, 2013, nine patients with a diagnosis of CP were referred to the UCLA Center for Pancreatic Diseases for pancreatic resection and AIT. The diagnosis was made by a history of chronic abdominal pain requiring narcotics, recurrent episodes of acute pancreatitis, and radiographic or endoscopic findings consistent with CP. Medical records were retrospectively reviewed to collect preoperative, operative, posttransplantation, and financial data.
Preoperative Assessment Before surgery, patients were evaluated by a local endocrinologist or by the UCLA endocrinology service. Glycated hemoglobin level, fasting C-peptide level, and a metabolic panel were obtained. Patients were evaluated by teams from the UCLA Center for Pancreatic Diseases (B.C., O.J.H., H.A.R., and G.S.L.) and the UCLA transplantation services (G.S.L.). All patients were offered the option of a Whipple procedure or TP and possible AIT. All patients who decided to undergo a Whipple procedure also elected to receive AIT to preserve functional islet tissue.
Operative and Autologous Islet Transplantation Procedures Patients who underwent pancreatic resection received a duodenum-preserving pancreatoduodenectomy or TP with splenectomy by standard technique. Effort was made to maintain arterial perfusion and unimpeded venous outflow from the pancreas for as long as possible. The pancreas was removed from the operating table, and a biopsy specimen was obtained for frozen section analysis. The gastroduodenal artery and splenic artery were flushed, and the pancreas was packaged in 3 sterile layers and transported to the University of California, San Francisco, Islet Preparation Core for islet isola(Reprinted) JAMA Surgery February 2015 Volume 150, Number 2
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Purdue University User on 05/19/2015
119
Research Original Investigation
Autologous Islet Transplantation for Pancreatitis
Table 1. Patient Demographics Variable
Value
Age, mean (range), y
26.7 (13-47)
Body mass index, mean (range)a
21.9 (18.4-27.0)
Sex, No. Female
4
Male
5
Pancreatitis diagnosis, No. Alcohol induced
1
Hereditary
4
Idiopathic
3
Hypertriglyceridemia
1
Genetic mutation identified, No. PRSS1b
2
SPINK1
2
Preoperative intervention, No. c
Prior surgery
3
Endoscopic retrograde cholangiopancreatography
6
Stent
3
Operation, No. Pylorus-preserving Whipple procedure
3
Total pancreatectomy
6
a
Calculated as weight in kilograms divided by height in meters squared.
b
One patient with the PRSS1 mutation was also positive for the CFTR mutation.
c
Includes cholecystectomy, duodenojejunostomy with Roux-en-Y reconstruction, and gastrostomy.
tion. On return with the islets, heparin sodium was administered intravenously to the patient. A 14-gauge catheter was placed in the portal vein, and islets were infused at approximately 30-mL intervals, with serial portal venous pressures obtained. After completion of infusion, the catheter was removed, the abdomen was closed in the normal fashion, and the patient was taken to the intensive care unit for monitoring.
Transport to the Remote Islet-Isolating Facility After resection and perfusion with a cold storage preservation solution (Cold Storage/Purification Stock Solution; Mediatech, Inc), the pancreas was transported via helicopter from the UCLA to Van Nuys Airport, Van Nuys, California, where a regional plane transported the transplant team (D.S.T., N.J.F., E.C., and G.S.L.) and pancreas to San Francisco International Airport. Car service was used for transportation to the University of California, San Francisco, Islet Preparation Core. Return transport to the UCLA was identically used.
Autologous Islet-Isolating Procedures Autologous islet isolation was performed and modified from a standard allogeneic islet-isolating procedure as previously described.11-14 Briefly, after removal of excess tissue and duodenum, the pancreas was immersed in an antibiotic and antimycotic solution. The pancreatic duct was catheterized and infused with collagenase (NB 1 GMP grade) and neutral proteases (NB 1 GMP grade) (Serva/Nordmark). After distension, the pancreas was divided into 7 to 10 pieces and trans120
ferred to a 600-mL digestion chamber (Ricordi; Biorep Technologies, Inc) to allow closed circulation of the enzyme solution at 37°C.15 Samples of digested tissue were periodically obtained and monitored closely to prevent overdigestion. When most of the islets observed in the samples were free of exocrine tissue, the digestion was stopped with cold solution. Tissue digest containing liberated islets and non–islet (acinar) cells was washed, counted, and evaluated for viability, sterility, and endotoxin. The release criteria for infusion was a yield exceeding 10 000 islet equivalents (IE) total. The final pellet was resuspended in 200 mL of transplant media, transferred to an islet infusion bag, and supplemented with heparin sodium (10003000 U total) and ciprofloxacin hydrochloride for infusion.
Postoperative Insulin Management and Follow-up Following surgery, patients were placed on an intensive intravenous insulin infusion protocol managed by the UCLA endocrinology service. Blood glucose levels were maintained between 70 and 110 mg/dL for 10 to 14 days to optimize islet engraftment (to convert glucose level to millimoles per liter, multiply by 0.0555). After beginning oral nutrition, patients were placed on subcutaneous prandial short-acting analogue insulin and intravenous insulin. After a period of stable nutrition, patients transitioned to a basal and bolus subcutaneous insulin regimen, and fasting C-peptide levels were obtained. On postoperative day 1, patients underwent liver and portal venous Doppler ultrasonography to evaluate for thrombosis. Patients underwent anticoagulation with intravenous heparin for the first 7 to 10 days after surgery and then transitioned to subcutaneous fractionated heparin for an additional 1 to 2 weeks. For further insulin management after discharge, patients were followed up in the UCLA Endocrinology Clinic or with their local endocrinologist if they lived beyond the local Los Angeles County area.
Results Demographics Between 2007 and 2013, nine patients (5 male) with CP underwent a duodenum-preserving Whipple procedure (n = 3) or TP (n = 6), followed by immediate AIT. Their mean (SD) age was 26.7 (13.4 years), and their mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 21.9 (3.0). The CP etiologies included hereditary, alcohol induced, hypertriglyceridemia, and idiopathic. All 4 patients with hereditary pancreatitis were positive for SPINK1 or PRSS1 mutations, and one patient was positive for both PRSS1 and CFTR mutations. One pediatric patient with hereditary pancreatitis was also positive for type 1 diabetes mellitus autoantibodies (glutamic acid decarboxylase 65 [GAD65], microinsulin autoantibody [MIAA], and islet cell antibody [ICA] antibodies) (Table 1). Before consideration for surgical resection, all patients had multiple documented episodes of acute pancreatitis and had undergone interventional procedures, including endoscopic retrograde cholangiopancreatography with sphincterotomy,
JAMA Surgery February 2015 Volume 150, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Purdue University User on 05/19/2015
jamasurgery.com
Autologous Islet Transplantation for Pancreatitis
Original Investigation Research
Table 2. Individual Patient Demographics
Patient No./Sex/ Age, y
Body Mass Indexa Pancreatitis Diagnosis
Genetic Mutation Identified
1/M/17
24.0
Idiopathic
NA
Pyloruspreserving Whipple procedure
2/M/16
20.2
Hypertriglyceridemia
NA
3/M/47
22.7
Alcohol induced
4/M/36
27.0
5/F/13
Islet Equivalents per Kilogram of Body Weight
Glycated Hemoglobin Level, %
C-peptide Level, ng/mL
Postoperative Insulin Use
Preoperative
Postoperative
Preoperative
Postoperativeb
951
5.7
5.6
1.7
0.8
None
Pyloruspreserving Whipple procedure
93
5.0
4.3
0.2
0.2
None
NA
Pyloruspreserving Whipple procedure
0
6.5
NA
1.4
NA
Unknown
Hereditary
PRSS1, CFTR
TP, splenectomy
130
6.2
8.3
2.0
