Surgical management of chronic pancreatitis and the role of islet cell autotransplantation

ORIGINAL REPORTS

Surgical Management of Chronic Pancreatitis and the Role of Islet Cell Autotransplantation Thomas S. Helling, MD Department of Surgery, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri Chronic pancreatitis is a disease characterized by disabling pain, inability to eat, steatorrhea, and eventual malnutrition. This often results in repeated hospitalizations and attempts to control symptoms with various analgesic regimens. As a result, the medical treatment of chronic pancreatitis is one of symptomatic management. Eventually, in some, nutritional supplementation becomes a necessity. For a fortunate few, the disease apparently burns itself out in time, lessening pain and improving appetite. In many patients, frustration over pain management and repeated hospitalizations leads to surgical treatment. Various procedures have been devised but, generally, fall into 2 categories: operations to decompress dilated ducts and operations to resect diseased pancreas. Results with either approach are unpredictable and often unsuccessful. For those without dilated ducts or with recurrent pain after surgery, total pancreatectomy has been suggested to remove all inflammatory tissue. This can be coupled with islet cell autotransplantation to avoid the dangers of pancreatogenic diabetes. Appropriate care of the removed pancreas and islet cell separation and purification are critical to this procedure to produce viable cells. Dispersed islets have been shown to successfully engraft and function for indefinite periods of time. Although insulin independence may not be achieved, easier maintenance of blood glucose can usually be realized. (Curr Surg 60:463-469. © 2003 by the Association of Program Directors in Surgery.) KEY WORDS: pancreas, chronic pancreatitis, islet cell trans-

plant

INTRODUCTION At the 33rd annual meeting of the Society of University Surgeons in 1972, Ballinger and Lacy1 reported their experience with transplantation of intact pancreatic islets of Langerhans into rats. A 60% to 70% pancreatectomy was performed with subsequent digestion of acinar, ductal, and vascular tissue by collagenase agitation. Islets were separated, resuspended, and implanted intraperitoneally into inbred recipients rendered diabetic. These isografts, comprising from 400 to 600 islets, Correspondence: Inquiries to Thomas S. Helling, MD, 4320 Wornall Road, Kansas City, MO 64111; fax: (816) 753-3368; [email protected]

maintained euglycemia and weight in recipient rats up to 3 months after implantation. In 1976, the same group2 reported equal success with the intraportal injection of islets into streptozotocin diabetic rats. Fasting plasma glucose and insulin levels normalized, and, after 5 months, hepatic insulin and glucagon reserves were still one-half to one-quarter (respectively) of normal hormonal reserves. Histologically, implanted islets were found widely dispersed throughout the liver, vascularized by periportal arterial and venous branches by the eleventh day after implantation.3 Similar results were obtained by others in both rat4 and canine5 models Although problems remained with allogeneic implantation, autologous infusion of pancreatic islets would prove effective in reversing the diabetic state.

CHRONIC PANCREATITIS Chronic pancreatitis is a disorder characterized by inflammatory changes and fibrosis affecting exocrine and, on occasion, endocrine function. This may ultimately lead to failure of glandular function as manifested by malabsorption (steatorrhea) and diabetes mellitus. With repeated episodes, loss of appetite and weight loss occur. In Western societies, the disease is most often produced by alcohol consumption, although other causes, such as hyperlipidemias, hyperparathyroidism, and familial or congenital predispositions, or idiopathic origins may be found. Etemad and Whitcomb6 have proposed the major risk factors as (1) toxic-metabolic, (2) idiopathic, (3) genetic, (4) autoimmune, (5) recurrent acute pancreatitis, and (6) obstructive. The disease generally occurs in a chronic relapsing form with recurrent pain, nausea, and vomiting.7,8 Histopathologically, there is scarring and loss of acinar tissue in a focal, segmental, or diffuse fashion with consequent dilation or stenoses of the ductal system. The Marseille-Rome classification9 defined chronic pancreatitis as “the presence of chronic inflammatory lesions characterized by the destruction of exocrine parenchyma and fibrosis and at least in the later stages, the destruction of endocrine parenchyma.” After a variable period of time, many patients develop pancreatic calcifications, seen on plain abdominal radiographs or on computerized tomography. These calcifications are thought to represent intraductal pancreatic calculi.10 Morphologically, 2 forms of the disease can be recog-

CURRENT SURGERY • © 2003 by the Association of Program Directors in Surgery Published by Elsevier Inc.

0149-7944/03/$30.00 doi:10.1016/S0149-7944(02)00789-4

463

MANAGEMENT OF CHRONIC PANCREATITIS

nized: large duct (diameter of the main pancreatic duct greater than 7 mm) and small duct (4 to 5 mm duct). In a series of 93 patients with chronic pancreatitis, Nealon et al11 reported 22 had small duct disease and the majority, 71 patients, was found to have large ducts. In alcoholic pancreatitis, pseudocyst formation is not uncommon and may occur in up to one-quarter of cases 12. The pathophysiology of chronic pancreatitis remains unclear. Different hypotheses have been proposed. Sarles et al13 have suggested a defect in the elaboration of a protein, for acquired or inherited reasons, which inhibits calcium carbonate precipitaion, lithostatin (also known as pancreatic stone protein). Formation of calcium carbonate deposits (micro-calculi) lead to small duct obstruction, which causes inflammation, and fibrosis of parenchyma drained by these ducts. Others14 have contended that repeated episodes of acute pancreatitis may lead to a necrosis—fibrosis sequence that gradually leads to widespread depletion of acinar tissue and sclerosis. Damage from oxidative stress has also been proposed as a mechanism.15 Excess-free radicals affect intracellular pathways and cause membrane lipid oxidation. Cell death results and inflammation is triggered. The dominant symptom, occurring in up to 90% of patients with chronic pancreatitis, is pain. The pain may be constant or intermittent and is often aggravated by eating. The pathogenesis of this pain is poorly understood. Possible etiologic mechanisms include elevated pancreatic ductal pressures, abnormalities in pancreatic blood flow, and changes in pancreatic nerves consisting of edema and loss of perineural sheaths 16 . Loss of the perineurium barrier would possibly subject these nerves to any number of bioactive products present in the connective tissue spaces of the chronically inflamed pancreas.17 More recent theories attribute pain to neuroimmune interactions of intrapancreatic nerves and inflammatory cells and an increase in levels of pain neurotransmitters.18, 19 More likely, the causes of pain in this disorder are multifactorial and not easily addressed by any one treatment modality. The course of chronic pancreatitis is difficult to predict. In an elegant prospective study by Ammann et al20, a mixed medical and surgical series of 245 patients were followed for over 10 years. During the follow-up period, 31% of those with alcoholic pancreatitis and 44% of those with nonalcoholic pancreatitis died. Mortality most often was not related to pancreatitis. Only 19% of deaths could be attributed to pancreatitis or its complications. Others died from a variety of causes from cardiovascular events to severe infections to cirrhosis and gastrointestinal bleeding. Pancreatic insufficiency as manifested by exocrine dysfunction developed in the majority (88%) of patients with calcific pancreatitis at a mean of 5.65 years after onset, and by 11 years, all were found to have steatorrhea. Diabetes mellitus was seen in 3 out of 4 patients at a mean of 5.72 years after onset.

Because of the uncertainty (and multiplicity) of its etiology, management of pain from chronic pancreatitis has been notoriously difficult. Abstinence from alcohol may produce relief of pain in up to 50% of patients.21 Pancreatic enzyme supplementation can be effective in pain relief by reducing exocrine pancreatic secretion through inhibition of cholecystokinin activity by proteases.22 This approach, however, has met with mixed results. 23, 24 Celiac plexus block with alcohol have been advocated by some,25 but results have been unpredictable, perhaps due to the intense inflammation and fibrosis around the celiac plexus.26 More commonly, pain management is by way of oral analgesics. Often, more potent narcotic analgesics are required, and addiction to pain medication is a frequently problem. Interestingly, according to Ammann et al,20 lasting pain relief was equally likely whether nonoperative or operative management was chosen. Others have found that there can be a significant decline in pain with time in both alcoholic and nonalcoholic varieties, although a sizable number of patients (over 50%) will still experience pain attacks beyond 10 years.27 In patients refractory to medical management, surgery has been attempted. The operative approach, to a large extent, depends on the ductal pattern of disease. When a dilated pancreatic duct is found, ductal hypertension is thought to be a cause of worsening pain. Bradley,28 using an endoscopic approach, found pancreatic ductal pressures significantly elevated in 19 patients with chronic pancreatitis compared to control patients. Likewise, Sato et al29 measured ductal pressures 2-fold higher than those seen in normal subjects. These data lent support to operations designed to decompress dilated pancreatic ducts such as those proposed by DuVal30 (end-to-side pancreaticojejunostomy), Peustow31 (lateral pancreatorrhaphy and immersion pancreatico-jejunostomy), and Partington and Rochelle32 (lateral pancreatico-jejunostomy). The attractiveness of these procedures is preservation of exocrine and endocrine pancreas and low postoperative mortality. In reported series followed over several years, partial or complete pain relief has been found in up to 80% of patients.33-35 However, only about 40% of patients will have the large duct variant, and results in smaller duct disease with decompressive procedures has been disappointing.36 An additional 20% to 50% will have persistent pain following lateral pancreaticojejunostomy, which, in the alcoholic variety, has been attributed in many cases to resumption of drinking.37 As might be expected, exocrine and endocrine function following pancreatic duct decompression is good (although not assured). For those patients with small duct disease whose pain may be due to the inflammatory process itself, resection of pancreas has been suggested. Any attempt at resection must balance removal of inflammatory disease with preservation of endocrine and exocrine function. Although involvement of the gland is most often diffuse,38 when an inflammatory process is localized to one part of the pancreas, such as the head or tail, limited resec-

464

CURRENT SURGERY • Volume 60/Number 4 • July/August 2003

Sutherland et al49 in 1980 reported their success in transplantation of autologous dispersed pancreatic islets in 3 patients who had received near-total pancreatectomies for benign disease. In 2 of the 3 patients, euglycemia and exogenous insulin independence resulted for at least 1 year following implantation. By 1980, their series had expanded to 10 patients.50 In these patients, a pancreatectomy was performed, the gland processed for islet tissue, and islets infused via an indwelling mesenteric vein catheter into the portal system, and dispersed in the liver while the patient remained in the operating room. One

patient died postoperatively, and one was lost to follow-up. Of the remaining 8 patients, followed from 1 to 38 months later, 7 were successfully withdrawn from narcotics. Three patients were insulin independent (at 1, 8, and 38 months). The other 5 required some exogenous insulin. Comparable results were obtained by Cameron et al,51 who reported their experience with 8 patients undergoing 95% pancreatectomy and islet cell autotransplantation. There was 1 postoperative death. Of the 7 survivors, 3 were pain free and 4 required some analgesia. Three remained insulin independent, and 4 required some exogenous insulin. No mention was made of exocrine management. That dispersed islet cell function was intact was demonstrated in a contemporaneous case report by the same authors,52 who found a 4-fold increase in hepatic vein insulin while portal vein insulin remained constant in response to an infusion of glucose via the portal vein. A more extensive experience with islet cell autotransplantation was reported by the Minnesota group in 1995 comprising 48 patients.53 Forty-seven of the 48 patients had small duct chronic pancreatitis. Only 1 postoperative death resulted, but 25% of patients encountered complications. There were 8 deaths in the follow-up period, none apparently attributable to the operation. In follow-up, from 1 month to 17 years, 39% of patients reported that pain was resolved, and 61% still had some degree of pain. Twenty of 39 evaluable patients (51%) had initial (less than 1 month) insulin independence, but this dropped to 15 patients (38%) beyond 1 month. A more recent European experience of 13 patients indicated sustained insulin independence in 5 of 9 surviving patients (4 late deaths) from 9 to 48 months after surgery.54 Initial attempts to isolate pancreatic islets were based on earlier animal methodology 1 of mincing and digestion of pancreatic parenchyma. In humans, after excision of the gland, the transected splenic artery was immediately flushed with cold Ringer’s lactate solution followed by injection of the pancreatic duct with cold Hank’s solution. The pancreas was then mechanically diced and the tissue digested with collagenase for a variable period of time. Following digestion, the tissue was resuspended in Hank’s solution, washed, and centrifuged. The tissue was again suspended in Hank’s solution and transported to the operating room for injection into the portal circulation. Although subtle adjustments in technique have evolved since, basic principles of islet cell preparation have persisted: (1) prompt cooling and infusion of preservation solution, (2) thorough digestion of pancreatic tissue, and (3) purification of islet tissue (Figure 1). The aim is to maximize yield of islet cells for implantation. From the use of cold Ringer’s lactate and then Eurocollin’s as a preservation solution, better tissue preservation has been achieved with the use of University of Wisconsin (UW) solution through more effective membrane stabilization and replenishment of intracellular energy stores.55 The UW solution has also been preferred over Hank’s solution for storage of purified islets because of the intracellular composition of the fluid. Unlike cadaver donors (for allogeneic islet retrieval) where vasomotor instability might affect organ perfusion, blood flow and

CURRENT SURGERY • Volume 60/Number 4 • July/August 2003

465

tion may be reasonable. In such cases, exocrine function is not altered and only a minority will be rendered diabetic.39 Often times, involvement of the pancreatic head by chronic inflammation dominates, leading to a mass effect. Traverso40 has even called the pancreatic head the “pacemaker” of chronic pancreatitis. In this setting, with no discernible ductal dilation, some have recommended pancreaticoduodenectomy.41, 42 Postoperatively, over one-third of these patients develop exocrine insufficiency, but through preservation of the body and tail of the pancreas, endocrine function usually remains unaltered.39 Long-term follow-up, though, shows an increasing rate of pain recurrence in up to 40% of patients, often associated with recurrent alcohol intake.41, 43 In patients with small duct disease, diffuse glandular involvement, or for whom previous operations have failed the surgical approach becomes more difficult. In these circumstances, some have advocated total pancreatectomy. The metabolic consequences of such an undertaking are substantial. Foremost, patients will be rendered diabetic, which is notoriously difficult to regulate. Pancreatogenic diabetes is characterized by an absolute deficiency in insulin, glucagon, and pancreatic polypeptide and is associated with enhanced peripheral insulin sensitivity 44 producing wide swings of blood glucose, which can result in dangerous hypoglycemia if not well monitored. The impact of total pancreatectomy was well illustrated by Braasch et al.45 Although there was no postoperative mortality, complications developed in 24 of 26 patients resulting in 55 readmissions to the hospital. Ten of 26 patients failed to gain or lost weight after surgery, and all experienced problems in blood glucose regulation. There were 12 deaths in the follow-up period, 4 perhaps due to hypoglycemic episodes. In long-term survivors, 9 of 14 were judged fair to poor health, although 12 of these patients were thought better off than before surgery. Similar results were obtained in a European series reported by Gall et al46 Operative mortality was 20%, and a late mortality of 24% was found. All patients were rendered diabetic and in 75% management was difficult. Six of the late deaths were due to “hypoglycemia.” The subtotal (95%) pancreatectomy described by Frey,47 retaining a rim of pancreas adjacent to the duodenum and common bile duct has proven no more effective than total pancreatectomy in avoiding later endocrine and exocrine problems.48

PANCREATIC ISLET AUTOTRANSPLANTATION

oxygen delivery should be relatively unaffected in the chronic pancreatitic, and warm ischemia thus kept at a minimum. However, following pancreatectomy, uniform perfusion of the gland with preservation solution might be compromised due to the fibrotic nature of chronic pancreatitis, and some areas of parenchyma could be inadequately preserved. Cold ischemic time should be kept to less than 8 hours from the time of arterial clamping to prevent early islet loss and less than 16 hours for any meaningful islet recovery.56 Mincing and digestion of the gland has been replaced with intraductal distension with collagenase solution as described by Ricordi et al.57 Early injection of collagenase into the pancreatic duct within 45 minutes of preservation may result in a better yield of islets.58 A major obstacle in islet retrieval has been the collagenase used for digestion and the lot variability that has occurred.59 This has been corrected to a large extent by the introduction of Liberase Purified Enzyme Blend (Roche Molecular Biochemicals/Boehringer, Mannheim, Germany), which contains highly purified collagenase isoforms I and II and thermolysin.60 The enzyme preparation is dissolved in Hank’s solution and injected into the pancreatic duct. The distension and enzymatic digestion in a heated environment results in liberation of islet tissue. Further liberation occurs in a digestion chamber augmented by gentle mechanical agitation. The preparation is then centrifuged to assist in separation of acinar tissue during the purification process. Purification of the islet preparation is yet another critical step in islet yield. Islets are physi-

cally less dense than acinar tissue so that separation can occur using density gradient centrifugation. The pellets that result from collagenase digestion are separated using a density gradient (continuous or discontinuous Ficoll—a polymer of sucrose) and produce a layer of islets either density bound or within a narrow density spectrum.61 Difficulties in isolation and purification of islets are a major cause of interinstitutional variability of islet yield.62 The dispersed purified islets are washed, suspended in plasma, and placed in syringes for portal vein infusion. Islet counts are made from aliquots of the final preparation either by measuring extracted insulin content/islet or by counting of stained islets.53 Engraftment occurs by infusion of the suspension of islet cells into a cannulated mesenteric vein and, hence, into the liver, with special care given to monitoring portal pressure. At least 2 cases of fatal portal hypertension have been reported after autotransplantation of islets.63,64 Possible mechanisms include mechanical plugging of portal vein radicles by clumps of islets and liberation of thromboplastins produced during tissue preparation causing a picture of disseminated intravascular coagulation. Heparinization of the recipient and careful manometric monitoring of portal pressure so as not to exceed 20 mm Hg are recommended. There are data to suggest that, experimentally, newly engrafted islets may be susceptible to hyperglycemia leading to beta cell exhaustion 65,66, so that use of exogenous insulin for a period of time may be advisable. Islet yield is thought critical to the success of autotransplantation. In the large series reported by the Minnesota group53 and in a smaller series published by others,67 at least 200,000 islets are required to produce any chance of insulin independence. Certainly, more than 100,000 islets, or more than 3000 IEQ/kg, are needed to ensure adequate beta cell function.54 Long-term insulin independence may even require more islets, in excess of 400,000 (greater than 5000 IEQ/kg).68 It is not entirely clear why such a large islet cell mass is required for euglycemia (compared to the 10% to 30% of islet cell mass that is sufficient after partial pancreatectomy). Clearly, islet cell isolation results in disruption of the cytoskeleton— extracellular matrix connections that may lead to anoikis, or apoptosis of ␤-cells due to lack of integrin transmission.69,70 Furthermore, islet recovery has been found to be a function of separation and purification methods, extent of pancreatic fibrosis, and extent of pancreatectomy. The probability of insulin independence fell from 40% to 16% if a previous pancreatic resection had been done prior to completion pancreatectomy.53 That pancreatic islets can be successfully preserved after extraction and purification was demonstrated by Arias-Diaz et al,71 who delayed implantation for 48 hours after pancreatectomy and in 5 patients receiving autotransplants at a considerable distance, 1500 miles, from the processing source.72 In the 5 patients who had distant processing of their pancreata, from 129,000 to 400,000 islets (1800 to 8000 IEQ/kg) were retrieved. One patient achieved insulin independence (400,000 islets infused), and 2 others were on low maintenance doses of insulin from 16 to 47

466

CURRENT SURGERY • Volume 60/Number 4 • July/August 2003

FIGURE 1. Pancreatic islet autografts.

months after surgery, indicating successful engraftment of their islets.

7. Holt S. Chronic pancreatitis. Southern Med J. 1993;86:

201-207. 8. Owang C, Levitt M. Chronic pancreatitis. In: T Yamada,

SUMMARY Chronic pancreatitis represents a challenging problem for surgeons. It is but one of only a few diseases where pain may be the only indication for operation. It is not surprising, due to the subjective nature of pain and the multiple causes of pain in this disease, that results are unpredictable and, at times, difficult to evaluate. Surgeons must keep in mind that many patients with chronic pancreatitis, treated nonoperatively, will experience less pain as their disease “burns out.” However, equally true, some operations are quite effective in relieving pain in the short term and in the long term. For patients whose pain is worsening and who may be developing malnutrition, surgery is an option. The operation should be tailored to the pancreatic pathology. For those who have small duct disease and no dominant inflammatory mass, or for those in whom pain has recurred following subtotal pancreatectomy—and who are not yet diabetic—total or completion pancreatectomy and islet cell autotransplantation can be considered. A number will be rendered pain free, and management of diabetes will be easier. Some may even be insulin independent. With selection of the appropriate laboratory, adequate and reproducible yield of islet cells can be obtained. Long distance transport of pancreata and islets with cold ischemic times approaching 24 hours have resulted in successful engraftment of islets.

editor. Textbook of Gastroenterology, Vol. 2. Philadelphia, PA: JB Lippincott Co; 1991:1875. 9. Sarles H, Adler G, Dani R, et al. The pancreatitis classifi-

cation of Marseilles-Rome, 1988. Scand J Gastroenterol. 1989;24:641-642. 10. Sarles H, Bernard JP, Gullo L. Pathogenesis of chronic

pancreatitis. Gut. 1990;31:1-3. 11. Nealon WH, Townsend CM Jr, Thompson JC. A com-

parison of large duct and small duct variants in chronic pancreatitis. Pancreas. 1988;3:610-616. 12. Kloppel G, Maillet B. Pseudocysts in chronic pancreatitis:

a morphological analysis of 57 resection specimens and 9 autopsy pancreata. Pancreas. 1991;6:266-274. 13. Miltigner I, Sarles H, Lombardo D, de Caro A. Pancreatic

stone protein II: implication in stone formation during the course of chronic calcifying pancreatitis. Gastroenterology. 1985;89:387-391. 14. Ammann RW, Muelhaupt B. Progression of alcoholic

acute to chronic pancreatitis. Gut. 1994;35:552-556. 15. Braganza JM. Pancreatic disease: a casuatly of hepatic “de-

toxification”? Lancet. 1983;ii:1000-1003. 16. Karanjia ND, Reber HA. The cause and management of

REFERENCES 1. Ballinger WF, Lacy PE. Transplantation of intact pancre-

atic islets in rats. Surgery. 1972;72:175-186. 2. Pipeleer-Marichal MA, Pipeleers DG, Cutler J, Lacy PE,

Kipnis DM. Metabolic and morphologic studies in intraportal-islet-transplanted rats. Diabetes. 1976;25:10411051. 3. Griffith RC, Scharp DW, Hartman BK, Ballinger WF,

the pain of chronic pancreatitis. Gastroenterol Clin N Am. 1990;19:895-903. 17. Bockman DE, Buchler M, Malfertheiner P, Beger HG.

Analysis of nerves in chronic pancreatitis. Gastroenterology. 1988;94:1459-1469. 18. Shrikhande SV, Friess H, di Mola FF, et al. Nk-1 receptor

gene expression is related to pain in chronic pancreatitis. Pain. 2001;91:209-217. 19. Zhu ZW, Friess H, Wang L, Zimmerman A, Buchler

Lacy PE. A morphologic study of intrahepatic portal-vein islet isografts. Diabetes. 1977;26:201-214.

MW. Brain-derived neurotrophic factor (BDNF) is upregulated and associated with pain in chronic pancreatitis. Dig Dis Sci. 2001;46:1633-1639.

4. Eloy R, Kedinger M, Garaud JC, et al. Intrahepatic trans-

20. Ammann RW, Akovbiantz A, Largiader F, Schueler G.

plantation of pancreatic islets in the rat. Horm Metab Res. 1977;9:40-46.

Course and outcome of chronic pancreatitis. Gastroenterology. 1984;86:820-828.

5. Kretschmer GJ, Sutherland DE, Matas AJ, Cain TL, Na-

21. Ihse I, Lankisch PG. Treatment of chronic pancreatitis-

jarian JS. Autotransplantation of pancreatic islets without separation of exocrine and endocrine tissue in totally pancreatectomized dogs. Surgery. 1977;82:74-81.

22. Halgreen H, Thorsgaard-Pedersen N, Worning H. Symp-

6. Etemad B, Whitcomb DC. Chronic pancreatitis: diagno-

current status. Acta Chir Scand. 1988;154:553-558. tomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis. Scand J Gastroenterol. 1986;21: 104-108.

sis, classification, and new genetic developments. Gastroenterology. 2001;120:682-707.

23. Isaksson G, Ihse H. Pain reduction by an oral pancreatic

CURRENT SURGERY • Volume 60/Number 4 • July/August 2003

467

enzyme preparation in chronic pancreatitis. Dig Dis Sci. 1983;28:97-102.

38. Singh SM, Reber HA. The pathology of chronic pancre-

24. Nasrallah SM. The effect of pancreatic enzyme supple-

39. Jalleh RP, Williamson RCN. Pancreatic exocrine and en-

ments on pain in chronic pancreatitis [abstracts]. Gastroenterology. 1981;80:1238.

docrine function after operations for chronic pancreatitis. Ann Surg. 1992;216:656-662.

25. Bell S, Cole R, Robert-Thomson IC. Coeliac plexus block

40. Traverso LW. The surgical management of chronic pan-

for control of pain in chronic pancreatitis. Br Med J. 1980; 281:1604.

creatitis: the Whipple procedure. Adv Surg. 1999;32:2340.

26. Leung JWC, Bowen-Wright M, Aveling W, Shorvon PJ,

Cotton PB. Coeliac plexus block for pain in pancreatic cancer and chronic pancreatitis. Br J Surg. 1983;70:730732. 27. Lankisch PG, Seidensticker F, Lohr-Happe A, Creutzfeldt

W. The course of pain is the same in alcoholic- and nonalcoholic-induced chronic pancreatitis. Pancreas. 1995;10:338-341. 28. Bradley EL. Pancreatic duct pressure in chronic pancreati-

tis. Am J Surg.. 1982;144:313-315. 29. Sato T, Miyashita E, Yamauchi H, Matsuno S. The role of

surgical treatment for chronic pancreatitis. Ann Surg. 1986;203:266-271. 30. DuVal MK Jr. Caudal pancreaticojejunostomy for

chronic relapsing pancreatitis. Ann Surg. 1954;140:775783. 31. Peustow CB, Gillesby WJ. Retrograde surgical drainage of

pancreas for chronic relapsing pancreatitis. Arch Surg. 1958;76:898-907. 32. Partington PF, Rochelle REL. Modified Puestow proce-

dure for retrograde drainage of the pancreatic duct. Ann Surg. 1960;152:1037-1043. 33. Warshaw AL. Conservation of pancreatic tissue by com-

bined gastric, biliary, and pancreatic duct drainage for pain from chronic pancreatitis. Am J Surg. 1985;149:563569. 34. Prinz RA, Greenlee HB. Pancreatic duct drainage in 100

patients with chronic pancreatitis. Ann Surg. 1981;194: 313-320. 35. Markowitz JS, Rattner DW, Warshaw AL. Failure of

symptomatic relief after pancreaticojejunal decompression for chronic pancreatitis: strategies for salvage. Arch Surg. 1994;129:374-380. 36. Brinton MH, Pellegrini CA, Stein SF, Way LW. Surgical

treatment of chronic pancreatitis. Am J Surg. 1984;148: 754-763. 37. Lucas CE, McIntosh B, Paley D, Ledgerwood AM, Vlahos

A. Surgical decompression of ductal obstruction in patients with chronic pancreatitis. Surgery. 1999;126:790797. 468

atitis. World J Surg. 1990;14:2-10.

41. Howard

JM, Zhang Z. Pancreaticoduodenectomy (Whipple resection) in the treatment of chronic pancreatitis. World J Surg. 1990;14:77-82.

42. Traverso LW, Kozarek RA. The Whipple procedure for

severe complications of chronic pancreatitis. Arch Surg. 1993;128:1047-1053. 43. Keith RG. Pancreaticoduodenectomy for chronic pancre-

atitis. In: Howard JM, Idezuki Y, Ihse I, Prinz RA, editors. Surgical Diseases of the Pancreas. Baltimore, MD: Williams and Wilkins; 1998. 44. Slezak LA, Andersen DK. Pancreatic resection: effects on

glucose metabolism. World J Surg. 2001;25:452-460. 45. Braasch JM, Vito L, Nugent FW. Total pancreatectomy

for end-stage chronic pancreatitis. Ann Surg. 1978;188: 317-322. 46. Gall FP, Muhe E, Gebhardt C. Results of partial and total

pancreaticoduodenectomy in 117 patients with chronic pancreatitis. World J Surg. 1981;5:269-275. 47. Frey C. Role of subtotal pancreatectomy and pancreati-

cojejunostomy in chronic pancreatitis. J Surg Res. 1981; 31:361-370. 48. Frey C, Child C, Fry W. Pancreatectomy for chronic pan-

creatitis. Ann Surg. 1984;196:403-414. 49. Sutherland DE, Matas AJ, Goetz FC, Najarian JS. Trans-

plantation of dispersed pancreatic islet tissue in humans: autografts and allografts. Diabetes. 1980;29(Suppl 1):3144. 50. Najarian JS, Sutherland DER, Baumgartner D, et al. To-

tal or near total pancreatectomy and islet autotransplantation for treatment of chronic pancreatitis. Ann Surg. 1980; 192:526-542. 51. Cameron JL, Mehigan DG, Broe PJ, Zuidema GD. Distal

pancreatectomy and islet autotransplantation for chronic pancreatitis. Ann Surg. 1980;193:312-317. 52. Cameron JL, Mehigan DG, Harrington DP, Zuidema

GD. Metabolic studies following intrahepatic autotransplantation of pancreatic islet grafts. Surgery. 1980;87:397400. 53. Wahoff DC, Papalois BE, Najarian JS, et al. Autologous CURRENT SURGERY • Volume 60/Number 4 • July/August 2003

islet transplantation to prevent diabetes after pancreatic resection. Ann Surg. 1995;222:562-579.

pancreatic islet 1982;91:485-487.

autotransplantation.

Surgery.

54. Oberholzer F, Triponez F, Mage R, et al. Human islet

64. Mittal VK, Toledo-Pereyra LH, Sharma M, et al. Acute

transplantation: lessons from 13 autologous and 13 allogeneic transplantations. Transplantation. 2000;69:11151123.

portal hypertension and disseminated intravascular coagulation following pancreatic islet autotransplantation after subtotal pancreatectomy. Transplantation. 1981;31:302304.

55. Delfino VDA, Gray DWR, Leow CK, Shimizu S, Fergu-

son DJP, Morris PJ. A comparison of four solutions for cold storage of pancreatic islets. Transplantation. 1993;56: 1325-1330. 56. Lakey JR, Rajotte RV, Warnock GL, Kneteman NM. Hu-

man pancreas preservation prior to islet isolation. Transplantation. 1995;59:689-694. 57. Ricordi C, Lacy PE, Scharp DW. Automated islet isola-

tion from human pancreas. Diabetes. 1989;38(Suppl 1): 140-142. 58. Socci C, Davalli AM, Vignali A, et al. A significant in-

crease of islet yield by early injection of collagenase into the pancreatic duct of young donors. Transplantation. 1993;55:661-663. 59. Benhamou PY, Watt PC, Mullen Y, et al. Human islet

isolation in 104 consecutive cases. Transplantation. 1994; 57:1804-1810.

65. Korsgren O, Jansson L, Andersson A. Effects of hypergly-

cemia on function of isolated mouse pancreatic islets transplanted under kidney capsule. Diabetes. 1989;38:510-515. 66. Yumiba T, Miyata M, Izukura M, et al. Islet rest protects

against exhaustion of insulin production in transplanted islets. Transplant Proc. 1992;24:995-996. 67. White SA, Dennison AR, Swift SM, et al. Intraportal and

splenic human islet autotransplantation combined with total pancreatectomy. Transplant Proc. 1998;30:312-313. 68. Teuscher AU, Kendall DM, Smets YF, Leone JP, Suther-

land DE, Roberston RP. Successful islet autotransplantation in humans: functional insuling secretory reserve as an estimate of surviving islet cell mass. Diabetes. 1998;47: 324-330. 69. Arias-Diaz J, Calleja J, Vara E, et al. Delayed islet auto-

60. Linetsky E, Bottino R, Lehman R, Alejandro R, Inverardi

transplantation after total pancreatectomy. Transplant Proc. 1994;26:3521-3522.

L, Ricordi C. Improved human islet isolation using a new enzyme blend, Liberase. Diabetes. 1997;46:1120-1123.

70. Rosenberg L, Wang R, Paraskevas S, Maysinger D. Struc-

61. Olack BJ, Hill A, Scharp DW, Lacy PE. Automated puri-

fication of canine islets. Transplant Proc. 1992;24:10031004. 62. Morrison CP, Wemyss-Holden SA, Dennison AR, Mad-

dern GJ. Islet yield remains a problem in islet autotransplantation. Arch Surg. 2002;137:80-83. 63. Walsh TJ, Eggleston JC, Cameron JL. Portal hyperten-

tural and functional changes resulting from islet isolation lead to islet cell death. Surgery. 1999;126:393-398. 71. Thomas FT, Contreras JL, Bilbao G, Ricordi C, Curiel D,

Thomas JM. Anoikis, extracellular matrix, and apoptosis factors in isolated cell transplantation. Surgery. 1999;126: 299-304. 72. Rabkin JM, Olyaei AJ, Orloff SL, et al. Distant processing

sion, hepatic infarction, and liver failure complicating

of pancreas islets for autotransplantation following total pancreatectomy. Am J Surg. 1999;177:423-427.

CURRENT SURGERY • Volume 60/Number 4 • July/August 2003

469