Pancreatectomy and Autologous Islet Transplan- Tation

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-)./01&234% Chronic pancreatitis results in an irreversible deterioration of the pancreas leading to anatomic destruction of the gland, disabling chronic pain and impaired physiologic function with progressive loss of exocrine and endocrine function. Regardless of etiology, the key histopathologic features of chronic pancreatitis are varying degrees and combinations of pancreatic fibrosis, acinar atrophy, acute and chronic inflammation, and distorted or blocked pancreatic ducts. The diagnosis of chronic pancreatitis is based on history and physical examination, clinical signs and symptoms, imaging studies, and supporting laboratory tests.

The major etiologic factors for chronic pancreatitis are best represented by the TIGAR-O (toxic, idiopathic, genetic, autoimmune, recurrent, obstructive) classification scheme put forth by Etemad and Whitcomb (1). Toxic-metabolic risk factors include alcohol, and hypercalcemia; idiopathic causes encompass such entities as tropical pancreatitis and minimal change disease; genetic risk factors encompass many recently-defined genetic mutations, including genetic mutations of the cationic trypsinogen or serine protease I genes; autoimmune defined by infiltration of the pancreas with CD4+ T cells, recurrent severe acute pancreatitis, and obstructive (biliary, congenital anomalies) round out the classification scheme.

Although severe, unrelenting abdominal pain is the cardinal symptom of the disease, regardless of the underlying etiology or risk factor, the diagnosis may be surprisingly diffi- cult in certain patients. A subset of patients have small ducts or minimal change disease (2)and in these patients, imaging studies appear to exclude the diagnosis of chronic pancreatitis. Further, a subset of patients do not have elevated amylase and lipase as the disease progresses and the gland becomes progressively fibrotic and diseased. Although it is now possible to obtain high resolution images of the pancreas through multi-slice cross-sectional imaging techniques, along with advancement in use of endoscopic ultra-

sonography, the sensitivity and specificity of these modalities in making a conclusive diagnosis of chronic pancreatitis is uncertain.

The exact incidence and prevalence of chronic pancreatitis is unknown, however it appears to be increasing on the proposed basis of broadened definitions of the disease, and more widespread use of sophisticated imaging modalities. An analysis of all published incidence and prevalence data published over the past several years performed by Spanier et al. (3) provides an incidence rate of 6.0 per 100,000 population in Europe and all Western countries. Spanier et al. also report an increased incidence in acute pancreatitis attacks and hospital admissions in Western countries, as are hospital admissions for chronic pancreatitis.

Recent epidemiologic data gives a range of 5.6-4.2 million prevalent cases of chronic pancreatitis in the United States, and in the year 2000, benign pancreatic diseases ac- counted for 327,000 hospitalizations, 200,000 emergency room visits, and 532,000 phy- sician visits (4). This burden on the health care system amounted to a total expenditure of $2.5 billion dollars, translating to a great impact on work-force productivity, and on claims for social security disability payments for inability to work.

(5,%6'',.$%&'%751&3".%8)3.1,)$"$"#%&3%92)+"$:%&'%!"',% Intractable pain and malnutrition are the most debilitating complications of chronic pancreatitis, with many patients requiring narcotic analgesics and total parenteral nutrition to tolerate the morbidity associated with the disease (5)(4). Every intervention offered to patients with chronic pancreatitis is aimed at reduction of pain, as this symptom has potential to interfere with every aspect of quality of life (13). Health-related quality of life is significantly worse in patients with chronic pancreatitis, as compared with a gender- and age-adjusted general population (6). Wehler et al. (7) evaluated quality of life in over 300 patients with chronic pancreatiits using a standardized assessment tool (SF-36). They compared results of this patient group with an age- and gender-matched general population and found that patients with chronic pancreatitis

scored lower on all domains of quality of life, but poorest in the physical, emotional, and general health perception domains.

Pezzeilli et al. (8) emphasize the great importance in the assessment of the patient’s sub- jective assessment of quality of life in a disease process such as chronic pancreatitis, where the goal of any intervention offered to the patient is to reduce pain and allow the resumption of a productive life. A review of quality of life studies in chronic pancreatitis reveals that pain is the one clinical symptom that can impair all domains of quality of life in the SF-36. Palliation of pain is the primary goal of any therapy or intervention in a patient with chronic pancreatitis.

Pain in chronic pancreatitis is multifactorial, including such possible etiologies as pancreatic ductal hypertension, elevations in pancreatic parenchymal pressure and changes at the level of the neuronal tissue of the pancreas (9). Intriguing concepts such as elevated pressure in pancreatic side branches leading to a “pancreatic compartment syndrome” and a drop in tissue pH, consistent with ischemia (animal studies), also histologic studies on pancreatic neuroanatomy in patients with chronic pancreatitis, including perineural in- flammatory infiltrates, damage to the neuronal sheath and differential expression of various proteins, may be correlated to increased perception of pain.

The need for opioids to control pain may be a marker for advanced disease as defined by number of hospitalizations preceding pancreatic resection and duration of symptoms. In a prospective study performed by Alexakis et al (10). in the UK, a requirement for opioids to control pain was correlated with a higher likelihood to be unemployed, and to have a severe restriction in daily activities as a result of their disease than patients who did not use opioids. This study provides evidence that earlier intervention is of great importance, before disease severity progresses concurrently with need for opioids to control pain.

In addition to the impact of chronic pancreatitis on development of opioid-dependent chronic pain and impairment in quality of life, the disease portends a risk for early mor-

tality. Lowelfels, et al (11) performed a survival analysis of over 2000 patients with chronic pancreatitis treated at seven centers in six countries. The 10-year survival of patients with chronic pancreatitis was 70% (CI 68-73%) and a 20 year survival was 45% (CI 41-49%). A total of 559 deaths occurred in this cohort, contrasting with an expected 157 deaths, resulting in a standardized mortality ratio of 3.6 (CI 3.3-3.9). The mean age at diagnosis in this series was 46 +/- 13 years. A multivariate analysis revealed age at diagnosis, smoking status and alcohol use to be predictors of mortality, each with hazard ratios above 1.5.

Chronic pancreatitis also results in an increased risk of pancreatic cancer, regardless of the underlying etiology or risk factor for the disease. According to the results of the In- ternational Pancreatitis Study Group’s multicenter cohort of 2015 patients with chronic pancreatitis (11), the cumulative risk of pancreatic cancer in patients with chronic pancreatitis is 1.8% at 10 years of disease duration and 4.0% at 20 years. Additional research has shown that the culmulative risk of pancreatic cancer in those with chronic pancreatitis to be 30% by age 70 (12)

634&#.&;".%)34%<210".)+%81&.,421,#%'&1%751&3".%8)3.1,)$"$"#% All therapeutic interventions in chronic pancreatitis are done in an attempt to control pain. This includes trials of non-narcotic analgesics, oral pancreatic enzymes (thought to result in a negative feedback inhibition to the pancreas with decreased release of cholecystokinin and and decreased release of pancreatic enzymes into the gastrointestinal tract), celiac plexus blocks, and endoscopic maneuvers. Depending on the degree of abdominal pain and evidence for obstruction of the pancreatic duct by stones, strictures or ampullary stenosis, multiple endoscopic interventions may be performed. As stated by Sarr et al.(13) in their review on the incapacitating pain of chronic pancreatitis, institution of opioids leads to a “vicious circle of ever-increasing needs for narcotics and the secondary physical and psychosocial problems of chemical addition.”

Although endoscopic interventions are successful in a percentage of patients, a large number of patients will respond temporarily or fail to respond at all. The overall efficacy

of endoscopic intervention in patients with chronic pancreatitis is unknown (14). Regard- ing the use of repeated endoscopic maneuvers, Gachago et al. (15) in their comprehensive review of pain in chronic pancreatitis, note that there are no published validated guide- lines for defining the pancreatic pathology amenable to treatment with endoscopy. A comprehensive review of the major published series on outcomes following endoscopic therapies such as extracorporeal shock-wave lithotripsy, placement of stents, and sphincterotomies reveals the large range of response to intervention in terms of pain relief, rang- ing from 30-76%. Because of the large number of non-responders in the population of patients with painful chronic pancreatitis.

Gachago et al. (15) suggest that endoscopic treatment may be more useful in treatment of acute relapsing pancreatitis; if a trial of endoscopic therapy is undertaken in a patient with chronic pancreatitis, stents should be used for only a short period of time. An unproven hypothesis is that repeated endoscopic interventions may exacerbate damage to an already-fragile gland, with potentiation of changes and continuation of pain after repeated endoscopic attempts, in essence an iatrogenic etiology for continuation of the damage of chronic pancreatitis.

Surgical intervention on the diseased pancreas falls into three categories: resections (Whipple procedure, head resection, distal, partial resection, segmental central pancreatectomy), ductal decompressions (pancreaticoenteric anastomosis ie longitudinal pancreaticojejunostomy, sphinceroplasty, internalized pseudocyst drainage procedure), and denervation (chemical or mechanical splanchnicectomy). Athough surgical drainage procedures and limited pancreatic resections appear superior to endoscopic therapies in providing long-term pain palliation, even these therapies may not provide durable pain relief.

Sarr et al. (13) performed a comprehensive review of studies on pancreatic ductal drainage procedures and parenchymal resections and found that approximately 60-70% of patients achieve durable pain relief. In a retrospective analysis of 372 patients who underwent partial parenchymal resections or ductal drainage procedures for chronic pancreatitis, Schnelldorfer et al. (16) reported approximately 50% of patients had good pain con-

trol or were pain free on follow-up (median duration 5.5 years following intervention). Riediger et al. (17) reviewed 224 cases of pancreatic parenchymal resection or drainage procedures and reported that 40% of patients still reported pain at median follow up of 56 months. In a review of nine series on longitudinal pancreaticojejunostomy for chronic pancreatitis, Gourgiotis et al. (18) reported a range of pain relief of 93% at short-term follow-up decreasing to 65% at 8 year follow up. They conclude that n LPJ, only 50% of patients achieve durable pain relief.

When examining the role of endoscopic interventions as compared to limited pancreatic parenchymal resections, two key randomized trials are found in the medical literature. Cahen et al. (19) published the results of their randomized trial of endoscopic versus surgical drainage in patients with chronic pancreatitis in which patients who underwent surgical drainage procedures (pancreatico-jejunostomy) had lower pain scores on a standardized pain assessmsent scale (Izbicki pain scale) at 24 months of follow up (p<0.001). Additionally, patients who underwent surgical drainage had better physical functioning scores on the SF-36. Importantly, however, is the report of the percentage of patients from each intervention group who did not achieve pain relief on follow-up: 68% of patients randomized to endoscopic drainage, and 25% of patients randomized to surgical drainage.

Similarly, Dite et al. (20) also performed a randomized trial comparing surgical to endoscopic therapy for painful chronic pancreatiits and reported that 35% of patients in the endoscopic group and 14% of patients in the surgical intervention group (partial pancreatectomy or draiage procedure) did not achieve pain relief at 5 years. Gress et al. performed one of the largest series on use of celiac plexus neurolysis for palliation of pain in chronic pancreatitis; in this series, 90 patients underwent EUS-guided celiac plexus block with just 4% of patients having sustained pain relief beyond 12 weeks of follow-up.

(&$)+%8)3.1,)$,.$&=:%>"$5%?3$1);&1$)+%@2$&+&0&2#%?#+,$%(1)3#;+)3$)$"&3% '&1%751&3".%8)3.1,)$"$"#A%%@%B,'"3"$"C,%(1,)$=,3$% Total or completion pancreatectomy then becomes the only treatment left for patients who fail medical management or partial resection or drainage procedures (5). Most pa-

tients are offered this option only after prior interventions have failed. The major sequela of total or completion pancreatectomy is diabetes mellitus with its associated complications. This morbidity can be mitigated through autotransplantation of islets isolated from the excised pancreas.

J61'(%6$"/+H(#'&K'+ The first islet autograft was done at the University of Minnesota (UM) in 1977 and clearly demonstrated that free islets could engraft and function in humans and establish an insulin-independent state (21). An allogenic islet transplant program had already been initiated at Minnesota (1974) for patients with type 1 diabetes but at the time the first islet autograft was done, none of the islet allografts had induced insulin independence in the recipients (21-23). Thus, the initial attempts at islet autografts were aimed at increasing the understanding of factors that might affect the success of allogenic islet transplants.

The first recipient in the Minnesota series underwent an intraportal islet autograft after near-total pancreatectomy and remained insulin independent and pain free until she died of an unrelated cause 6 years later (24-26). This case proved that a viable islet preparation could be made from a freshly excised human pancreas. It also showed that the previous failures with islet allografts were either due to low viability related to preservation of the deceased donor pancreas or to rejection. Since the initial reports (21,25,26), the Minnesota experience and outcomes have been published in a series of papers(24,27-33).

Shortly after the initial reports on IAT from Minnesota, several centers worldwide began performing islet autografts. The world literature reflects a collective experience with about 300 islet autografts, including the Minnesota cases cited above and those done elsewhere (34-43). Since the first case nearly 30 years ago, islet autografts have been performed by more than 20 centers world-wide.

Segmental pancreatic autotransplantion is another method for preserving beta-cell mass after pancreatic resection (44-48). The first segmental pancreatic autotransplant was performed around the time of the first islet autograft (44) This approach appears to be used less frequently than IAT to preserve beta cell mass after total panceatectomy, and indeed

there are no reports in the literature on segmental pancreas autotransplants for the past decade.

96'&%"'.%&+@&;6&L+ The largest series published to date on patients undergoing panc4eatectomy and autoislet transplants have come from the University of Minnesota (23-27,32,33,49), the University of Cincinnati (34,35,50), and the University Hospitals of Leicester in the United King- dom(41-43). Reports have focused on metabolic outcomes, quality of life, and pain reduction.

Minnesota Series Our first series of 10 cases was published in 1980 (26). We performed a >95% pancreatectomy in all patients except one who underwent a total pancreatectomy, and we reported pain relief in all patients available for follow-up. Three patients of the 8 available for follow-up reported insulin independence, with the remaining 5 patients on full diabetic regimens.

In 1991 we published our second series, in which 26 patients underwent >95% pancreatectomy (N=24), or partial pancreatectomy (N=2) (24). Ninety percent of patients reported pain improvement or resolution. With regard to graft function, 6 patients were insulin-independent, with 3 additional patients reporting an 18-month period of insulin- independence following TP/IAT. We found a correlation between likelihood of insulin- independence if >200,000 islets were transplanted (p=0.008).

Our third series was published in 1995 (27). Of 46 cases, we performed a total pancreatectomy in 27, near-total in 16, and partial in 5 patients. Pain was resolved or improved in 83% and 81% were able to withdraw from narcotics. We found that the probability of insulin independence did not differ according to procedure (total versus near-total). The probability of insulin independence among patients having no history of prior resection was 40%. This contrasted with a 16% probability of insulin independence in patients who had undergone previous resection (p=0.4). We recorded our lowest islet yield in

patients with a prior Puestow procedure, with only an 18% insulin independence rate in this group. We again found that the main predictor of insulin independence was the islet yield. The highest insulin independence rate was in patients who received >300,000 islets (74% insulin independence rate >2 years following TP/IAT).

Our most recent series was published in 2004 (32). We reported on 112 cases, up through June 2003. Here we found pain improvement in 72% of patients. Fourty-four patients ere insulin-independent, and an additional 12% had partial graft function. The probability of achieving insulin independence was correlated with an islet yield of >2500 IEQ/kg. In this subset of patients, 72% achieved insulin independence, with an additional 14% achieving partial graft function. Of patients receiving <2500 IEQ/kg, only 5% achieved insulin independence.

Leicester Series In 2003, Clayon et al. (41) published the Leicester experience with 40 cases (33 total pancreatectomy, 7 partial or completion). Data was not provided on the probability of achieving insulin independence or partial graft function, however they did report that 18 of 44 patients had evidence of beta cell function at 2 years following the procedure by way of c-peptide levels. The analysis did not show any correlation between islet yield and insulin independence (41). The authors propse that their results may be due to the underlying cause of pancreatitis and possibly to patient compliance issues with follow-up care: the largest proportion of patients had chronic pancreatitis from alcoholism. Of the 44 patients in the series, the majority no longer require opioids and 68% have been able to re- turn to work. No information is provided on quality of life.

Cincinnati Series In 2003, Rilo et al. (35) published their series of 22 patients, of which 12 underwent total pancreatectomy, 7 underwent completion and 3 underwent partial pancreatectomy. This is the first series to report on pain and quality of life outcomes using standardized assessment tools (SF-36 and McGill Pain Questionnaire). The authors reported a median follow-up of 19 months, with 82% of patients were able to discontinue narcotics. Only

50% of patients (N=11) completed the standardized pain and quality of life assessments, so there is no analysis of these results. Based on preliminary findings, however, the authors state that the vast majority of patients had an improvement in pain and a significant increase in quality of life following the procedure.

Regarding graft function, 41% of patients in this series were insulin-independent, 27% required once-daily long acting insulin, and 32% of patients needed a full diabetic regi- men. A higher probability of graft function was seen in those who received >3000 IEQ/kg.

An update of the series, including 45 cases, was published in 2005 (34).. Similar to the previous series, 40% of patients were insulin independent at a mean follow-up of 18 months. Factors that the Cincinnati group correlated with postoperative insulin independence included the recipient’s weight, body mass index, and gender. Patients with a BMI >28 had a higher chance of insulin dependence Lastly, the Cincinnati group reported that insulin independent recipients had lower mean insulin requirements during the first 24 hours posttransplant, possibly relating to the detrimental effect of hyperglycemia on islet function.

Long-Term Metabolic Outcomes One long-term study of metabolic outcomes in 6 recipients from our center reported that islet autografts prevented diabetes mellitus for up to 13 years (mean follow-up, 6.2 ± 1.7 years)(31). Islet function was assessed by measuring fasting plasma glucose, intravenous glucose disappearance rate (!"), hemoglobin A1c, insulin responses to IV glucose and arginine, and insulin secretory reserve. Stable insulin secretory reserve was maintained, but insulin responses to glucose tended to decrease over time; the IV glucose disappearance rate significantly correlated with the number of islets transplanted(31). However, despite normoglycemia and insulin independence, another Minnesota study showed reduced functional beta-cell secretory reserve in autograft recipients compared to normal individuals(36). A third Minnesota study showed that intrahepatic islet grafts (despite se- creting glucagon in response to arginine) failed to secrete glucagon in response to sus-

tained hypoglycemia, a peculiarity that may be site-dependent (51). Nonetheless, intraportal autografts of as few as 265,000 islets can result in release of insulin and glucagon, at appropriate times, and result in prolonged insulin independence (52).

Narcotic independence may not be obtainable in patients with opioid-induced hyperalgesia (OIH). Such patients, after receiving narcotics for chronic pain, paradoxically become more sensitive to pain, via mechanisms originating in afferent neurons and in the spinal cord (53-59). Future studies are needed to identify patients at risk of OIH and to develop effective strategies for narcotic weaning. OIH in patients referred for pancreatectomy and autologous islet transplants may be highly prevalent; accordingly, an end- point such as narcotic independence may not be ideal for assessing postoperative success.

Islet Autotransplants in Children Chronic pancreatitis is less common in children than in adults, but should be treated the same. The aim, as in adults, is to relieve pain, eliminate need for narcotics and preserve beta cell mass. We reported our first pediatric case in detail (60). We recently published a comprehensive series of all pediatric cases through June 2006. Of the 24 patients younger than 18 years of age, 94% had improvement in pain, with 61% able to discontinue narcotics. With regard to graft function, 78% of patients had evidence of beta cell function at 1 year following TP/IAT, with 56% insulin-independent (61).

Opioid-Induced Hyperalgesia One proposed mechanism of maladaptive pain thresholds and sensitivity involves an increase in levels of dynorphin at the neuronal level in the spinal cord. The upregulation of dynorphin is hypothesized to result from opioid-triggered increases in the neuropeptide cholecystokinin which leads to increased excitatory pathways in the brainstem, all of which result in an increased perception of pain (57)

Sensitization of neurons in the superficial laminae of the dorsal horn of the spinal cord plays a key role in the development of both opioid-induced hyperalgesia and opioid tolerance. Mayer et al. (62) have performed animal studies that support the hypothesis that

tissue injury and inflammation results in a tonic activation in excitatory neurons of the spinal cord (primarily NMDA receptors), which leads to activation of second-messenger systems that ultimately result in spontaneous and stimulus-evoked neuronal activity. This state of “central sensitization” ultimately results in exaggerated response to both innocu- ous and noxious stimuli.

A key concept that has evolved through research on opioid-induced hyperalgesia and tolerance is that pathologic pain is associated with a dynamic, progressive underlying disease process resulting in nerve injury, tissue inflammation and ongoing input to the pain centers in the brain (62). As the pain state evolves, neuronal changes take place that result in a common pathway between hyperalgesia and tolerance to opioids (a “common channel”), both involving NMDA receptors. Mayer et al, hypothesize that if the cycle of ongoing input to the pain centers of the brain can be interrupted early in its course (resulting in reduced NMDA receptor activation in the central nervous system), the long-term changes to pain processing may be abated. If the cycle continues without interruption, eventually a state of chronic pain and opioid tolerance results. The ultimate recommen- dation is to treat the root cause of pain before the pain centers of the spinal cord and brain undergo structural change.

Chu et al. performed the first prospective evaluation of the development of opioid- induced hyperalgesia by studying chronic pain patients at baseline and 1 month after initiation of morphine therapy. All patients in their series developed hyperalgesia to a cold stimulus and tolerance after 1 month of treatment (54), thus providing direct evidence that a short course of opioid treatment can result in OIH. Once OIH has occurred, an escalation of dose should not be implemented. Instead, one recommended approach is to rotate opioids or add non-opioid medications (63).

In 2005, Buscher et al published the results of their pilot study on hyperalgesia in patients with chronic pancreatitis on long-term opioid therapy. Compare to age- and gender- matched controls, these patients exhibited generalized central pain sensitization and segmental spinal inhibition based on results of quantitative sensory testing.

The need for opioids to control pain may be a marker for advanced disease as defined by number of hospitalizations preceding pancreatic resection and duration of symptoms. In a prospective study performed by Alexakis et al in the UK, a requirement for opioids to control pain was correlated with a higher likelihood to be unemployed, and to have a severe restriction in daily activities as a result of their disease than patients who did not use opioids. This study provides evidence that earlier intervention is of great importance, before disease severity progresses concurrently with need for opioids to control pain.

Expanding Application of Intraportal Autografts Recently, islet autografts have been reported after resection for benign pancreatic proc- esses including pancreatic pseudocyst with compressive symptoms (41), cystic neoplasms of the pancreas (64,65), insulinomas (65,66), and, in one case, a neuroendocrine tumor of the pancreas(65). Pathologic evaluation was completed prior to autologous islet infusion in all recipients to confirm that the lesions were benign. An islet autograft has also been reported a patient with pancreatic adenocarcinoma (67); that patient underwent a pylorus- preserving pancreaticoduodenectomy, complicated by an anastomotic leak at the pan- creaticojejonostomy. The leak was treated by emergent completion pancreatectomy with an islet autotransplant. The patient died 2.5 years later of recurrent disease (68). We have four cases of IAT after partial pancreatectomy for benign neoplasm (unpublished).

Transplants of islets isolated from pancreas allografts excised for technical problems or allograft pancreatitis (“islet auto-allo-grafts”) have also been performed, at least at our institution, with one case reported (69) In this case the islet yield was >8000 islet equivalents (IEQ) /kg body weight. The patient remained insulin independent for >1 year while on immunosuppression and up to the time of the report, indicating successful engraftment and maintenance of islet “auto-allo” function, but ultimately had to take exogenous insulin indicating decline or loss of islet function for immunological or non-immunological reasons (unpublished observation).

D2$21,%B"1,.$"&3#% A basic but important limitation to a more widespread clinical application of islet autografts after pancreas resection is the limited number of centers with the facilities and technology to isolate and prepare pancreatic islets for human recipients. A few centers, including our own, have successfully used distance processing for both allogenic and autologous islets(70-72) The feasibility of this approach is enhanced by improvements in preservation methods that have extended ischemic pancreas preservation time and increased islet yield and viability from suboptimal pancreata (73-77).

The long-term success of islet autografts in patients with chronic pancreatitis (31) con- trasts with the apparently less favorable long-term results for islet allotransplants in patients with type 1 diabetes mellitus(78). In the Edmonton islet allograft series, only 20% of recipients who achieved insulin independence remained so at 5 years, but nearly all remained C-peptide positive(78), indicating survival of beta cells. The difference in outcomes may be due to the rejection rate of islet allografts, or if not rejected, to the neces- sity of immunosuppressive therapy (calcineurin-inhibitors). However, a controlled study comparing long-term function of islet auto- and allografts of comparable beta cell mass remains to be done.

Autologous islets are as fresh as possible. They are procured from a pancreas that, though diseased, is not under the stress of brain death and is not subjected to prolonged ischemia or to hours of cold preservation before isolation (as is the case for allogenic islets). In animals, islet yields and islet functionality are negatively affected by brain death, presumptively because of activation of proinflammatory cytokines that occurs during brain death (79). Additional research is needed to develop strategies to minimize the biochemical effects of brain death on allogenic islet function (79).

Single-donor islet allografts have resulted in insulin independence in diabetic recipients at Minnesota (80), yet in most cases, multiple donors are required (81) Even when a single-donor islet allograft results in insulin independence, the insulin reserve may be mar-

ginal. Increasing islet viability for transplants is important; one possibility is to use a living donor (23,82-84). This approach is almost certain to be effective, given the good outcomes in autograft recipients, whose islet mass is well below the islet mass effective with allografts.

E)$"&3)+,%'&1%$5,%7211,3$%F&1/% Chronic pancreatitis imparts a major impact on every facet of the sufferer’s life and health, most prominently because of the high likelihood of chronic narcotic usage to control pain. Among the various treatments offered to patients with this disease, a total pancreatectomy with islet autograft provides the most definitive treatment to the ravages of this disease. Pain is abated because of resection of the diseased gland, and inevitable post-pancreatectomy diabetes is addressed through the autotransplantation of islets. Cur- rently, islet autotransplantation is a safe, effective procedure. Pancreatic resection (even partial) with an islet autograft should always be considered the primary surgical option for patients with chronic pancreatitis and intractable pain refractory to medical therapy. Relief of pain to allow withdrawal from narcotics is the primary objective and the prevention of diabetes a secondary goal. Long-term follow up studies are needed to evaluate and compare differences in islet durability between islet auto- and allografts of the same beta cell mass. Such a comparison may allow us to make a distinction between immunological and non-immunological factors that affect declines in or sustenance of islet graft function over time.

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7'.,*+!(4./"'6(#+ + Between February 1977 and December 2007 we performed 228 (adult = 196, pediatric = 32) pancreatectomies with autologous islet transplants (TP/IAT). The indication for operation was chronic pancreatitis with intractable pain in all patients with the exception of

two patients with benign pancreatic lesions. The vast majority of patients were referred to our center after multiple attempts at pain palliation, including prior endoscopic interventions (pancreatic duct stenting and/or sphincterotomies), surgical drainage procedures, or prior resections. We confirmed the diagnosis of chronic pancreatitis through review of clinical and laboratory data, and the results of previous endoscopic interventions and surgical pathology reports. Our study protocol was reviewed and approved by the Univer- sity of Minnesota Institutional Review Board.

We reviewed the medical record for etiology of chronic pancreatitis, prior intervention or surgical resection, duration of disease, duration of pain, preoperative exocrine and endocrine deficiency, details of the operative procedure and islet transplant, and perioperative information, including complications and re-operations. We also recorded laboratory data, including blood glucose, hemoglobin A1C and c-peptide levels.

We then contacted all available patients for a telephone survey of outcomes with regard to graft function, pain and quality of life. We asked patients about insulin use, hemoglobin A1C and/or c-peptide test results, nutritional status, quality of life (assessed by a 5 point Likert-type scale), pain status and need for narcotic pain medications, satisfaction with the results of the procedure, and ability to work or attend school.

To categorize graft function, we used medical chart review data and information obtained from the telephone survey, if available. We assigned patients to one of five classification schemes based on insulin usage through medical record or self-report, documentation of hemoglobin A1C levels, and c-peptide levels, if known (Table 1).

Table 1. Graft Function Categories Category Insulin Status Hemoglobin A1C c-peptide level level 1 None <6.5% positive 2 None Unknown Unknown 3 Once-daily long act- <6.5% positive

ing insulin 4 Once-daily long act- Unknown Unknown ing insulin 5 Full diabetic regi- Any men or insulin pump

To perform actuarial probability of insulin independence and graft function, we recorded dates of insulin initiation or discontinuation based on data available in the medical record and by patient self-report at the time of the telephone survey. For purposes of analysis, we combined graft function categories into three classifications: full, partial, and fail (Ta- ble 2).

Table 2. Functional Classification of Grants for Analysis Graft Function Classification Graft Function Category Scheme Number FULL 1 & 2 PARTIAL 3 & 4 FAIL 5

Because our series spans 30 years and surgical technique and islet isolation techniques have become more refined and changes have taken place with regard to post-operative care and management, especially with regard to blood glucose management, we stratified our series by era for purposes of analysis. Era 1 spans from 1977 through 1994 and includes our first case up through the year preceding our last major analysis and publication in 1995. Era 2 is the period between 1995-2000, and Era 3, our “modern era,” encom- passes 2001-2007.

7'"'61'6$"/+-#"/*161+ We used descriptive statistics to analyze demographic data. For categorical variables, we used the Pearson chi-square test. We used the Kaplan-Meier method to calculate the probability of overall patient survival, probability of insulin independence and graft func-

tion. To analyze group differences, we used the Wilcoxon test for short-term differences, and the log-rank test for long-term differences. We used Cox proportional hazards regression models to analyze the effects of independent variables outcome. We set our sig- nificance level at 0.05.

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Resection The initial step of the operation is inspection of the pancreas and assessment of the severity and extent of disease. In the event only a portion of the pancreas is involved, we leave as much residual pancreatic tissue behind by performing either a Whipple operation if disease is head-dominant, or a distal resection. During resection, the blood supply of the pancreas is preserved as long as possible to minimize the detrimental effects of warm ischemia on the islets (27,85,86).

Prior to 1986, we only performed near-total (>95%) pancreatectomies. This original technique was after Barret and Bowers in which the duodenal C-loop is left intact with a small rim of pancreas along the common bile duct and pancreaticoduodenal arteries. Af- ter 1986, we evolved to the Easter/Cuschieri technique, where all pancreatic tissue was removed. The majority of our cases are now total or completion pancreatectomies. For the past 15 years we have routinely done a duodenectomy, pylorus- and fourth portion- sparing whenever possible with orthotopic reconstruction via a duodeno-duodenostomy and choledocho-duodenostomy, as we previously reported a lower complication rate in those who had part or all of the duodenum resected (24).

When we perform a total pancreatectomy or an isolated head resection, we spare the pylorus whenever possible. In the event we are unable to preserve the pylorus due to exten- sive inflammation or scarring from previous operations, we resect the distal stomach, entire duodenum and proximal jejunum, with reconstruction by a gastrojejunostomy and choledochojejunostomy. Since the splenic artery and vein are usually included with the pancreas specimen to preserve islet blood supply during the procedure, the spleen must

survive on the often marginal collateral circulation if it is to be spared. The spleen is only left if its appearance is unchanged by the pancreatectomy.

A small section of pancreas (0.5 cm2 piece) is biopsied for routine pathologic analysis, with the remainder of the pancreas sent for islet processing. An insulin infusion is started immediately upon removal of the pancreas to prevent glucose toxicity to the islets.

Islet Isolation Islet isolation must be done in a laboratory that meets all of the FDA criteria for processed tissue, something that exists at only a few medical centers currently, though more and more are acquiring the technology. The islet isolation laboratory at the University of Minnesota is located in a building dedicated to Molecular and Cellular Therapeutics.

We used a semi-automated method of islet preparation (87) for all cases since 1991; our first 26 cases were processed using a method of mechanical chopping of the pancreas fol- lowed by collagenase digestion (88), or by intraductal collagenase injection. Immedi- ately upon arrival to our islet processing facility, the pancreas is transferred into the lami- nar flow hood in the cold clean room, removed from the transport container and rinsed with approximately 500 mL of fresh cold transport solution. We then place the pancreas in a sterile tray with cold transport solution dissect off extraneous fat and non-pancreatic tissue. The pancreas is washed with 8 oz. of 10% Povidone/Iodine solution and a topical antibiotic solution of 80 mg gentamicin, 1g cefazolin, and 100 mg amphotericin-B in cold transport solution for 5 seconds, respectively. We then rinse then gland with 350 mL of Hanks’ Balanced Salt Solution (phenol red-free). The pancreatic duct is cannulated with angiocatheters (14-20 gauge). We then perfuse the pancreas with collagenase solution [1-2 mg/mL collagenase (depending on enzyme activities of a given lot; Liberase HI or Liberase™- Collagenase/Liberase™-Thermolysin Blend Enzyme, Roche Molecular Biochemicals, Indianapolis, IN or VitaCyte 60%:40% purified Class I:Class II collagenase/VitaCyte purified Thermolysin, VitaCyte LLC, Indianapolis, IN or Collagenase NB1/Protease NB, Nordmark, Uetersen, Germany)] while maintaining constant pressure of 60-80 mmHg for

the first 4 minutes and 160-180 mmHg for the next 6-8 minutes (89). After 10 - 12 minutes of cold perfusion, the pancreas is further trimmed of remaining capsule and placed into the dissociation chamber.

The distended pancreas is then cut into 6 - 12 pieces and placed in a sterile stainless steel chamber. The collagenase solution is warmed to 25oC to 37oC and samples taken at regular intervals to monitor, via inverted microscope, the breakdown of the pancreas. The digest containing the free islets is collected and re-suspended in recombination solution and kept cold. Once the entire digest is collected, the combined pellets are washed, pellet volume documented, and samples taken for counts. If the packed tissue volume is > 20 mL, we may proceed with purification, at surgeon discretion.

Islet Purification We do not routinely purify the preparation because of concerns about reducing the islet yield (90). If the final crude tissue volume exceeds 15 ml, we reduce the volume by puri- fying all or part of the islet preparation, so that infusion via the portal vein can occur without undue rise in portal pressure (91,92). If portal pressure reaches 30 cm water, or if the recipient previously had prior portal vein occlusion or preexisting portal hypertension, excessive islets or the whole preparation can be freely dispersed in the peritoneal cavity or transplanted beneath the kidney capsule or submucosal layer of the stomach in the hope that they engraft, even though no studies have been done to ensure that this occurs(27,93). If purification is performed, we run test gradients on a small volume of pancreatic tissue to determine the density distribution of acinar tissue. The pellet is loaded onto a continu- ous density gradient (modified-UW/iodixanol (OptiPrep!, Axis-Shield, Norton, MA; 3 3 light 1.050 to 1.080 g/cm ; heavy 1.080 to 1.120 g/cm ) using a Cobe 2991 cell processor (Cobe, Lakewood, CO) and centrifuged at 1800 rpm for 3 minutes. Purification fractions are collected and screened for the presence of islets. Fractions with islet purities (percentage of dithizone positive cells) > 10% are combined for culture.

Islet infusion Clinical observations and animal studies indicate that the liver (via the portal vein) is the most efficient site for islet engraftment (94,95). It is the only site in humans associated with achieving insulin independence(27).Therefore, we routinely infuse the islet preparation into the portal system. Other sites have been used, such as the renal capsule (96-99), spleen (95,100), omentum, (101)and peritoneal cavity (102,103), but have rarely been associated with function of islet autografts in humans (104,105). Presumably, once the islets embolize into venous tributaries of the liver, they islets survive by nutrient diffu- sion. Until neovascularization occurs, the islets have reduced functional capacity (106,107).

Before islet infusion, we administer heparin (70U/kg) to prevent intraportal clotting from tissue thromboplastin (which is assumed to be in the preparation) (108). We have admin- istered heparin since our very first cases in the 1970s(25,27). Nearly all of the reports of complications related to portal infusion of islets(108-112) were published before the development of standardized semiautomated pancreas dispersion techniques and before the routine use of heparinization before to islet infusion.

The stump of the splenic vein is cannulated and the islets are infused slowly over several minutes. Portal pressures are checked intermittently and in the event the portal pressure rises to >25 mmHg, the intraportal islet infusion is terminated and the remainder of the preparation dispersed into other locations, such as the under the kidney capsule (n=2), freely into the peritoneal cavity (n=11), into the subserosa of the stomach (n=3), or into the falciform ligament of the liver (n=1).

Post-operative management Glucose monitoring of islet autotransplant recipient is handled in a manner similar to that of diabetic pancreas transplant recipients (113). Animal studies have shown a decrease in islet engraftment with hyperglycemia; furthermore, glucose toxicity may cause structural lesions in the transplanted islets(114). We continue to promote islet engraftment posttransplant by an exogenous insulin drip to maintain euglycemia, minimizing the need for

insulin secretion from the freshly infused islet autograft by theoretically decreasing islet stress.

Pancreatic enzyme replacement is then initiated, and the patient is transitioned to subcu- taneous insulin injections, typically in the form of a long-acting insulin preparation such as Lantus. Sliding scale insulin coverage is given as needed. Patients are counseled by a Diabetic Educator and are maintained on long-acting once-daily insulin. After a number of weeks, the insulin may be weaned and discontinued if normoglycemia is maintained.

We do not attempt to wean narcotic-dependent patients off pain medications during the immediate post-operative time period. The majority of patients begin a slow taper of pain medications within 6-8 weeks following surgery. The length of time required to discontinue narcotics is variable.

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Table 3. Patient Demographics and Preoperative Status No. of patients 228 Adults 196 Children 32 Indication for operation (n) total series, adults + peds Idiopathic 124 (55%) Pancreas divisum 28 (12%) Alcohol 24 (11%) Hereditary 21 (9%) SOD 11 (5%) Biliary 11 (5%) Cystic Fibrosis 4 (2%) Stricture 2 (1%) Benign tumor 2 (1%)

Etiology of pancreatitis (n) adults only, less 2 benign tumors Idiopathic 108 Pancreas divisum 24 Alcohol 24 Hereditary 12 SOD 11 Biliary 11 Cystic Fibrosis 4 Stricture 2 Mean Age (y) 39 +/- 10 (range 19-69) Sex (n) Female 142 (74%) Male 51 (26%) Mean duration of disease (y) 6.6 +/- 6 Mean duration of pain (y) 7.4 +/- 7 Previous endoscopic intervention (n) 154 Previous cholecystectomy (n) 123 Previous operations Cholecystectomy Beger 3 Puestow 21 Whipple 19 Distal 16 Pseudocyst drain 16 Pretransplant insulin resistance 13

C(%I6,6'*+M+C(%'"/6'*+ We recorded a total of 42 adult deaths in the series, 23 (55%) in era 1, 7 (17%) in era 2, 12 (29%) in era 3. A total of 3 deaths occurred in the year following TP/IAT, all during the perioperative time period: one patient had an intraoperative colon perforation and died immediately after surgery; one died of disseminated intravascular coagulation also

immediately following surgery, and the third died of sepsis within the first month following surgery. The cause of death was recorded in 11 patients and included causes such as enterocutaneous fistula (1), MVA (1), diabetic complications (1), pneumonia or respira- tory causes (3), and small bowel infarction (1), cardiac arrest (1), alcoholism (1), post- splenectomy syndrome (1), drug overdose (2).

There were 26 surgical complications during the first thirty days after the procedure, leading to a 14.5% complication rate. The rate of complication did not vary by type of pancreatectomy (completion 14%, near-total 11%, and total 15%, p=0.46).

We performed actuarial probability of survival for all adult patients in the series (n=193) and found a 1 year survival of 96%, 5 year survival of 85%, 10 year survival of 76%, 20 year survival of 51% and 25 year survival of 45% (see Figure 1). There was no difference in probability of survival between eras (p= 0.90 Wilcoxon, 0.71 Log-rank).

Table 4. Types of Resections Performed N %

Total pancreatectomy 126 84%

Near-Total (>95%) 18 9% Partial 14 7% Body/tail 10 Head 3 Not-Specified 1 Completion 35 18% Body/Tail 18 Head 13 Not-specified 4

>%"+-#"/*1&1++ For purposes of comparing variables within our series over time, we divided the series into three eras: 1977-1994 (Era 1), 1995-2000 (Era 2), and 2001-2007 (Era 3). Table shows a comparison of several variables by era. Notable differences are seen in the percent of patients who underwent previous endoscopic intervention (p=0.0006), with a larger percentage in the modern era, as expected, as technologies have evolved and endoscopy has become wide-spread. A larger percentage of patients in Era 3 underwent previous pancreatic resection as compared to the 2 other eras (p<0.0001). There was no difference between eras in terms of percentage of patients who received <2500, 2501-5000, or >5000 IEQ/kg. Table 5 shows the mean and range of IEQ/kg for each graft function category per era.

Table 5. Characteristics of Resections Performed, by Era 77-94 95-00 01-07 p-value

N 43 34 116 Ave age (y) 37 39 40 Dur Px (y) 6.4 7.1 6.5 Dur pain(y) 6.4 4.5 8.3 Prev interv 97 97 99 0.62 (%) Prev rxn 72 44 87 <0.0001 (%) Prev endo 60 76 88 0.0006 (%) Splenect 42 56 83 (%) Total (%) 13 20 67 NT (%) 100 0 0 Completion 14 14 71 Partial 21 29 50 Mean 3803 3247 3218

IEQ/kg <2500 (%) 48 41 38 Overall for all 3 categories p=0.44 2501-5000 25 38 42 (as above) (%) >5000 (%) 28 21 20 (as above)

!"6#NO."/6'*+(8+968&+++ Overall, we were able to reach 71% of available patients by phone for a comprehensive telephone follow-up survey on graft function, pain outcome and quality of life outcome. As noted in the table, of all available patients, we reached 50% in era 1, 78% in the era 2, and 85% in era 3. (Table 6).

Table 6. Follow-up Characteristics, by Era. ERA 1 ERA 2 ERA 3

Adult N 47 29 80 Deaths 25 6 8 %deaths 53% 21% 10% Adult N 22 23 72 alive Adult N 11 18 61 reached for telephone survey %Contacted 50% 78% 85% of available adults

The mean age of the patients reached for the telephone survey was 37 +/- 10. Median follow up was 42 months (range 2 months-330 months). Their etiologies for pancreatitis were idiopathic (60%), alcohol (17%), pancreas divisum (12%), biliary (7%), and hereditary (5%). A total pancreatectomy was performed in 68%, partial or distal in 11%, completion in 17%, and near-total in 4%.

Fifty-four percent of patients reported needing total parenteral nutrition (TPN) before the time of their TP/IAT. Only 7% reported continuing to need TPN following TP/IAT.

One-hundred percent of patients reported having pain prior to TP/IAT, and 60% still had pain present afterwards. However, when asked how their pain compares to the pain present before TP/IAT, 76% of patients stated their pain was better, 12% somewhat better, 5% same, 1% worse, and 6% did not answer.

Ninety-two percent of patients required daily narcotics to control pain prior to TP/IAT, with 51% still on narcotics at the time of telephone follow-up. Of those still on narcotics, 33% stated they were on a taper or wean of their narcotics.

When asked to rate their current quality of life, 42% of patients reported an excellent quality of life, 26% very good, 14% good, 12% fair, 4% poor and 1 patient was unsure. Seventy-nine percent of patients stated that their self-reported quality of life was improved compared to the time before their TP/IAT, while 9% said it was the same, 8% thought it was worse and 4% were unsure.

2#'%"(4&%"'6;&+M+61/&'+*6&/,+$(#16,&%"'6(#1+ The number of islets prepared from the pancreata resected from all patients, excluding those who underwent partial pancreatectomy, ranged from 400 to 868,900 (mean 221483). The number of islet equivalents per kilogram ranged from 9-18035 (mean 3411). Wahoff et al. previously reported a significant improvement in islet yield when comparing methods (the old method, pre-1991, to the new automated method): 345,000 vs 151,192 (p=0.005).

We divided our series into three categories based on number of IEQ/kg transplanted: <2500, 2501-2500, and >5000 IEQ/kg. Of all analyzed adults, 64 received <2500 IEQ/kg, 65 received 2501-5000, and 35 received >5000 IEQ/kg. Type of previous pancreatic resection predicted islet yield (p<0.0001) When evaluating mean IEQ/kg based on type of previous pancreatic resection, a significantly lower number of islets was procured in patients who had undergone previous distal (1482 IEQ/kg) and Puestow (1488 IEQ/kg), while the mean IEQ/kg after a Whipple operation (3927 IEQ/kg) was very close to the mean IEQ/kg in those who had never undergone previous pancreatic resection(3804 IEQ/kg). Analysis of variance gave a p-value of <0.0001.

Islet infusion site The intraportal islet infusion is terminated and the remainder of the preparation dispersed into other locations, such as the under the kidney capsule (n=2), freely into the peritoneal cavity (n=11), into the subserosa of the stomach (n=3), or into the falciform ligament of the liver (n=1).

Alternate islet transplant sites were used in 5 cases in the series: in 3 instances, the en- tirety of the islet preparation was placed under the kidney capsule, and in 2 instances into the splenic capsule.

Graft function Analysis of graft function excluded patients who underwent partial pancreatectomy with IAT (N=x) because of the potential for confounding of results by the residual pancreatic mass. The mean IEQ/kg of those who achieved full graft function at 1 year was 5822 (range 1262-17,053). The mean IEQ/kg required to achieve partial graft function at 1 year was 3155 (range 99-6821), while the mean IEQ/kg of those with graft failure at 1 year was 1974 (range 9-8769). There was no difference in the probability of graft function depending on type of pancreatectomy performed (total, near-total, completion) with p=0.86.

The overall probability of full graft function was 26% at 1 year, 16% at 5 years, and 11% at 10 years. The overall probability of any graft function (full or partial) was 60% at 1 year, 48% at 5 years and 37% at 10 years. The probability of insulin independence or partial graft function did not differ between eras (p=0.36 and p=0.14, respectively).

The probability of both full and partial graft function depended on IEQ/kg category of the recipient (p <0.001 for both categories) (Table 7). Recipients of >5000 IEQ/kg had a 63% probability of full graft function at one year, with an 86% probability of any graft function (full/partial) at one year. At 5 years, probabilities of full and partial graft function in recipients of >5000 IEQ/kg fell to 42% and 69%, respectively, and at 10 years, probabilities fell to 36% and 60% respectively. Recipients of <2500 IEQ/kg had a 7% probability of full graft function and a 32% probability of partial graft function at 1 year. By 5 years, the probability of full graft function fell to 3% and 18%, respectively, and by 10 years, there were no recipients with full graft function in this IEQ/kg category, and only 18% probability of partial graft function.

Table 7. Crude Comparison of Long-term Graft Function by Total Islets Transplanted N Total Islet Equivalents Range IEQ/Kg Range

Full Function 39 349, 610 +/- 148,294 89,633-868,8000 5822 +/-2999 1262-17,035

Partial Function 29 207,396 +/- 118978 7700-446,654 3155 +/- 1846 99-6821

Fail 66 135,999 +/- 133,268 400-570,000 1974 +/- 1871 9-8769

We examined the probability of insulin-independence and graft function in recipients of each of the IEQ/kg categories according to era (Table 8), and found no difference in probability of either insulin-independence or graft function with the exception of the probability of insulin independence in recipients of 2500-5000 IEQ/kg and >5000 IEQ/kg. The 1 year probability of insulin in dependence in recipients of 2500-5000 IEQ/kg was 22% in era 1, 50% in era 2 and 22% in era 3 (p=0.01). The 1 year probability of insulin independence in recipients of >5000 IEQ/kg was 80% in Era 1, 20%, 40% in Era 2 and 60% in era 3 (p=0.05).

Table 8. Crude Comparison of Graft Function by Era, According to Islet Yield ERA IEQ/KG mean (range) to IEQ/KG mean (range) IEQ/KG mean (range) achieve full graft function to achieve partial graft to achieve graft failure at 1 year function at 1 year at 1 year

1 8532 (4828-17035) 1935 (99-3897) 1998 (9-8769) 2 3841 (1262-5676) 4980 (3554-6406) 2450 (225-7200) 3 5277 (3004-8558) 3266 (226-6821) 1663 (92-5309)

Prior to the year 2000, we recorded the total number of IEQ/kg transplanted, regardless of infusion site. For the modern era, we were able to determine the probability of graft function using the exact number of islets transplanted into the portal system according to IEQ/kg category. Again, we found a significant difference between IEQ/kg categories (p<0.0001). For recipients of <2500 IEQ/kg, the 1- and 5- year probability of graft function was 42% and 18%, respectively. For recipients of 2501-5000 IEQ/kg, the probability was 88% and 52%, respectively, and for recipients of >5000 IEQ/kg, the probability was 95% and 48% respectively.

Knowing the islet yield following a distal pancreatectomy and Puestow procedure is lower than the islet yield in those with no previous pancreatic resection or a previous Whipple procedure, we calculated the probability of insulin independence and graft function according to previous pancreatic resection. We found a significant difference in the probability of both insulin independence (p < 0.02) and graft function (p< 0.0001) based on type of previous pancreatic resection. The 1 year probability of insulin independence in patients with a previous distal or Puestow procedure was 13% and 8%, respectively, whereas the probability of insulin independence in patients with a previous Whipple procedure or no prior pancreatic resection was 45% and 29%, respectively.

Likewise, the 1-year probability of any graft function in patients with a previous distal or Puestow procedure was 33% and 15%, respectively, and in patients with a previous Whipple or no prior pancreatic resection was 91% and 64%, respectively.

We performed two Cox proportional hazards regression models to evaluate variables that would influence the hazard for not achieving insulin independence. (hazard = not achieving insulin independence). In our first model (Table 9), we included age, sex, duration of pancreatitis, and history of prior pancreatic resection (distal, Puestow procedure, and Whipple procedure), however this model was not a good fit, with no significant variable. When the model included islet yield, we found that a 51% higher probability of achieving insulin-independence with an islet yield of >5000 IEQ/kg (p=0.009) i.e. a 51% lower chance of not reaching insulin-independence, or a 51% lower chance of needing insulin, or a 52% higher probability of achieving insulin-independence.

We then considered variables influencing the hazard of failure to achieve any beta cell function, encompassing both full and partial graft function (Table 10). We ran an analysis using our base variables and identified a previous distal pancreatectomy and previous Puestow procedure as predictive of failing to achieve beta cell function, with hazard ratios of 1.8 and 2.2, respectively. When islet yield was included in the model, the impact of previous distal pancreatectomy and Puestow was lessened, and low islet yield (<2500 IEQ/kg) had a stronger impact on failure to achieve beta cell function with a hazard ratio of 2.6 (p-value = 0.002).

Table 9. Cox Proportional Hazards Model for Insulin Independence

Variable Likelihood Ra- Hazard Ratio p-value tio

Base Model 0.81

Age 18-30 0.97 0.88 Age >30 1.10 0.58 Male gender 1.10 0.57 Duration of adz 1.10 0.44 Previous distal 1.30 0.36 Previous Puestow 1.30 0.37 Previous Whipple 0.79 0.42

Base Model plus islet yield 0.05

Age 18-30 1.08 0.74 Age >30 1.07 0.74 Male gender 1.00 0.98 Duration of pancreatitis 1.10 0.54 Previous distal 1.06 0.83 Previous Puestow 1.02 0.94 Previous Whipple 0.84 0.55 IEQ <2500 1.34 0.16 IEQ >5000 0.49 0.01

Table 10. Cox Proportional Hazards Model for Beta-cell Function

Variable Likelihood Ra- Hazard Ratio p-value tio

Base Model 0.01

Age 18-30 1.20 0.49 Age >30 0.74 0.36 Male gender 1.20 0.52 Duration of adz 0.94 0.78 Previous distal 1.80 0.08 Previous Puestow 2.20 0.01 Previous Whipple 0.32 0.05

Base Model plus islet yield <0.0001

Age 18-30 1.34 0.30 Age >30 0.79 0.46 Male gender 1.06 0.83 Duration of pancreatitis 0.93 0.72 Previous distal 1.19 0.62 Previous Puestow 1.48 0.22 Previous Whipple 0.34 0.10 IEQ <2500 2.60 0.002 IEQ >5000 0.69 0.37

!&,6"'%6$+="'"+ We recently published a comprehensive review of our pediatric cases (N=24) done through June 2006. Ninety-four percent of patients available for follow-up reported improvement in pain, with 61% able to discontinue narcotics. Eighty percent were able to attend school or work and 73% reported an excellent or good quality of life.

At one year following TP/IAT, 78% of pediatric patients had evidence of beta cell function, and 56% were insulin-independent. Predictors of graft function included higher islet yields

As in adults, the pediatric series found a considerable overlap in IEQ/kg associated with each of the three graft function categories. Patients with the lowest yields (<2000 IEQ/kg) were unlikely to achieve insulin-independence. We also found a correlation between history of pancreatic surgery and failure to achieve insulin-independence. At one year post-transplant, patients without a history of pancreatic surgery had a 67% probability of insulin independence as compared to 33% probability in those with a history of pancreatic surgery (p<0.021). A Cox regression analysis for insulin independence showed a correlation with lack of prior pancreatic surgery and islet yield >2000 IEQ/kg as predictors of achieving insulin independence. The hazard for insulin dependence was 5.0 (p=0.02) for patients with prior pancreatic surgery and 0.26 (p=0.06) for patients receiving an islet yield of >2000 IEQ/kg.

In a later update of the Minnesota series, at a time when we were much more likely to treat even mild hyperglycemia, and nearly all cases were total pancreatectomies, insulin independence was achieved in only 16% of patients with prior resections versus 40% in those without prior resections(32). A prior Whipple operation has less effect on the islet yield than a distal pancreatectomy because less of the pancreatic parenchyma has been removed.

B"#.2##"&3% Chronic pancreatitis is a challenging disease, often not easily diagnosed and typically disabling for those afflicted with this condition, rendering many patients dependent on

narcotics to control excruciating abdominal pain. Among treatments offered for chronic pancreatitis, only total pancreatectomy provides a chance at a definitive cure. And, with autologous islet transplantation, the chance of post-pancreatectomy diabetes is mini- mized.

At the University of Minnesota we are very liberal at applying total pancreatectomy and islet autotransplantation in patients with intractable pain who have failed prior medical and oftentimes surgical interventions. If endoscopic procedures, including pancreatic duct sphincterotomies and stent placement do not permanently relieve the pain, as is often the case (20), we go right to resection. A Whipple procedure can be tried first and if pain persists, a completion pancreatectomy with IAT done later. A distal pancreatectomy is done only if there is one mid-duct stricture and it is likely that only the body and tail is involved with chronic pancreatitis. The majority of patients with chronic pancreatitis referred for surgical treatment have longstanding intractable pain requiring narcotic analgesics, and most want the most definitive procedure that can be done, total pancreatectomy and, if non-diabetic, IAT in order to preserve insulin-independence or minimize the severity of post-pancreatectomy diabetes.

The severity of the gross morphological changes associated with pancreatitis, as detected by imaging studies, including computerized tomography (CT) scans, duct irregularities on endoscopic retrograde cholangiopancreatography (ERCP) , or endoscopic ultrasound (EUS) do not necessarily correlate with the degree of pain the patient is experiencing (115,116). Minimal change chronic pancreatitis was first described by Walsh et al (2) in patients who had severe abdominal pain with minimal gross morphologic changes but clear histopathologic changes in the gland, with resolution of pain in most patients following pancreatectomy. Layer et al (117) have also described two forms of chronic pancreatitis, relatively early onset where pain precedes by years the gradual development of gross pathology, and late onset where gross changes are detectable when the patient pre- sents with pain.

Some patients with chronic pancreatitis have diabetes when referred for surgical consul- tation, and in these the decision for resection is easy, especially when exocrine deficiency also exists as is often the case. However, most patients are seen when diabetes does not exist and thus the total pancreatectomy must be undertaken with the acceptance of diabetes as a tradeoff for relief of pain and the chance to wean off narcotics. . If the IAT pre- vents diabetes, it is a bonus. However, when a total pancreatectomy is done for chronic pancreatitis in a non-diabetic patient, an IAT to preserve beta cell mass should be done whenever possible.

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