destroyed by the disease process (Bellin & Sutherland, 2010; Kobayashi et al., 2010)

at baseline but normalizes on average by 1 year postoperatively (Bellin et al., 2011b).

The islet auto-transplant procedure is the same in children as that performed in adults. Including the cases done outside the University Of Minnesota, IATs have been performed in at least 50 children (not all published) with the majority of islet grafts infused intraportally (Bellin et al., 2008a; Bellin et al., 2011b; Sutherland et al., 2011a). There is one case report of intramuscular autoislet transplant in a 7 year old child; this patient had documented graft function and good metabolic control for over 2 years post-IAT but did not achieve insulin independence (Rafael et al., 2008). In children undergoing intraportal IAT, 40-50% of patients achieve insulin independence in the first 1 year after IAT, with the highest rate of

Most important is the effect of TP-IAT on the CP pain syndrome. Sixty to seventy percent of children completely discontinue narcotic pain medications, while the majority of the remaining patients require only intermittent or low dose narcotics for pain control (Bellin et al., 2008a; Bellin et al., 2011b). Complete discontinuation of narcotics is more frequent in preadolescent patients (younger than 13 years of age) (Bellin et al., 2008a). Over 90% of all children report no pain or significant improvement in pain compared to before surgery (Bellin et al., 2008a). Health-related quality of life, as measured by the Medical Outcomes Study (MOS) Short-Form 36 (SF-36) is nearly two standard deviations below the population

**10. Islet autotransplantation in children**

#### **9. Expanding application**

IATs have been done after pancreatic resection for focal benign pancreatic processes, including pancreatic pseudocysts (Clayton et al., 2003) cystic neoplasms such as intrapapillary mucinous neoplasms IPMN (Berney et al. 2004; Lee et al., 2005), insulinomas (Berney T et al., 2004; Oberholzer et al. 2003) neuroendocrine and other tumors (Berney T et al., 2004; Ris; 2011). In a series of 14 patients in Seoul, Korea with a mixture of benign tumors, including IPMN (Jung et al., 2009), pathologic evaluation was completed in each before the IAT to confirm that the lesions were benign.

In the UMN series, IATs have been done at the time of distal pancreatectomy for benign cystic tumors in 5 patients (Blondet et al., 2007; Braganza et al., 2011). In these cases the authors are uncertain how well the intrahepatic islets are functioning, because those in the native pancreatic remnant also are functioning.

In the Seoul series mentioned above (Jung et al., 2009), however, the investigators did a formal comparison of 14 patients who had partial pancreatectomy (PP) with an IAT and 6 who had PP without an IAT. Glucose tolerance was abruptly impaired in both groups immediately after surgery, including reduced indices of insulin secretion, but beginning at 6 months and persisting at 24 months, the PP-IAT group had statistically better insulin secretion and glucose tolerance than the PP-alone group. Thus, even with a PP there is a metabolic advantage to doing an IAT; and this would especially be the case if a completion pancreatectomy has to be done later for any reason. The lessons from the Korean experience can be extended to the CP group where a partial pancreatctomy before a completion pancreatectomy is quite common (usually a Whipple, but sometimes a distal).

An IAT also has been reported in a patient with pancreatic adenocarcinoma who had an extended Whipple operation complicated by an anastomotic leak at the pancreaticojejunostomy (Forster et al., 2004). . The leak was treated by an urgent completion pancreatectomy with an IAT. The portion of the pancreas used for islet isolation had margins free of tumor. The patient remained C-peptide positive until death from metastases 2.5 years later, but there was no tumor in the liver.

The risk of doing an IAT when a completion pancreatectomy is done because of a technical complication of a Whipple procedure cannot be calculated from one case, but conceptually the procedure is valid, because the judgment must be that the distal pancreas was tumorfree by leaving it in (otherwise a Whipple operation would not have been done). A case also could be made for doing a TP-IAT, even in situations where a Whipple would otherwise suffice, but where a TP would be safer by avoiding an enteric anastomosis to a soft pancreas that has a higher than average leakage or breakdown probability These cases are anecdotal and there is at this time no technique to assure that isolated islets are not contaminated by tumor. However, at least for hereditary CP with gene mutations associated with risk for pancreatic cancer, there are no reports yet of cancer arising in the liver after TP-IAT, including those done more than 20 years ago (Blondet et al., 2007).

A case can be made for doing a TP-IAT in patients with hereditary chronic pancreatitis in whom pain is not an issue (for example, "burned out") but has reached the age (>35 years) where the risk of pancreatic cancer associated with the gene mutations is significant and it increases with age (Farrow & Evers, 2002; Whitcomb, 2004; Whitcomb & Pogue-Geile, 2002).

On another note, the authors' TP-IAT series includes a few CP patients whose IATs were done after only a distal pancreatectomy, with the head remaining (Sutherland et al., 2011b). For those in whom a completion pancreatectomy was done later, insulin-independence was preserved, indicating good engraftment at the initial IAT (Blondet et al., 2007).

Transplants of islets isolated from pancreas allografts excised for technical problems or allograft pancreatitis (islet auto-allografts) also have been performed, with one case published by the authors (Leone et al., 1998) . This patient remained insulin-independent for more than 1 year while on immunosuppression, but ultimately needed exogenous insulin from decline or loss of islet function for immunologic or non-immunologic reasons. The other islet auto-allografts had limited duration of function (Blondet et al., 2007).

### **10. Islet autotransplantation in children**

110 Chronic Pancreatitis

IATs have been done after pancreatic resection for focal benign pancreatic processes, including pancreatic pseudocysts (Clayton et al., 2003) cystic neoplasms such as intrapapillary mucinous neoplasms IPMN (Berney et al. 2004; Lee et al., 2005), insulinomas (Berney T et al., 2004; Oberholzer et al. 2003) neuroendocrine and other tumors (Berney T et al., 2004; Ris; 2011). In a series of 14 patients in Seoul, Korea with a mixture of benign tumors, including IPMN (Jung et al., 2009), pathologic evaluation was completed in each

In the UMN series, IATs have been done at the time of distal pancreatectomy for benign cystic tumors in 5 patients (Blondet et al., 2007; Braganza et al., 2011). In these cases the authors are uncertain how well the intrahepatic islets are functioning, because those in the

In the Seoul series mentioned above (Jung et al., 2009), however, the investigators did a formal comparison of 14 patients who had partial pancreatectomy (PP) with an IAT and 6 who had PP without an IAT. Glucose tolerance was abruptly impaired in both groups immediately after surgery, including reduced indices of insulin secretion, but beginning at 6 months and persisting at 24 months, the PP-IAT group had statistically better insulin secretion and glucose tolerance than the PP-alone group. Thus, even with a PP there is a metabolic advantage to doing an IAT; and this would especially be the case if a completion pancreatectomy has to be done later for any reason. The lessons from the Korean experience can be extended to the CP group where a partial pancreatctomy before a completion

An IAT also has been reported in a patient with pancreatic adenocarcinoma who had an extended Whipple operation complicated by an anastomotic leak at the pancreaticojejunostomy (Forster et al., 2004). . The leak was treated by an urgent completion pancreatectomy with an IAT. The portion of the pancreas used for islet isolation had margins free of tumor. The patient remained C-peptide positive until death from metastases

The risk of doing an IAT when a completion pancreatectomy is done because of a technical complication of a Whipple procedure cannot be calculated from one case, but conceptually the procedure is valid, because the judgment must be that the distal pancreas was tumorfree by leaving it in (otherwise a Whipple operation would not have been done). A case also could be made for doing a TP-IAT, even in situations where a Whipple would otherwise suffice, but where a TP would be safer by avoiding an enteric anastomosis to a soft pancreas that has a higher than average leakage or breakdown probability These cases are anecdotal and there is at this time no technique to assure that isolated islets are not contaminated by tumor. However, at least for hereditary CP with gene mutations associated with risk for pancreatic cancer, there are no reports yet of cancer arising in the liver after TP-IAT,

A case can be made for doing a TP-IAT in patients with hereditary chronic pancreatitis in whom pain is not an issue (for example, "burned out") but has reached the age (>35 years) where the risk of pancreatic cancer associated with the gene mutations is significant and it increases with age (Farrow & Evers, 2002; Whitcomb, 2004; Whitcomb & Pogue-Geile, 2002).

pancreatectomy is quite common (usually a Whipple, but sometimes a distal).

**9. Expanding application**

before the IAT to confirm that the lesions were benign.

native pancreatic remnant also are functioning.

2.5 years later, but there was no tumor in the liver.

including those done more than 20 years ago (Blondet et al., 2007).

CP is less common in children than in adults, but should be treated with the same aim: to relieve pain, eliminate the need for narcotics, and preserve ß-cell mass (Schmulewitz, 2011). The first known case of TP-IAT in a child was done at the University of Minnesota in 1989 and was reported in detail by the authors 7 years later with islet function maintained, though the patient was not insulin-independent (Wahoff et al., 1996). The authors have done TP-IAT in more than 40 children since the initial report (Bellin & Sutherland, 2010). Although the experience with TPIAT in children is less extensive than in adults, the data suggests this procedure is particularly successful in the youngest patients with insulinindependence rates of over 50% and the younger the patient the more likely insulinindependence is achieved (Bellin et al., 2008a; Bellin & Sutherland, 2010). Most of the ones that do require insulin retain some beta cell function as manifested by C-peptide positivity and thus are stable. In the historical series, more than three-quarters of the children had islet function after TP-IAT (Bellin et al., 2008a) Brittle diabetes is very rare after TP-IAT unless virtually no islets are obtained because of delaying the TP until nearly all the islets are destroyed by the disease process (Bellin & Sutherland, 2010; Kobayashi et al., 2010)

Most important is the effect of TP-IAT on the CP pain syndrome. Sixty to seventy percent of children completely discontinue narcotic pain medications, while the majority of the remaining patients require only intermittent or low dose narcotics for pain control (Bellin et al., 2008a; Bellin et al., 2011b). Complete discontinuation of narcotics is more frequent in preadolescent patients (younger than 13 years of age) (Bellin et al., 2008a). Over 90% of all children report no pain or significant improvement in pain compared to before surgery (Bellin et al., 2008a). Health-related quality of life, as measured by the Medical Outcomes Study (MOS) Short-Form 36 (SF-36) is nearly two standard deviations below the population at baseline but normalizes on average by 1 year postoperatively (Bellin et al., 2011b).

The islet auto-transplant procedure is the same in children as that performed in adults. Including the cases done outside the University Of Minnesota, IATs have been performed in at least 50 children (not all published) with the majority of islet grafts infused intraportally (Bellin et al., 2008a; Bellin et al., 2011b; Sutherland et al., 2011a). There is one case report of intramuscular autoislet transplant in a 7 year old child; this patient had documented graft function and good metabolic control for over 2 years post-IAT but did not achieve insulin independence (Rafael et al., 2008). In children undergoing intraportal IAT, 40-50% of patients achieve insulin independence in the first 1 year after IAT, with the highest rate of

Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis 113

largely focus on metabolic outcomes, QOL, and pain reduction., but there are many publications on specialized aspects of TP-IAT as have been referenced in this chapter.

The ability to achieve insulin independence after IATs appears to correlate directly with the islet equivalents (IEs) infused. IEs serve as an indirect measurement of β-cell mass, but there is much overlap, in that a small percentage of patients receiving less than 2000 IE/kg will become insulin-independent, while some receiving more than 5000 IE/kg will not (Ahmad et al., 2005; Bellin et al., 2009; Blondet et al., 2007; Dong et al., 2011; Jie et al., 2005; Sutherland et al., 2008; Sutherland et al., 2009a; Takita et al., 2011a). The Leicester group finds very little correlation of insulin-independence with islet yield (Webb et al., 2008). The authors have shown that islet yields are poorest in patients who have prior pancreatic resections (distal pancreatectomies or surgical drainage procedures such as the Puestow procedure) (Blondet et al., 2007; Gruessner et al., 2004; Sutherland et al., 2011b; Wahoff et al.,1995c). In addition, fewer islets are recovered as histopathologic changes of CP increase in severity (Gruessner

The timing of the procedure has a direct impact on islet yield. Maximal islet yield and insulin independence may be attained more easily if the IAT is performed earlier in the disease course, (Ahmad et al., 2006; Balamurugan et al., 2011a; Bellin et al., 2010a; Kobayashi

In regard to durability of insulin independence when it is achieved after TP-IAT, it is much more durable than in islet allografts, even though the number of islets transplanted is less than for islet allografts (Sutherland et al., 2008). In a retrospective analysis of the first 173 patients to undergo TP-IAT at the University of Minnesota (20 year follow-up on the longest), the incidence of graft function and insulin-independence and decline over time once achieved was calculated and compared to the same calculations made for islet

Islet allografts are currently associated with a high rate of early insulin independence, but after 1 year insulin-independence rates have declined relatively rapidly in the CITR analyses overall (CITR; 2009) and at most (Jahansouz et al., 2011) but, more recently, not all (Bellin et al., 2008b) institutions,. The 2008 analysis of islet auto-transplants (IATs) done at the University Of Minnesota over a 30 year period in those who achieved function showed to be relatively durable compared to the islet allografts, despite a lower beta-cell mass (Bellin et al., 2008b). IAT function (full/partial combined) and insulin independence correlated with islet yield. Overall only 65% functioned within the first year, and only 32% were insulin independent, but of IATs that functioned initially, 85% remained so 2-years later, in contrast to 66% of allografts Of IAT recipients who became insulin independent, 74%remained so 2 years later versus 45%of initially insulin-independent allograft recipients. Of IATs that functioned or induced insulin independence, the rates at 5 years were 69% and 47%, respectively. Thus, islet function is more resilient in autografts than allografts. Indeed, in this analysis, the 5-year insulin-independence persistence rate for IATs was similar to the 2-year rate for allografts. Several factors unique to allocases are likely responsible for the differences, including donor brain death, longer cold ischemia time, diabetogenic immunosuppression, and auto- and alloimmunity. IAT outcomes provide a minimum theoretical standard to work

et al., 2004; Kobayashi et al., 2010; Kobayashi et al., 2011; Wahoff et al., 1995a).

et al., 2011; Rodriguez et al., 2003; Sutherland et al., 2011; Takita et al., 2010).

allografts in the Collaborative Islet Transplant Registry (CITR) (Figure 3).

**11.1 Insulin independence**

insulin independence in preadolescent children (Bellin & Sutherland, 2010). In addition to young age, higher islet mass transplanted and lack of prior distal resection and/or lateral pancreatico-jejunostomy are important prognostic factors for insulin independence (Bellin et al., 2008a; Bellin et al., 2011b). More extensive fibrosis and longer duration of disease have been associated with lower islet yields and hence higher risk of insulin dependence in children (Kobayashi et al., 2010). As in adults, baseline glucose, C-peptide (fasting and stimulated), and hemoglobin A1c are measured before surgery. Lower hemoglobin A1c, lower fasting blood glucose, and higher stimulated C-peptide levels are associated with higher islet yields but do not predict the islet count prior to pancreatectomy for any individual patient (Bellin et al., 2010a)

Most important of all is the dramatic improvement in quality of life that can be documented in children undergoing TP-IAT for CP, both retrospectively (Bellin et al., 2008a) and in a recent prospective study at the University Of Minnesota (Bellin et al., 2011b). In the prospective study, nineteen consecutive children (aged 5–18 years) undergoing TP/IAT from December 2006 to December 2009 at the University of Minnesota completed the Medical Outcomes Study 36-item Short Form (SF-36) health questionnaire before and after surgery. Before TP/IAT, the children had below average health-related quality of life, based on data from the Medical Outcomes Study SF-36; they had a mean physical component summary (PCS) score of 30 and mental component summary (MCS) score of 34 (2 and 1.5 standard deviations, respectively, below the mean for the US population). By 1 year after surgery, PCS and MCS scores significantly improved to 50 and 46, respectively Mean scores improved for all 8 component subscales. More than 60% of IAT recipients were insulin independent or required minimal insulin. Patients with prior surgical drainage procedures (Puestow) had significantly lower yields of islets and greater incidence of insulin dependence

Although the number of patients is relatively small, this study (Bellin et al., 2011b) shows that the physical and emotional components that define quality of life significantly improve after TP/IAT in subsets of pediatric patients with CP. Children who have had surgical drainage procedures prior to TP-IAT are disadvantaged in regard to islet yield and none yet have had sustained insulin independence,; however even in this subset some had islet function as manifested by C-peptide positivity or need for only once daily long acting insulin. Children should not be allowed to suffer the pain of CP when it can be relieved by TP and beta cell function preserved by IAT, and quality of life is restored in nearly all cases.

#### **11. Literature review**

The largest series published to date on patients undergoing pancreatectomy and IAT have come from the University of Minnesota (Farney et al., 1991; Gores et al., 1992; Gruessner et al., 2004; Jie et al., 2005; Najarian et al., 1979; Najarian et al., 1980; Sutherland et al., 1978; Sutherland et al., 1980a; Sutherland et al., 2004a; Sutherland et al., 2009a; Sutherland et al., 2009b; Sutherland et al., 2011b; Wahoff et al., 1995a) (>400), the University of Cincinnati (Ahmad et al., 2005; Rodriguez et al., 2003; Sutton et al., 2010) (>100), the University of Leicester (Clayton et al., 2003;; Garcea et al., 2009; White SA et al., 1998; White SA et al., 2001; Webb et al., 2008) (>50 cases), but there are many center that are building their series (Argo et al., 2008; Berney T et al., 2000; Desai et al., 2011; Dixon et al., 2008; Jahansouz et al., 2011; Takita et al., 2010; Takita et al., 2011b; Valente et al., 1986) The reports from these centers largely focus on metabolic outcomes, QOL, and pain reduction., but there are many publications on specialized aspects of TP-IAT as have been referenced in this chapter.

#### **11.1 Insulin independence**

112 Chronic Pancreatitis

insulin independence in preadolescent children (Bellin & Sutherland, 2010). In addition to young age, higher islet mass transplanted and lack of prior distal resection and/or lateral pancreatico-jejunostomy are important prognostic factors for insulin independence (Bellin et al., 2008a; Bellin et al., 2011b). More extensive fibrosis and longer duration of disease have been associated with lower islet yields and hence higher risk of insulin dependence in children (Kobayashi et al., 2010). As in adults, baseline glucose, C-peptide (fasting and stimulated), and hemoglobin A1c are measured before surgery. Lower hemoglobin A1c, lower fasting blood glucose, and higher stimulated C-peptide levels are associated with higher islet yields but do not predict the islet count prior to pancreatectomy for any

Most important of all is the dramatic improvement in quality of life that can be documented in children undergoing TP-IAT for CP, both retrospectively (Bellin et al., 2008a) and in a recent prospective study at the University Of Minnesota (Bellin et al., 2011b). In the prospective study, nineteen consecutive children (aged 5–18 years) undergoing TP/IAT from December 2006 to December 2009 at the University of Minnesota completed the Medical Outcomes Study 36-item Short Form (SF-36) health questionnaire before and after surgery. Before TP/IAT, the children had below average health-related quality of life, based on data from the Medical Outcomes Study SF-36; they had a mean physical component summary (PCS) score of 30 and mental component summary (MCS) score of 34 (2 and 1.5 standard deviations, respectively, below the mean for the US population). By 1 year after surgery, PCS and MCS scores significantly improved to 50 and 46, respectively Mean scores improved for all 8 component subscales. More than 60% of IAT recipients were insulin independent or required minimal insulin. Patients with prior surgical drainage procedures (Puestow) had significantly lower yields of islets and greater incidence of insulin

Although the number of patients is relatively small, this study (Bellin et al., 2011b) shows that the physical and emotional components that define quality of life significantly improve after TP/IAT in subsets of pediatric patients with CP. Children who have had surgical drainage procedures prior to TP-IAT are disadvantaged in regard to islet yield and none yet have had sustained insulin independence,; however even in this subset some had islet function as manifested by C-peptide positivity or need for only once daily long acting insulin. Children should not be allowed to suffer the pain of CP when it can be relieved by TP and beta cell function preserved by IAT, and quality of life is restored in nearly all cases.

 Literature review**

The ability to achieve insulin independence after IATs appears to correlate directly with the islet equivalents (IEs) infused. IEs serve as an indirect measurement of β-cell mass, but there is much overlap, in that a small percentage of patients receiving less than 2000 IE/kg will become insulin-independent, while some receiving more than 5000 IE/kg will not (Ahmad et al., 2005; Bellin et al., 2009; Blondet et al., 2007; Dong et al., 2011; Jie et al., 2005; Sutherland et al., 2008; Sutherland et al., 2009a; Takita et al., 2011a). The Leicester group finds very little correlation of insulin-independence with islet yield (Webb et al., 2008). The authors have shown that islet yields are poorest in patients who have prior pancreatic resections (distal pancreatectomies or surgical drainage procedures such as the Puestow procedure) (Blondet et al., 2007; Gruessner et al., 2004; Sutherland et al., 2011b; Wahoff et al.,1995c). In addition, fewer islets are recovered as histopathologic changes of CP increase in severity (Gruessner et al., 2004; Kobayashi et al., 2010; Kobayashi et al., 2011; Wahoff et al., 1995a).

The timing of the procedure has a direct impact on islet yield. Maximal islet yield and insulin independence may be attained more easily if the IAT is performed earlier in the disease course, (Ahmad et al., 2006; Balamurugan et al., 2011a; Bellin et al., 2010a; Kobayashi et al., 2011; Rodriguez et al., 2003; Sutherland et al., 2011; Takita et al., 2010).

In regard to durability of insulin independence when it is achieved after TP-IAT, it is much more durable than in islet allografts, even though the number of islets transplanted is less than for islet allografts (Sutherland et al., 2008). In a retrospective analysis of the first 173 patients to undergo TP-IAT at the University of Minnesota (20 year follow-up on the longest), the incidence of graft function and insulin-independence and decline over time once achieved was calculated and compared to the same calculations made for islet allografts in the Collaborative Islet Transplant Registry (CITR) (Figure 3).

Islet allografts are currently associated with a high rate of early insulin independence, but after 1 year insulin-independence rates have declined relatively rapidly in the CITR analyses overall (CITR; 2009) and at most (Jahansouz et al., 2011) but, more recently, not all (Bellin et al., 2008b) institutions,. The 2008 analysis of islet auto-transplants (IATs) done at the University Of Minnesota over a 30 year period in those who achieved function showed to be relatively durable compared to the islet allografts, despite a lower beta-cell mass (Bellin et al., 2008b). IAT function (full/partial combined) and insulin independence correlated with islet yield. Overall only 65% functioned within the first year, and only 32% were insulin independent, but of IATs that functioned initially, 85% remained so 2-years later, in contrast to 66% of allografts Of IAT recipients who became insulin independent, 74%remained so 2 years later versus 45%of initially insulin-independent allograft recipients. Of IATs that functioned or induced insulin independence, the rates at 5 years were 69% and 47%, respectively. Thus, islet function is more resilient in autografts than allografts. Indeed, in this analysis, the 5-year insulin-independence persistence rate for IATs was similar to the 2-year rate for allografts. Several factors unique to allocases are likely responsible for the differences, including donor brain death, longer cold ischemia time, diabetogenic immunosuppression, and auto- and alloimmunity. IAT outcomes provide a minimum theoretical standard to work

Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis 115

In a later update of the UMN series, at a time when the authors were much more likely to treat even mild hyperglycemia, and nearly all patients underwent a TP, insulin independence was achieved in only 16% of patients with prior resections versus 40% in those without prior resections (Gruessner et al., 2004) . A prior Whipple operation had less

Fig. 4. Islet autograft experience at the University of Minnesota by year, in 407 patients (360

The outcomes in the University of Minnesota series were again updated in 2005 when it included 136 patients 971% female) undergoing IAT from 1977 through 2004 (Jie et al., 2005). Further details on this cohort were added in 2007 (Blondet et al., 2007). Patient age ranged from 5 to 70 years (mean 36 years); duration of disease ranged from 1 to 30 years (mean 5.9 years). The etiology of CP was idiopathic in 43%, alcohol in 15%, divisum in 13%, familial in 11%, biliary in 10% and other in 7% of the patients. Most (93%) had had previous operations (cholecystectomy in 42%), 33% directly on the pancreas including duct drainage in 13%, Whipple procedure in 7%, distal pancreatectomy in 9% and combined drainage and

 A TP or completion pancreatectomy was done in 77% and a near total (duodenal sparing) in 15%, while 10 had a distal pancreatectomy only (some later had a completion pancreatectomy). This analysis (Jie et al.; 2005) confirmed that a prior Puestow procedure was associated with low islet yields (mean of 1531 IE/kg) as compared to no previous direct surgery on the pancreas (mean of 3996 IE/kg). Prior resection was associate with a slightly

adults, 47 children <18 years old) from February 1977 to July 2011.

resection in 4%. .

effect on the islet yield than a distal pancreatectomy (Sutherland et al., 2004a) .

Fig. 3. Rates of loss of islet graft function or insulin independence (II) in University Of Minnesota 1977 to 2007 adult TP recipients of islet AUTO-transplants who achieved islet function or II versus in 1999-2006 type 1 diabetic recipients of islet ALLO-transplants who likewise achieved islet function or II as reported to the Collaborative Islet Transplant Registry (CITR) (Reproduced from Sutherland et al., 2008; with Copyright © , Lippincott Williams & Wilkins, Inc.**)**

toward in allotransplantation. However, not all islet autografts that initially function continue to do so, and beta cell mass is important, the more the islets, the more durable the function, particularly in adults. Preadolescent children are a special group where even a low islet mass can function long term, and possibly the mass expands in young children (Bellin & Sutherland, 2010).

#### **11.1.1 University of Minnesota series**

As referenced above, the University Of Minnesota has published extensively on their series of TP-IAT cases, numbering more than 400 between 1977 and 2011 (Fig 4). In a comprehensive 1995 report (Wahoff et al., 1995a), of the first 50 cases, significant pain relief occurred in >80%. Over half had a period of insulin-independence and a third maintained insulin independence for the 2 to 10 years they had been followed. If over 300,000 islets were transplanted, three-quarters maintained insulin independence by the protocol in place at the time (which did not include adding insulin for perturbations in metabolism as we do now). A major point of this paper (Wahoff et al., 1995a) was that the lowest islet yields were in patients who had a prior Puestow procedure, with only an 18% rate of insulin independence in this group, in contrast to 71% in patients without a prior resection or drainage procedure.

Fig. 3. Rates of loss of islet graft function or insulin independence (II) in University Of Minnesota 1977 to 2007 adult TP recipients of islet AUTO-transplants who achieved islet function or II versus in 1999-2006 type 1 diabetic recipients of islet ALLO-transplants who likewise achieved islet function or II as reported to the Collaborative Islet Transplant Registry (CITR) (Reproduced from Sutherland et al., 2008; with Copyright © , Lippincott

toward in allotransplantation. However, not all islet autografts that initially function continue to do so, and beta cell mass is important, the more the islets, the more durable the function, particularly in adults. Preadolescent children are a special group where even a low islet mass can function long term, and possibly the mass expands in young children (Bellin

As referenced above, the University Of Minnesota has published extensively on their series of TP-IAT cases, numbering more than 400 between 1977 and 2011 (Fig 4). In a comprehensive 1995 report (Wahoff et al., 1995a), of the first 50 cases, significant pain relief occurred in >80%. Over half had a period of insulin-independence and a third maintained insulin independence for the 2 to 10 years they had been followed. If over 300,000 islets were transplanted, three-quarters maintained insulin independence by the protocol in place at the time (which did not include adding insulin for perturbations in metabolism as we do now). A major point of this paper (Wahoff et al., 1995a) was that the lowest islet yields were in patients who had a prior Puestow procedure, with only an 18% rate of insulin independence in this group, in contrast to 71% in patients without a prior resection or drainage procedure.

Williams & Wilkins, Inc.**)**

& Sutherland, 2010).

**11.1.1 University of Minnesota series**

In a later update of the UMN series, at a time when the authors were much more likely to treat even mild hyperglycemia, and nearly all patients underwent a TP, insulin independence was achieved in only 16% of patients with prior resections versus 40% in those without prior resections (Gruessner et al., 2004) .

Fig. 4. Islet autograft experience at the University of Minnesota by year, in 407 patients (360 adults, 47 children <18 years old) from February 1977 to July 2011.

The outcomes in the University of Minnesota series were again updated in 2005 when it included 136 patients 971% female) undergoing IAT from 1977 through 2004 (Jie et al., 2005). Further details on this cohort were added in 2007 (Blondet et al., 2007). Patient age ranged from 5 to 70 years (mean 36 years); duration of disease ranged from 1 to 30 years (mean 5.9 years). The etiology of CP was idiopathic in 43%, alcohol in 15%, divisum in 13%, familial in 11%, biliary in 10% and other in 7% of the patients. Most (93%) had had previous operations (cholecystectomy in 42%), 33% directly on the pancreas including duct drainage in 13%, Whipple procedure in 7%, distal pancreatectomy in 9% and combined drainage and resection in 4%. .

 A TP or completion pancreatectomy was done in 77% and a near total (duodenal sparing) in 15%, while 10 had a distal pancreatectomy only (some later had a completion pancreatectomy). This analysis (Jie et al.; 2005) confirmed that a prior Puestow procedure was associated with low islet yields (mean of 1531 IE/kg) as compared to no previous direct surgery on the pancreas (mean of 3996 IE/kg). Prior resection was associate with a slightly

Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis 117

combined) 5 years later, while it was slightly less than half for those who received <2500 IE/kg (Figure 7).  Actuarial patient survival rates, IAT graft function rates(full-partial combined) and insulin-independence rates from time of transplant for adult Patients undergoing TP-IAT at

Since many modifications in islet isolation, surgical technique and patient selection have occurred over the decades since the first TP-IAT case, the outcomes at the University Of Minnesota in the modern era alone have been the subject of recent analyses of pain relief and quality of life (Sutherland et al., 2009a) and metabolic outcome (Sutherland et al., 2009b). Of 67 adult patients undergoing TP-IAT for CP between January, 2006 and February 2008 (Sutherland et al., 2009a), all had had attempts at pain relief by prior endoscopic duct drainage (EDD) procedures. In all the pain had persisted in spite of the EDD. EDD is a minimally invasive approach that should almost always be tried before major surgery for

 The patients were assessed by written surveys and clinic interviews and metabolic testing in 2009, with more than 1 year of follow-up (16-44 months) in all (Sutherland et al., 2009a). Mean age was 36 years and 72% were female. Etiology of CP was unknown in 40%); from pancreas divisums in 14%; genetic in 14%; associated with Sphincter of Oddi dysfunction (SOD) in 12%; with alcohol use in 9%; and other in 11%. Patients were surveyed for outcomes with a median follow-up of 1.7yrs Actual survival at 1 year was 98.5%; actuarial survival at 2 years was 95.5%. The collective number of EDD procedures prior to surgery was 264 (mean of

University Of Minnesota from 1977 to 2007 (data from Sutherland et al, 2008)

CP, but in these 67 patients the pain had persisted in spite of the EDD.

while it was less than a third for those who received <2500 IE/kg (Figure 8).

lower yield (3687 IE/kg), but the difference was much more striking after a distal pancreatectomy than a Whipple operation. Again, there was a correlation between islet yield and insulin independence. Of patients receiving >2000 IEQ/kg, nearly three-quarters had at least a period off insulin (Jie et al., 2005). Of those completely dependent on insulin, the mean IE/kg transplanted was 1239, while in those in whom it was intermittent it was 3064; in those who maintained insulin-independence it was 5118/kg. About a third of patients fall into each category (Blondet et al., 2007).

Most important was formal patient self-assessment of quality of life after TP-IAT as the University Of Minnesota program progressed (Carlson et al., 2007). Of 90 patients transplanted between 1996 and 2005 with >1 year follow-up in all, 83% reported good to excellent outcome and less than 5% considered their outcomes poor [Figure 5]. This retrospective survey has since been followed by prospective studies of quality of life in both children and adults in the Minnesota series.

Fig. 5. Patient subjective perception of their outcome post-TP-IAT (1-10 years follow-up) , for 1996-2005 adult cases at University of Minnesota ( data from Carlson et al 2007).

Patient survival and durability of IAT graft function (either insulin-independent or on once daily insulin only and C-peptide positive) and insulin-independence in the Minnesota TP-IAT series for 1977-2007 cases (Figure 6) was detailed in a 2008 publication (Sutherland et al., 2008). Patient survival at 1 year was 95% and more than three-quarters were alive at 10 years. More than two thirds had partial or full function of the IAT, with a third achieving insulin independence. At 20 years more than half who exhibited IAT function initially still had function, so overall more than one-third of the original cohort had functioning islets for two decades in this series that includes the earliest cases. Half of those who were insulin independent initially were still so at 5 years; none were insulin-independent at 20 years but at least partial function was maintained for at least this length.(Figure 6). The durability of IAT function (Figure 7) and of insulin-independence (Figure 8) in those who did initially achieve partial or full function, correlated with the number of islets transplanted. For those receiving >5000 IE/kg, more than three quarters still had function (full and partial

lower yield (3687 IE/kg), but the difference was much more striking after a distal pancreatectomy than a Whipple operation. Again, there was a correlation between islet yield and insulin independence. Of patients receiving >2000 IEQ/kg, nearly three-quarters had at least a period off insulin (Jie et al., 2005). Of those completely dependent on insulin, the mean IE/kg transplanted was 1239, while in those in whom it was intermittent it was 3064; in those who maintained insulin-independence it was 5118/kg. About a third of

Most important was formal patient self-assessment of quality of life after TP-IAT as the University Of Minnesota program progressed (Carlson et al., 2007). Of 90 patients transplanted between 1996 and 2005 with >1 year follow-up in all, 83% reported good to excellent outcome and less than 5% considered their outcomes poor [Figure 5]. This retrospective survey has since been followed by prospective studies of quality of life in both

Fig. 5. Patient subjective perception of their outcome post-TP-IAT (1-10 years follow-up) , for

Patient survival and durability of IAT graft function (either insulin-independent or on once daily insulin only and C-peptide positive) and insulin-independence in the Minnesota TP-IAT series for 1977-2007 cases (Figure 6) was detailed in a 2008 publication (Sutherland et al., 2008). Patient survival at 1 year was 95% and more than three-quarters were alive at 10 years. More than two thirds had partial or full function of the IAT, with a third achieving insulin independence. At 20 years more than half who exhibited IAT function initially still had function, so overall more than one-third of the original cohort had functioning islets for two decades in this series that includes the earliest cases. Half of those who were insulin independent initially were still so at 5 years; none were insulin-independent at 20 years but at least partial function was maintained for at least this length.(Figure 6). The durability of IAT function (Figure 7) and of insulin-independence (Figure 8) in those who did initially achieve partial or full function, correlated with the number of islets transplanted. For those receiving >5000 IE/kg, more than three quarters still had function (full and partial

1996-2005 adult cases at University of Minnesota ( data from Carlson et al 2007).

patients fall into each category (Blondet et al., 2007).

children and adults in the Minnesota series.

combined) 5 years later, while it was slightly less than half for those who received <2500 IE/kg (Figure 7). Similarly, of those who achieved insulin independence, nearly threequarters of those who received >5000 IE/kg were still insulin-independent 5 years later, while it was less than a third for those who received <2500 IE/kg (Figure 8).

Fig. 6. Actuarial patient survival rates, IAT graft function rates(full-partial combined) and insulin-independence rates from time of transplant for adult Patients undergoing TP-IAT at University Of Minnesota from 1977 to 2007 (data from Sutherland et al, 2008)

Since many modifications in islet isolation, surgical technique and patient selection have occurred over the decades since the first TP-IAT case, the outcomes at the University Of Minnesota in the modern era alone have been the subject of recent analyses of pain relief and quality of life (Sutherland et al., 2009a) and metabolic outcome (Sutherland et al., 2009b). Of 67 adult patients undergoing TP-IAT for CP between January, 2006 and February 2008 (Sutherland et al., 2009a), all had had attempts at pain relief by prior endoscopic duct drainage (EDD) procedures. In all the pain had persisted in spite of the EDD. EDD is a minimally invasive approach that should almost always be tried before major surgery for CP, but in these 67 patients the pain had persisted in spite of the EDD.

 The patients were assessed by written surveys and clinic interviews and metabolic testing in 2009, with more than 1 year of follow-up (16-44 months) in all (Sutherland et al., 2009a). Mean age was 36 years and 72% were female. Etiology of CP was unknown in 40%); from pancreas divisums in 14%; genetic in 14%; associated with Sphincter of Oddi dysfunction (SOD) in 12%; with alcohol use in 9%; and other in 11%. Patients were surveyed for outcomes with a median follow-up of 1.7yrs Actual survival at 1 year was 98.5%; actuarial survival at 2 years was 95.5%. The collective number of EDD procedures prior to surgery was 264 (mean of

Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis 119

4.1/patient; max ~60). Ten patients (15%) had had a partial pancreatectomy elsewhere before a total (completion) pancreatectomy-IAT at the University Of Minnesota, and did not

Patients were assessed at follow-up for pain, narcotic use, quality of life (QOL) and IAT function: full if insulin-independent; partial if euglycemic on once daily long-acting insulin; failed if on a basal-bolus insulin regime). Function was correlated with islet (IE) yield.

97 % were on narcotics before the TP-IAT; 51 % were on at the time of the post-surgery

Of those who required insulin, 98% preferred diabetes to the former pain.

have EDD in the interval.

<2500 IE/kg in 22 (34%); 2501-5000 IE/kg in 30 (46%); >5000 IE/kg in 13 ( 20%).

IAT function was a combined

83% with 2501-5000 IE/kg;

Perception of health was: good-excellent in 75 %;

better in 85 %(absent in 39 %);

survey (85% of these were on a wean schedule).

Patients rated quality of life (QOL) after TP-IAT as:

Asked would they do the TP-IAT again, 98% said yes.

QOL change from before to after TP-IAT:

fair in14 %; poor in 11 %. Pain was:

the same in 13 %; worse in 2 %.

excellent-good in 60 %;

improved in 80 %; was the same in 15 %; was worse in 5 %.

fair in 30 %; poor in 10 %.

full-partial in:100% with >5000 IE/kg;

and 59% with <2500 IE/kg (p<.0011).

IAT function was: Full in 21 (32 %); partial in 28 (43 %); failed in 16 (25 %).

Yield was:

Fig. 7. Actuarial duration of islet graft function (full-partial combined) according to islet yield in adult patients who achieved function after TP-IAT at University Of Minnesota from 1977 to 2007 (data from Sutherland et al, 2008).

Fig. 8. Actuarial duration of insulin independence according to islet yield in adult patients who achieved insulin-independence after TP-IAT at University Of Minnesota from 1977 to 2007 (data from Sutherland et al, 2008).

4.1/patient; max ~60). Ten patients (15%) had had a partial pancreatectomy elsewhere before a total (completion) pancreatectomy-IAT at the University Of Minnesota, and did not have EDD in the interval.

Patients were assessed at follow-up for pain, narcotic use, quality of life (QOL) and IAT function: full if insulin-independent; partial if euglycemic on once daily long-acting insulin; failed if on a basal-bolus insulin regime). Function was correlated with islet (IE) yield.

Yield was:

118 Chronic Pancreatitis

Fig. 7. Actuarial duration of islet graft function (full-partial combined) according to islet yield in adult patients who achieved function after TP-IAT at University Of Minnesota from

Fig. 8. Actuarial duration of insulin independence according to islet yield in adult patients who achieved insulin-independence after TP-IAT at University Of Minnesota from 1977 to

1977 to 2007 (data from Sutherland et al, 2008).

2007 (data from Sutherland et al, 2008).

<2500 IE/kg in 22 (34%); 2501-5000 IE/kg in 30 (46%); >5000 IE/kg in 13 ( 20%).

IAT function was:

Full in 21 (32 %); partial in 28 (43 %); failed in 16 (25 %).

IAT function was a combined

full-partial in:100% with >5000 IE/kg; 83% with 2501-5000 IE/kg; and 59% with <2500 IE/kg (p<.0011).

Perception of health was:

good-excellent in 75 %; fair in14 %; poor in 11 %.

Pain was:

better in 85 %(absent in 39 %); the same in 13 %; worse in 2 %.

97 % were on narcotics before the TP-IAT; 51 % were on at the time of the post-surgery survey (85% of these were on a wean schedule).

Of those who required insulin, 98% preferred diabetes to the former pain.

Patients rated quality of life (QOL) after TP-IAT as:

excellent-good in 60 %; fair in 30 %; poor in 10 %.

QOL change from before to after TP-IAT:

improved in 80 %; was the same in 15 %; was worse in 5 %.

Asked would they do the TP-IAT again, 98% said yes.

Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis 121

This large series, as well as those of others cited above and below, shows definitively that TP can ameliorate pain and improve QOL in patients with otherwise refractory CP, , even if narcotic-withdrawal is delayed or incomplete because of prior long-term use. IAT preserves substantial islet-function in >2/3 of patients with insulin-independence occurring in a

The Cincinnati series of TP-IAT cases (Ahmad et al., 2005; Ahmad et al., 2006; Sutton et al., 2010) is the second largest in the literature with their latest report including 118 cases (Sutton et al., 2010). The early reports from this group (Ahmad et al., 2005; Ahmad et al., 2006) showed a 40% rate of insulin independence after TP/IAT, with a mean follow-up of 18 months. Factors that correlated with postoperative insulin independence included the patient's weight, body mass index (BMI), and gender (Rodriguez Rilo et al., 2003). Patients who had a BMI greater than 28 had a higher chance of insulin dependence (Rodriguez Rilo et al., 2003). Reduction to ideal body weight to minimize insulin resistance may maximize the chance for insulin independence after TP-IAT. Insulin-independent patients had lower mean insulin requirements during the first 24 hours after transplant, possibly relating to the detrimental effect of hyperglycemia on islet function (Ahmad et al., 2006). Of their first 54 CP patients who underwent a TP-IAT ,about two thirds had discontinued narcotics at the time of the report and two-thirds had full or partial islet function, (Ahmad et al., 2006). The most recent report from Cincinnati on their TP-IAT series focuses on 16 patients (out of 118, or 14%) with genetic mutations associated with CP (Sutton et al., 2010)[. At a mean followup of 22 months, 69% of patients had good islet function and 25% were insulin-independent. All were on narcotics before TP-IAT while only 37% were at follow-up and at lower doses.. An SF-36 survey and pain questionnaire in this cohort demonstrated significant improvement in quality of life and reduction or elimination of pain following TP-IAT for genetically linked pancreatitis. The Cincinnati experience shows that patients with painful hereditary pancreatitis respond well to TP-IAT and should be considered for early

The Leicester series of TP-IAT for CP is the third largest in the literature with more than 50 cases since 1996 (Clayton et al., 2003; Garcea et al., 2009; Webb et al., 2008; Ong et al., 2008). Interestingly, early reports from Leicester did not show a correlation between islet yield and insulin independence (Clayton et al., 2003), in contrast to the Minnesota series (Blondet et al., 2007; Sutherland et al., 2009b; Wahoff et al., 1995a). The results may relate to the cause of the CP (mostly alcohol) and possibly to patient compliance issues (Clayton et al., 2003).

The two most recent publications of the Leicester TP-IAT series for CP focus on metabolic outcomes (Webb et al., 2008) and on pain and narcotic reduction or elimination (Garcea et al., 2009), with a comparison in the latter paper to patients with CP who underwent only a TP. In the paper assessing long term IAT graft function in 46 IAT recipients (followup 2-63 months, median 16.5 months), all (100%) were C-peptide function and therefore had functioning islets. Twelve achieved insulin-independence for 2-63 months (median 16.5 months) and 5 remain insulin-independent. Over time insulin requirement tended to increase as did glycohemoglobin levels but all the recipients remained C-peptide positive

quarter of adults and half the children.

intervention in the course of their disease.

**11.1.3 Leicester series**

**11.1.2 Cincinnati series**

In these modern era studies (Braganza et al., 2011; Casadei et al., 2010a) in patients with pain after EDD for CP, TP-IAT gave relief in most, preserved meaningful insulin secretion in three-fourths, and improved QOL in four-fifths. Nearly all would do the TP-IAT again, but that fact that not all would indicates an effort is needed to identify in advance patients who will not be made better. Right now that is difficult to do, so to help the many who can be helped, a few will have to be resigned to failure but the percentage is low, and in this study improvement in quality of life was often strikingly dramatic.

The latest analysis of the Minnesota IAT series of IAT includes >400 cases as of mid**-**2011 (Sutherland et al., 2011b), more than half of them since 2006 (Fig. 3). The results are briefly summarized here.

The etiology of CP in the entire series is currently classified as idiopathic in 44%; sphincter of Oddi dysfunction or biliary in 16%; genetic-in 15%; divisum in 2%; alcohol in only 8%; other in 5%). At least 1 yr follow-up outcomes were available in 313 patients (278 adults, mean age 35.6 yrs,; and 35 children); 74% were female; prior-surgeries had been done in 25%--Peustow- y in 7%, resection in 18%) done before June 2009. Islet-function was considered full for patients insulin-independent; partial if euglycemic on once-daily-insulin; and failed if on a standard-diabetic-regimen even if C-peptide-positive. The SF-36-survey (Quality-of-Life (QOL)) was retrospectively completed by 101 patients done before Sep/2006 and prospectively before and after TP-IAT in 201 patients thereafter.

The results showed actuarial-patient-survival post-TP-IAT was 96% in adults and 98% in children (1-year) and; 89% and 98% (5-years). Overall, IAT-function was achieved in 70% (insulin-independence in 28%); 69% (25%) in adults, 78% (52%) in children. Prior-surgery lowered islet-yield (2712vs4077/kg,p=.003). Islet yield [<2500/kg (38%); 2501-5000/kg (34%); >5000/kg (28%)] correlated with glucose control: full-partial rates at 1-year: 26, 79 and 82%, respectively; insulin-independence rates:5, 41 and 65%. All adults retrospectively (1977-2006) surveyed had pain before TP-IAT and 95% were on daily-narcotics. Afterwards, 94% had pain-improvement and 49% ceased-narcotics. 85% of adults stated QOL improved; 8% stated it was same; 5% said it was worse. All children were on narcotics before, 39% at follow-up; pain improved in 94%; 67% became pain-free. In the prospective-QOL-studysince-2006, there was improvement after TP-IAT in all 8 SF-36-subscale-scores (p<0.001) with the greatest effect on bodily-pain, as was previously reported in another publication (Bellin et al., 2011c).

 In this prospective study of health related quality of life (HRQoL) of patients transplanted since September 2006 (mean age 37, 77% female), prior to surgery, mean Physical Component Score (PCS) was 27 and Mental Component Score (MCS) was 32 (standardized normal=50, SD=10). Both PCS and MCS significantly improved after surgery. At 1 and 2 years, mean PCS scores were 37 and 42 respectively and MCS scores were 42 and 46. Change in PCS from baseline to 1y was greater for children than adults (+15 v. +10). All 8 subscale scores significantly improved over time), with the greatest effect on bodily pain. Children demonstrated more rapid improvement, particularly for bodily pain and role physical.

This prospective study showed meaningful improvement in HRQoL after TPIAT. Although the greatest improvement was in bodily pain, other dimensions of physical, social, and emotional health improved.

This large series, as well as those of others cited above and below, shows definitively that TP can ameliorate pain and improve QOL in patients with otherwise refractory CP, , even if narcotic-withdrawal is delayed or incomplete because of prior long-term use. IAT preserves substantial islet-function in >2/3 of patients with insulin-independence occurring in a quarter of adults and half the children.

#### **11.1.2 Cincinnati series**

120 Chronic Pancreatitis

In these modern era studies (Braganza et al., 2011; Casadei et al., 2010a) in patients with pain after EDD for CP, TP-IAT gave relief in most, preserved meaningful insulin secretion in three-fourths, and improved QOL in four-fifths. Nearly all would do the TP-IAT again, but that fact that not all would indicates an effort is needed to identify in advance patients who will not be made better. Right now that is difficult to do, so to help the many who can be helped, a few will have to be resigned to failure but the percentage is low, and in this study

The latest analysis of the Minnesota IAT series of IAT includes >400 cases as of mid**-**2011 (Sutherland et al., 2011b), more than half of them since 2006 (Fig. 3). The results are briefly

The etiology of CP in the entire series is currently classified as idiopathic in 44%; sphincter of Oddi dysfunction or biliary in 16%; genetic-in 15%; divisum in 2%; alcohol in only 8%; other in 5%). At least 1 yr follow-up outcomes were available in 313 patients (278 adults, mean age 35.6 yrs,; and 35 children); 74% were female; prior-surgeries had been done in 25%--Peustow- y in 7%, resection in 18%) done before June 2009. Islet-function was considered full for patients insulin-independent; partial if euglycemic on once-daily-insulin; and failed if on a standard-diabetic-regimen even if C-peptide-positive. The SF-36-survey (Quality-of-Life (QOL)) was retrospectively completed by 101 patients done before

The results showed actuarial-patient-survival post-TP-IAT was 96% in adults and 98% in children (1-year) and; 89% and 98% (5-years). Overall, IAT-function was achieved in 70% (insulin-independence in 28%); 69% (25%) in adults, 78% (52%) in children. Prior-surgery lowered islet-yield (2712vs4077/kg,p=.003). Islet yield [<2500/kg (38%); 2501-5000/kg (34%); >5000/kg (28%)] correlated with glucose control: full-partial rates at 1-year: 26, 79 and 82%, respectively; insulin-independence rates:5, 41 and 65%. All adults retrospectively (1977-2006) surveyed had pain before TP-IAT and 95% were on daily-narcotics. Afterwards, 94% had pain-improvement and 49% ceased-narcotics. 85% of adults stated QOL improved; 8% stated it was same; 5% said it was worse. All children were on narcotics before, 39% at follow-up; pain improved in 94%; 67% became pain-free. In the prospective-QOL-studysince-2006, there was improvement after TP-IAT in all 8 SF-36-subscale-scores (p<0.001) with the greatest effect on bodily-pain, as was previously reported in another publication

 In this prospective study of health related quality of life (HRQoL) of patients transplanted since September 2006 (mean age 37, 77% female), prior to surgery, mean Physical Component Score (PCS) was 27 and Mental Component Score (MCS) was 32 (standardized normal=50, SD=10). Both PCS and MCS significantly improved after surgery. At 1 and 2 years, mean PCS scores were 37 and 42 respectively and MCS scores were 42 and 46. Change in PCS from baseline to 1y was greater for children than adults (+15 v. +10). All 8 subscale scores significantly improved over time), with the greatest effect on bodily pain. Children demonstrated more rapid improvement, particularly for bodily pain and role physical.

This prospective study showed meaningful improvement in HRQoL after TPIAT. Although the greatest improvement was in bodily pain, other dimensions of physical, social, and

Sep/2006 and prospectively before and after TP-IAT in 201 patients thereafter.

improvement in quality of life was often strikingly dramatic.

summarized here.

(Bellin et al., 2011c).

emotional health improved.

The Cincinnati series of TP-IAT cases (Ahmad et al., 2005; Ahmad et al., 2006; Sutton et al., 2010) is the second largest in the literature with their latest report including 118 cases (Sutton et al., 2010). The early reports from this group (Ahmad et al., 2005; Ahmad et al., 2006) showed a 40% rate of insulin independence after TP/IAT, with a mean follow-up of 18 months. Factors that correlated with postoperative insulin independence included the patient's weight, body mass index (BMI), and gender (Rodriguez Rilo et al., 2003). Patients who had a BMI greater than 28 had a higher chance of insulin dependence (Rodriguez Rilo et al., 2003). Reduction to ideal body weight to minimize insulin resistance may maximize the chance for insulin independence after TP-IAT. Insulin-independent patients had lower mean insulin requirements during the first 24 hours after transplant, possibly relating to the detrimental effect of hyperglycemia on islet function (Ahmad et al., 2006). Of their first 54 CP patients who underwent a TP-IAT ,about two thirds had discontinued narcotics at the time of the report and two-thirds had full or partial islet function, (Ahmad et al., 2006). The most recent report from Cincinnati on their TP-IAT series focuses on 16 patients (out of 118, or 14%) with genetic mutations associated with CP (Sutton et al., 2010)[. At a mean followup of 22 months, 69% of patients had good islet function and 25% were insulin-independent. All were on narcotics before TP-IAT while only 37% were at follow-up and at lower doses.. An SF-36 survey and pain questionnaire in this cohort demonstrated significant improvement in quality of life and reduction or elimination of pain following TP-IAT for genetically linked pancreatitis. The Cincinnati experience shows that patients with painful hereditary pancreatitis respond well to TP-IAT and should be considered for early intervention in the course of their disease.

#### **11.1.3 Leicester series**

The Leicester series of TP-IAT for CP is the third largest in the literature with more than 50 cases since 1996 (Clayton et al., 2003; Garcea et al., 2009; Webb et al., 2008; Ong et al., 2008). Interestingly, early reports from Leicester did not show a correlation between islet yield and insulin independence (Clayton et al., 2003), in contrast to the Minnesota series (Blondet et al., 2007; Sutherland et al., 2009b; Wahoff et al., 1995a). The results may relate to the cause of the CP (mostly alcohol) and possibly to patient compliance issues (Clayton et al., 2003).

The two most recent publications of the Leicester TP-IAT series for CP focus on metabolic outcomes (Webb et al., 2008) and on pain and narcotic reduction or elimination (Garcea et al., 2009), with a comparison in the latter paper to patients with CP who underwent only a TP. In the paper assessing long term IAT graft function in 46 IAT recipients (followup 2-63 months, median 16.5 months), all (100%) were C-peptide function and therefore had functioning islets. Twelve achieved insulin-independence for 2-63 months (median 16.5 months) and 5 remain insulin-independent. Over time insulin requirement tended to increase as did glycohemoglobin levels but all the recipients remained C-peptide positive

Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis 123

One long-term study of metabolic outcomes in six TP-IAT recipients from the authors' center reported that diabetes mellitus was prevented for up to 13 (now 20) years (mean follow-up at study, 6.2 plus or minus 1.7 years) (Robertson et al., 2001). Normal fasting plasma glucose, intravenous glucose disappearance rate (κĢ), hemoglobin A1c, insulin responses to intravenous glucose and arginine, and insulin secretory reserve were maintained, but insulin responses tended to decrease over time. The intravenous glucose disappearance rate correlated with the number of islets transplanted (Robertson et al., 2001). Another study showed reduced functional β-cell secretory reserve in IAT recipients, as compared with healthy individuals (Teuscher et al., 1998). Still another study showed that intrahepatic islet grafts failed to secrete glucagon in response to sustained hypoglycemia, but did in response to arginine, a peculiarity that may be site-dependent (Kendall et al., 1997). However, a study in dogs by another group indicated that alpha cell function was normal in the liver but not the omentum and spleen (Gustavson et al., 2005), so there are contradictory results Nonetheless, intraportal islet autografts at least release of insulin

In regard to IAT durability, there are case reports in which a long-functioning graft failed when the patient was given steroids for some reason, and often not an essential reason, with glucose toxicity killing the beta cells before it was realized that insulin to protect the stressed islets needed to be given (Ngo et al., 2011). Steroids should nearly never be administered to an IAT recipient. If there is a compelling reason to do so, insulin must be started or

It should also be mentioned that exocrine deficiency can be a serious problem after TP, with or without an IAT (Stauffer et al., 2009), and unpredictable absorption can make diabetic management more difficult (Bellin et al., 2009). Exocrine deficiency has more of an impact on diabetic management after TP in those who do not than those that do have an IAT, especially those who are insulin-independent. Patients rank exocrine deficiency more of a problem than endocrine deficiency after TP-IAT (Braganza et al., 2011; Sutherland et al.,

Health-related QOL is significantly worse in patients who have CP, as compared with a gender- and age-adjusted general population (Berney et al, 2000). The primary goal in performing TP-IAT is to improve QOL by alleviating pain and giving patients a chance to discontinue narcotics, while preventing or minimizing surgical diabetes. Studies evaluating health-related QOL outcomes after TP-IAT have been recently published. In reports from Cincinnati, QOL as measured by a standard assessment tool (SF-36) showed significant improvement a mean follow-up of .19 months (Rodriguez Rilo et al., 2003), and these

Prospective studies of quality of life before and after TP-IAT have been conducted at the University Of Minnesota in both children (Bellin et al., 2011a) and adults (Bellin et al., 2011b). Both show significant improvement in QOL, as detailed above in the section on this

increased the moment steroids are begun in order to maintain euglycemia.

findings were confirmed as more patients were included (Sutton et al., 2010).

**12. Long-term metabolic outcomes**

appropriately (Pyzdrowski et al., 1992).

**13. Quality of life and pain relief**

2011b).

institution.

for up to 10 years (maximum follow-up). They also assessed renal function over time and it was stable in all suggesting diabetic nephropathy did not occur to any significant degree. The main point of the paper was that even though a decline in IAT function over time could be detected, total loss of function did not occur and protection against diabetic complications was likely (Webb et al., 2008).

In the other recent paper from Leicester (Garcea et al., 2009) the focus was on a comparison of 85 patients who underwent TP for CP, 50 with and 35 without an IAT. In the entire series, 90% of patients were on narcotics at the time of surgery; it fell to 40% by one year and 16% by 5 years. At 5 years insulin requirements were significantly lower in the IAT group, median of 16 units per 24 hours vs. 40 units in the TP alone group and 5 patients in the IAT group were insulin-independent.

The Leicester series complements those of other centers, as described above in the previous sections, in showing the effectiveness of TP in reducing or eliminating the pain of CP and in documenting the metabolic benefit of adding an IAT to the procedure.

#### **11.2 Comments**

Insulin independence is only partially the goal of an IAT, because preserving any β-cell mass is beneficial (Pezzilli, 2006; Robertson, 2010a). Indeed, islet allograft recipients who remain insulin dependent but have β-cell function and are C-peptide positive are metabolically more stable and less prone to hypoglycemic unawareness than those who have no β-cell function ( Jahansouz et al., 2011; Paty et al., 2006; Robertson, 2010b; Ryan et al., 2002; Ryan et al., 2005). Furthermore, the risk of secondary complications is less in diabetics who receive or are C-peptide-positive (Jahansouz et al., 2011; Johansson et al., 2000; Kamiya et al., 2004). By extrapolation, IAT recipients who are C-peptide-positive, even with an insulin requirement, have a metabolic advantage (Dong et al., 2011). Although only about one-third or less of IAT recipients in the various series are insulin-independent longterm; another third have enough islets to achieve near-normoglycemia with exogenous insulin, usually with one injection daily of the long-acting variety (Bellin et al., 2009; Jie et al., 2005; Sutherland et al., 2009b; Sutherland et al., 2011b), and even those who are on basalbolus insulin regimens are usually C-peptide positive in the modern era (Sutherland et al., 2011b; Webb et al., 2008).

Although about one third of IAT recipients in the various series require a basal-bolus insulin regimen because of low viable islet yield (Jie et al., 2005; Sutherland et al., 2004a; Sutherland et al., 2011b), as long as pain is relieved or improved, the operation is considered a success. One should only do a TP-IAT in patients who are fully informed about the risk of becoming diabetic, and who accept this risk in exchange for reasonable chances at both pain reduction and narcotic withdrawal. Some patients who became fully diabetic after TP-IAT because of inadequate viable islet yield, and who were particularly labile, have gone on to have a pancreas (allograft) transplant, and thus achieved insulin independence (Gruessner et al., 2004; Gruessner et al., 2008), but at the expense of needing immunosuppression (Sutherland et al., 2001).. An islet allograft also could be done in this situation (Sakata et al., 2008), but an enteric-drained pancreas transplant is more attractive, because exocrine deficiency also can be corrected (Gruessner et al., 2004; Gruessner et al., 2008).

### **12. Long-term metabolic outcomes**

122 Chronic Pancreatitis

for up to 10 years (maximum follow-up). They also assessed renal function over time and it was stable in all suggesting diabetic nephropathy did not occur to any significant degree. The main point of the paper was that even though a decline in IAT function over time could be detected, total loss of function did not occur and protection against diabetic

In the other recent paper from Leicester (Garcea et al., 2009) the focus was on a comparison of 85 patients who underwent TP for CP, 50 with and 35 without an IAT. In the entire series, 90% of patients were on narcotics at the time of surgery; it fell to 40% by one year and 16% by 5 years. At 5 years insulin requirements were significantly lower in the IAT group, median of 16 units per 24 hours vs. 40 units in the TP alone group and 5 patients in the IAT

The Leicester series complements those of other centers, as described above in the previous sections, in showing the effectiveness of TP in reducing or eliminating the pain of CP and in

Insulin independence is only partially the goal of an IAT, because preserving any β-cell mass is beneficial (Pezzilli, 2006; Robertson, 2010a). Indeed, islet allograft recipients who remain insulin dependent but have β-cell function and are C-peptide positive are metabolically more stable and less prone to hypoglycemic unawareness than those who have no β-cell function ( Jahansouz et al., 2011; Paty et al., 2006; Robertson, 2010b; Ryan et al., 2002; Ryan et al., 2005). Furthermore, the risk of secondary complications is less in diabetics who receive or are C-peptide-positive (Jahansouz et al., 2011; Johansson et al., 2000; Kamiya et al., 2004). By extrapolation, IAT recipients who are C-peptide-positive, even with an insulin requirement, have a metabolic advantage (Dong et al., 2011). Although only about one-third or less of IAT recipients in the various series are insulin-independent longterm; another third have enough islets to achieve near-normoglycemia with exogenous insulin, usually with one injection daily of the long-acting variety (Bellin et al., 2009; Jie et al., 2005; Sutherland et al., 2009b; Sutherland et al., 2011b), and even those who are on basalbolus insulin regimens are usually C-peptide positive in the modern era (Sutherland et al.,

Although about one third of IAT recipients in the various series require a basal-bolus insulin regimen because of low viable islet yield (Jie et al., 2005; Sutherland et al., 2004a; Sutherland et al., 2011b), as long as pain is relieved or improved, the operation is considered a success. One should only do a TP-IAT in patients who are fully informed about the risk of becoming diabetic, and who accept this risk in exchange for reasonable chances at both pain reduction and narcotic withdrawal. Some patients who became fully diabetic after TP-IAT because of inadequate viable islet yield, and who were particularly labile, have gone on to have a pancreas (allograft) transplant, and thus achieved insulin independence (Gruessner et al., 2004; Gruessner et al., 2008), but at the expense of needing immunosuppression (Sutherland et al., 2001).. An islet allograft also could be done in this situation (Sakata et al., 2008), but an enteric-drained pancreas transplant is more attractive, because exocrine deficiency also can

be corrected (Gruessner et al., 2004; Gruessner et al., 2008).

documenting the metabolic benefit of adding an IAT to the procedure.

complications was likely (Webb et al., 2008).

group were insulin-independent.

**11.2 Comments**

2011b; Webb et al., 2008).

One long-term study of metabolic outcomes in six TP-IAT recipients from the authors' center reported that diabetes mellitus was prevented for up to 13 (now 20) years (mean follow-up at study, 6.2 plus or minus 1.7 years) (Robertson et al., 2001). Normal fasting plasma glucose, intravenous glucose disappearance rate (κĢ), hemoglobin A1c, insulin responses to intravenous glucose and arginine, and insulin secretory reserve were maintained, but insulin responses tended to decrease over time. The intravenous glucose disappearance rate correlated with the number of islets transplanted (Robertson et al., 2001). Another study showed reduced functional β-cell secretory reserve in IAT recipients, as compared with healthy individuals (Teuscher et al., 1998). Still another study showed that intrahepatic islet grafts failed to secrete glucagon in response to sustained hypoglycemia, but did in response to arginine, a peculiarity that may be site-dependent (Kendall et al., 1997). However, a study in dogs by another group indicated that alpha cell function was normal in the liver but not the omentum and spleen (Gustavson et al., 2005), so there are contradictory results Nonetheless, intraportal islet autografts at least release of insulin appropriately (Pyzdrowski et al., 1992).

In regard to IAT durability, there are case reports in which a long-functioning graft failed when the patient was given steroids for some reason, and often not an essential reason, with glucose toxicity killing the beta cells before it was realized that insulin to protect the stressed islets needed to be given (Ngo et al., 2011). Steroids should nearly never be administered to an IAT recipient. If there is a compelling reason to do so, insulin must be started or increased the moment steroids are begun in order to maintain euglycemia.

It should also be mentioned that exocrine deficiency can be a serious problem after TP, with or without an IAT (Stauffer et al., 2009), and unpredictable absorption can make diabetic management more difficult (Bellin et al., 2009). Exocrine deficiency has more of an impact on diabetic management after TP in those who do not than those that do have an IAT, especially those who are insulin-independent. Patients rank exocrine deficiency more of a problem than endocrine deficiency after TP-IAT (Braganza et al., 2011; Sutherland et al., 2011b).

### **13. Quality of life and pain relief**

Health-related QOL is significantly worse in patients who have CP, as compared with a gender- and age-adjusted general population (Berney et al, 2000). The primary goal in performing TP-IAT is to improve QOL by alleviating pain and giving patients a chance to discontinue narcotics, while preventing or minimizing surgical diabetes. Studies evaluating health-related QOL outcomes after TP-IAT have been recently published. In reports from Cincinnati, QOL as measured by a standard assessment tool (SF-36) showed significant improvement a mean follow-up of .19 months (Rodriguez Rilo et al., 2003), and these findings were confirmed as more patients were included (Sutton et al., 2010).

Prospective studies of quality of life before and after TP-IAT have been conducted at the University Of Minnesota in both children (Bellin et al., 2011a) and adults (Bellin et al., 2011b). Both show significant improvement in QOL, as detailed above in the section on this institution.

Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis 125

pancreatic cancer developing in a liver after IAT when the TP is done for benign disease,

A basic but important limitation to more widespread clinical application of IATs is the limited number of centers with the facilities and technology to isolate and prepare human islets. Few centers, including the authors', have used distance processing for both allogenic and autologous islets successfully (Langer et al., 2004; Rabkin et al., 1999; Rabkin et al., 1997). The feasibility of distance processing is enhanced by new preservation methods that extend cold ischemic times and increase islet yield and viability from suboptimal organs (Farrow & Evers, 2002; Fraker et al., 2002; Fujino et al., 1991; Langer et al, 2004; Lowenfels et al., 1993; Liang et al, 2006; Matsuda et al, 2003; Matsumoto, 2011; Mercadante,2005; Rabkin et al., 1997; Rabkin et al., 1999; Tsujimura et al., 2004; Tsujimura Tet al, 2004b; Whitcomb,

The long-term success of IATs in patients who have CP (Robertson et al., 2001) contrasts with the apparently less favorable long-term results for islet allotransplants in patients who have type 1 diabetes mellitus (Jahansouz et al., 2011; Ryan et al., 2005; Sabeck et al., 2009; Sutherland et al., 2008;), though in some center durable function does occur (Bellin et al., 2008b). The difference in outcomes may be because of the rejection rate of islet allografts, or if allografts are not rejected, to the diabetogenic effect of the necessary immunosuppression

Autologous islets are as fresh as possible. They are isolated from a pancreas that, although diseased, is not under the stress of brain death (which in animal models decreases islet yield and function by the activation of proinflammatory cytokines that occurs from central nervous system (CNS) injury (Contreras et al, 2003). A native pancreas removed for IAT also is not subjected to prolonged ischemia or to hours of cold preservation that occur with

Single-donor islet allografts have resulted in insulin independence in diabetic recipients at UMN (Bellin et al., 2008b; Hering et al., 2005); yet in many cases, multiple donors are required (Jahansouz et al., 2011; Sutherland et al., 2004b). Increasing islet viability for transplants is important; for allografts, one possibility is to use a living donor (Matsumoto et al., 2005; Sutherland et al., 1980a; Sutherland et al., 1980b). This approach should be effective, given the good outcomes in IAT recipients with an islet mass well below that required for a successful outcome with deceased donor islet allografts (Sutherland, 2005;

A comparison of outcomes for IAT and ilset allogfafts provides an opportunity to distinguish between immunologic and nonimmunologic factors that affect declines in, or sustenance of, islet graft function over time. Whatever the variables, it is apparent that currently IATs are more successful than their allogenic counterparts (Sutherland et al., 2008)

TP-IAT has been used to treat painful CP for over 30 years. IAT is safe and prevents or minimizes surgical diabetes after TP for CP or even neoplastic disease in which a non-

including genetically linked CP (Sutton et al., 2010), is likely very low.

**15. Future directions**

(Jahansouz et al., 2011).

Sutherland et al., 2008).

**16. Summary**

2004; Whitcomb & Pogue-Geile, 2002).

deceased donor pancreases processed for allogenic islets.

As far as abdominal pain from CP that is refractory to high-dose narcotics, the Cincinatti group has published pain scores as assessed before after TP-IAT (Ahmad et al., 2005; Rodriguez Rilo et al., 2003). Narcotic independence was achieved in nearly two-thirds of patients after surgery, with a marked reduction in narcotic use by pre- and postoperative morphine-equivalent determinations (Ahmad et al., 2005).

These findings are similar to those in the University of Minnesota series with pain resolved or improved in nearly all and more than two-thirds able to eliminate narcotics while the remainder needed reduced doses (Bellin et al., 2011c;Carlson et al., 2007; Jie et al., 2005; Sutherland et al., 2009a; Sutherland et al., 2011b; Wahoff et al., 1995a) . Similar pain relief statistics are reported for CP patients undergoing TP without IAT (Behrman & Mulloy, 2006; Casadei et al., 2010b; Stauffer et al., 2009).

 The patients who cannot withdraw completely from narcotics after TP usually have opioidinduced hyperalgesia (OIH) (Angst & Clark, 2006) from long term use prior to the surgery, a reason to not delay once it is apparent that a patient needs narcotics for pain in spite of other measures to treat the CP. Patients with OIH, are paradoxically become more sensitive to pain, by means of mechanisms originating in afferent neurons and in the spinal cord (Angst & Clark, 2006; Chuet al., 2006; Dogrul et al, 2005; Gardell et al, 2006; Liang et al, 2006; Mercadante , 2005). OIH may be highly prevalent in patients with long-standing CP and on narcotics for years before being referred for TP-IAT; accordingly, an endpoint such as narcotic independence may not be ideal for assessing postoperative success.

#### **14. Cancer risk of chronic pancreatitis patients**

The association between longstanding CP and cancer has been established (Ahmad et al., 2006; Braganza et al., 2011; Farrow & Evers , 2002; Lowenfels et al., 1993; Whitcomb & Pogue-Geile , 2002; Whitcomb, 2004). It is believed that pancreatic cancer develops in the setting of CP, independent of the underlying etiology, but appears to require 30 to 40 years of inflammation before manifesting in an appreciable percentage of patients (Whitcomb, 2004). This increased risk for pancreatic cancer is potentiated by cofactors such as tobacco and likely by genetic factors that are not yet entirely identified (Whitcomb & Pogue-Geile, 2002; Whitcomb DC, 2004).

A TP by itself for CP completely eliminates the risk of pancreatic cancer, but even with an IAT, the risk is lowered considerably, given the marked reduction in pancreatic tissue. The autologous islets infused into the portal system are never totally pure, but the use of tissue at risk for pancreatic cancer must be minimal. Sampling the whole gland for pathologic testing is impossible in the setting of an IAT. Patients who have hereditary and tropical pancreatitis are at higher risk for developing malignant cells than the rest of CP population (Farrow & Evers, 2002; Whitcomb DC, 2004) but again the amount of residual pancreatic tissue after TP-IAT is very small.

In the entire series of TP-IAT patients from UMN, no patients are known to have developed cancer in the liver or in any other site where the islets were auto-grafted, so the risk of cancer appears to be extremely low. In one case of IAT after a TP for pancreatic adenocarcinoma, cancer was not found in the liver at an autopsy two years later in which the patient died with metastatic disease elsewhere (Forster et al., 2004). Thus, the risk of pancreatic cancer developing in a liver after IAT when the TP is done for benign disease, including genetically linked CP (Sutton et al., 2010), is likely very low.

#### **15. Future directions**

124 Chronic Pancreatitis

As far as abdominal pain from CP that is refractory to high-dose narcotics, the Cincinatti group has published pain scores as assessed before after TP-IAT (Ahmad et al., 2005; Rodriguez Rilo et al., 2003). Narcotic independence was achieved in nearly two-thirds of patients after surgery, with a marked reduction in narcotic use by pre- and postoperative

These findings are similar to those in the University of Minnesota series with pain resolved or improved in nearly all and more than two-thirds able to eliminate narcotics while the remainder needed reduced doses (Bellin et al., 2011c;Carlson et al., 2007; Jie et al., 2005; Sutherland et al., 2009a; Sutherland et al., 2011b; Wahoff et al., 1995a) . Similar pain relief statistics are reported for CP patients undergoing TP without IAT (Behrman & Mulloy, 2006;

 The patients who cannot withdraw completely from narcotics after TP usually have opioidinduced hyperalgesia (OIH) (Angst & Clark, 2006) from long term use prior to the surgery, a reason to not delay once it is apparent that a patient needs narcotics for pain in spite of other measures to treat the CP. Patients with OIH, are paradoxically become more sensitive to pain, by means of mechanisms originating in afferent neurons and in the spinal cord (Angst & Clark, 2006; Chuet al., 2006; Dogrul et al, 2005; Gardell et al, 2006; Liang et al, 2006; Mercadante , 2005). OIH may be highly prevalent in patients with long-standing CP and on narcotics for years before being referred for TP-IAT; accordingly, an endpoint such as

The association between longstanding CP and cancer has been established (Ahmad et al., 2006; Braganza et al., 2011; Farrow & Evers , 2002; Lowenfels et al., 1993; Whitcomb & Pogue-Geile , 2002; Whitcomb, 2004). It is believed that pancreatic cancer develops in the setting of CP, independent of the underlying etiology, but appears to require 30 to 40 years of inflammation before manifesting in an appreciable percentage of patients (Whitcomb, 2004). This increased risk for pancreatic cancer is potentiated by cofactors such as tobacco and likely by genetic factors that are not yet entirely identified (Whitcomb & Pogue-Geile,

A TP by itself for CP completely eliminates the risk of pancreatic cancer, but even with an IAT, the risk is lowered considerably, given the marked reduction in pancreatic tissue. The autologous islets infused into the portal system are never totally pure, but the use of tissue at risk for pancreatic cancer must be minimal. Sampling the whole gland for pathologic testing is impossible in the setting of an IAT. Patients who have hereditary and tropical pancreatitis are at higher risk for developing malignant cells than the rest of CP population (Farrow & Evers, 2002; Whitcomb DC, 2004) but again the amount of residual pancreatic

In the entire series of TP-IAT patients from UMN, no patients are known to have developed cancer in the liver or in any other site where the islets were auto-grafted, so the risk of cancer appears to be extremely low. In one case of IAT after a TP for pancreatic adenocarcinoma, cancer was not found in the liver at an autopsy two years later in which the patient died with metastatic disease elsewhere (Forster et al., 2004). Thus, the risk of

narcotic independence may not be ideal for assessing postoperative success.

**14. Cancer risk of chronic pancreatitis patients**

morphine-equivalent determinations (Ahmad et al., 2005).

Casadei et al., 2010b; Stauffer et al., 2009).

2002; Whitcomb DC, 2004).

tissue after TP-IAT is very small.

A basic but important limitation to more widespread clinical application of IATs is the limited number of centers with the facilities and technology to isolate and prepare human islets. Few centers, including the authors', have used distance processing for both allogenic and autologous islets successfully (Langer et al., 2004; Rabkin et al., 1999; Rabkin et al., 1997). The feasibility of distance processing is enhanced by new preservation methods that extend cold ischemic times and increase islet yield and viability from suboptimal organs (Farrow & Evers, 2002; Fraker et al., 2002; Fujino et al., 1991; Langer et al, 2004; Lowenfels et al., 1993; Liang et al, 2006; Matsuda et al, 2003; Matsumoto, 2011; Mercadante,2005; Rabkin et al., 1997; Rabkin et al., 1999; Tsujimura et al., 2004; Tsujimura Tet al, 2004b; Whitcomb, 2004; Whitcomb & Pogue-Geile, 2002).

The long-term success of IATs in patients who have CP (Robertson et al., 2001) contrasts with the apparently less favorable long-term results for islet allotransplants in patients who have type 1 diabetes mellitus (Jahansouz et al., 2011; Ryan et al., 2005; Sabeck et al., 2009; Sutherland et al., 2008;), though in some center durable function does occur (Bellin et al., 2008b). The difference in outcomes may be because of the rejection rate of islet allografts, or if allografts are not rejected, to the diabetogenic effect of the necessary immunosuppression (Jahansouz et al., 2011).

Autologous islets are as fresh as possible. They are isolated from a pancreas that, although diseased, is not under the stress of brain death (which in animal models decreases islet yield and function by the activation of proinflammatory cytokines that occurs from central nervous system (CNS) injury (Contreras et al, 2003). A native pancreas removed for IAT also is not subjected to prolonged ischemia or to hours of cold preservation that occur with deceased donor pancreases processed for allogenic islets.

Single-donor islet allografts have resulted in insulin independence in diabetic recipients at UMN (Bellin et al., 2008b; Hering et al., 2005); yet in many cases, multiple donors are required (Jahansouz et al., 2011; Sutherland et al., 2004b). Increasing islet viability for transplants is important; for allografts, one possibility is to use a living donor (Matsumoto et al., 2005; Sutherland et al., 1980a; Sutherland et al., 1980b). This approach should be effective, given the good outcomes in IAT recipients with an islet mass well below that required for a successful outcome with deceased donor islet allografts (Sutherland, 2005; Sutherland et al., 2008).

A comparison of outcomes for IAT and ilset allogfafts provides an opportunity to distinguish between immunologic and nonimmunologic factors that affect declines in, or sustenance of, islet graft function over time. Whatever the variables, it is apparent that currently IATs are more successful than their allogenic counterparts (Sutherland et al., 2008)

#### **16. Summary**

TP-IAT has been used to treat painful CP for over 30 years. IAT is safe and prevents or minimizes surgical diabetes after TP for CP or even neoplastic disease in which a non-

Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis 127

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