Chronic pancreatitis (CP) is a long-standing inflammation of the pancreas that alters its normal structure and functions (1, 2). Approximately 15,000 Americans are diagnosed with CP each year. Current therapies for CP patients focus on pain relief medically, endoscopically, and surgically (by resection of diseased parenchyma and drainage of obstructed ducts) (3). The latter includes several commonly used operations, including transduodenal sphincteroplasty (TDS), Whipple or Beger procedure (WB), distal pancreatectomy (DP), and lateral pancreaticojejunostomy (LPJ). TDS is a procedure to resolve obstruction at the ampulla/sphincter, in which an incision is made through the duodenum and the pancreatic and bile ducts are identified and sewn open widely to allow for proper drainage (4). The Whipple procedure consists of the removal of the distal segment of the stomach, first and second portions of the duodenum, the head of the pancreas, the common bile duct, and the gallbladder. The Beger procedure involves the removal of the head of the pancreas with preservation of the duodenum, stomach, and bile duct. DP allows for proper drainage of the neck region of the pancreas by removal of the tail and body of the pancreas. LPJ involves excising the entire pancreatic duct lengthwise and suturing it into the intestine to allow direct drainage into the intestine (5).
Controlling pain in CP patients with medications and the above-mentioned surgeries is successful approximately 80% of the time over the short-term (3, 6–8). In patients with intractable pain and those with diffuse small duct diseases, total pancreatectomy with islet autotransplantation (TP-IAT) can be an ideal treatment option.
Compared with other treatment options for CP, TP-IAT has a higher potential to eliminate pancreatic pain without total sacrifice of the endocrine function of the pancreas. This procedure is currently performed in several centers across the United States, Australia, and Europe. Data from other studies and our own show that TP in combination with IAT is a safe and effective option for patients with end stage CP (9–15). Improved quality of life and decreased requirement for narcotic analgesics were shown after TP-IAT. A significant percentage of patients are diabetes free, with some being insulin independent for the rest of their lives (16, 17). All patients who do require insulin have hypoglycemic awareness and are shown to have improved metabolic control and quality of life. Nonetheless, because the etiology of pancreatic pain is extremely complex and poorly understood, TP-IAT is not currently being considered first line of treatment for most CP patients. However, because resection and drainage procedures can damage pancreatic islets and affect harvest (due to lower achievable intraductual pressures) and yield (due to lower available parenchyma), further data are needed to help identify the patient population who can benefit the most from each procedure and to explore and better understand the potential downsides of advising a conservative resection or drainage procedure before a TP-IAT vs. TP-IAT alone is undertaken in selected patients to achieve optimal outcome.
We undertook this study to investigate how different types of surgeries performed before TP-IAT determines final islet yield and insulin requirement in patients after TP-IAT. Such information is crucial for physicians and patients to choose the optimal therapy for patients with CP.
Prior Surgery Versus Pancreas Quality
To evaluate the effect of prior surgeries on the extent of tissue fibrosis, each pancreas was examined in the pathology laboratory using a semiquantitative score system. As shown in Table 1, in TDS/no prior surgery (NPS) patients, 41.67% of the pancreases were soft, 41.67% were moderate, and the other 16.67% were hard (n=48; data from two patients were missing). The majority of pancreases (64.4%; n=14) from patients who had WB procedures were moderate in fibrosis and had the least number of severely fibrotic tissues (7.14%) compared with those from other groups. In contrast, the majority of the pancreases (87.5%; n=8) derived from patients who had DP were severely fibrotic, with one being moderate in fibrosis. Pancreases from patients who had LPJ tended to be harder as well (50% of them were moderate and 25% were hard; n=4), which correlated with significantly longer disease duration in this group of patients (see Table S1, SDC, http://links.lww.com/TP/A780).
Type of Surgery Versus Islet Yield
Total islet yield from each patient was assessed in aliquots from final islet preparation. On average, the islet equivalent (IEQ) number obtained from the different patient population was 364,344±268,504 (range, 4288–1,168,725) for TDS/NPS, 206,975±213,640 (range, 14,312–816,425) for WB, 113,689±191,492 (range, 969–534,015) for DP, and 37,418±26,835 (range, 3667–64,562) for LPJ. There is a significant difference of islet yield among different groups as analyzed by the analysis of variance test (P<0.001). The IEQ/kg body weight transplanted were also significantly different among different groups (P<0.05), with 4980±3791 (range, 49–16,010) for patients in the TDS/NPS group, 3163±3962 (range, 235–15,404) for patients in the WB group, and 1011±1421 (range, 14–3317) and 579±408 (range, 61–1058) for patients who had DP or LPJ, respectively (Fig. 1A). The differences among the groups on IEQ/kg appeared driven by the difference between TDS/NPS/WB and DP/LPJ. We also measured the final pellet weight after islet harvest. The value was 16.44±11.39 g for TDS/NPS and 3.84±4.54 g for LPJ patients, which was significantly different (P=0.002). However, the pellet weights in patients who had WB and DP were very similar, at 7.41±5.57 and 6.20±9.53 g, respectively (Fig. 1B), although the islet yield was significantly higher in those who had WB.
Prior Surgery Versus Elapsed Time From Tissue Excision to Islet Transplantation
The average time elapsed from pancreas excision to islet reinfusion into the patient was 314.24±52.44 min for TDS/NPS patients, 289.00±32.40 min for WB patients, 292.38±84.55 min for DP patients, and 280.50±24.57 min for LPJ patients (Fig. 2). Thus, it seems that longer time is needed to process the pancreas from TDS/NPS patients than pancreases from the other groups. If anything, this potential confounding would have lowered yield in TDS/NPS patients compared with patients with prior resections.
Type of Surgery Versus Insulin Requirement Before and After Operation
To evaluate the function of transplanted islets, daily insulin requirements were measured before surgery, at discharge after TP-IAT, and 6 months after surgery. As shown in Fig. 3A, most patients who had TDS/NPS and WB procedures were diabetes free before TP-IAT compared with only 50% of the patients who were diabetes free in the DP and LPJ groups. At 6 months after surgery, the diabetes-free rate was 46% in the TDS/NPS group (n=50), 43% in the WB group (n=14), and 25% in the DP group (n=8; Fig. 3B). In addition, 20% of the TDS/NPS group, 14% of the WB group, and 25% of the LPJ group required less than 10 U per day of daily insulin at 6 months after surgery. All four patients from the LPJ group required insulin treatment.
Among the patients requiring insulin on a daily basis, the average insulin requirements at 6 months ranged from 22 to 35 U per day, which was not significantly different between the groups (Fig. 4A). Most TDS/NPS and WB patients have detectable C-peptide value 6 months after surgery (Fig. 4B) and had a relatively lower HbA1c level (Fig. 4C). In contrast, patients in the DP group had the highest HbA1c level and the lowest proportion of patients with detectable C-peptide compared with those who had TDS/NPS and WB preoperatively.
TP-IAT is currently undertaken to attempt to eliminate pancreatic pain, while avoiding surgically induced diabetes, in selected patients with end-stage CP. Long-term pain relief and glycemic control have been achieved in a high percentage of patients (18–20). However, this procedure is currently not the first-line surgical therapy for CP patients partly due to operative morbidity and lack of data to predict outcomes, especially in patients with earlier disease (21–23). Thus, indicators that can predict the outcomes of TP-IAT are urgently needed for the advancement of this field. Studies have shown that the degree of histopathologic changes and stimulated C-peptide level before surgery determine islet yield (24–26). Our study showed strong evidence that prior pancreatic surgery before TP-IAT can affect islet yield and insulin requirement after TP-IAT. Although it has been observed that patients who have had DP or LPJ procedures have lower islet yield and a lower rate of insulin independence (27), this is the first detailed report that compares side-by-side how different commonly used surgeries predict islet yield and graft function after TP-IAT.
In our patient population, we observed a strong correlation between types of prior surgeries and total islet yield per pancreas. First, surgeries involving resection of pancreatic parenchyma, not surprisingly, negatively affected islet yield, that is, pancreas from patients in TDS/NPS group had the highest islet yield compared with other groups. TDS and NPS patients were grouped together here because there was no major resection of pancreatic parenchymal involved in those patients. Sphincteroplasty has been shown to lead to colonization of the duct by bacteria from the colon and therefore may play a role in fibrosis (28), which was not observed in our study. Second, it appears that resection of different regions of the pancreas determines islet yield as well. Although the head of the pancreas is generally more fibrotic than the resection area in CP patients (29), islet yield from the WB group was still significantly greater than in the DP group. This appears to be explained by the fact that there are more islets residing in the pancreas tail compared with the pancreatic head, so resection of the pancreatic tail (DP) leads to more islet loss compared with the resection of the head and body of the pancreas (WB).
Islet yield in patients who had LPJ (Puestow) procedure before TP-IAT had the lowest islet yield compared with other procedures, although only drainage procedures (without resection) had been performed in these patients, thus keeping with findings from other groups (30). The lower yield in LPJ has several potential explanations. It may be explained by the fact that patients who have a LPJ procedure usually have dilated duct disease, with atrophy, and a greater extent of parenchymal destruction (31). That is, the pancreases in the LPJ group have greater exocrine and endocrine tissue destruction than those with minimal duct disease or nondilated CP. Moreover, in addition to possible parenchymal destruction, drainage procedures themselves may increase scarring in the pancreas, compromise the ability to perform intraductual perfusion of collagenase due to the increased ductal pressures, and reduce islet yield. Lastly, LPJ patients had the longest duration of disease (e.g., 17.6±16.5 for LPJ vs. 6.1±4.4 for TDS/NPS; see Table S1, SDC, http://links.lww.com/TP/A780), which may significantly impact the islet yield due to long-term inflammation in the diseased pancreas.
Our study reveals that the extent of tissue fibrosis determines islet yield as well. The more fibrotic the pancreas, the fewer number of islets can be obtained. This may be due to diminished islets in the fibrotic pancreas due to the disease process or that fibrotic pancreases are more difficult to process and harder to digest by enzyme and mechanical activity. There was no difference in islet cell viability observed from the islets isolated from pancreases from different groups. Islet cells have an average viability of greater than 95% after isolation and before transplantation (data not shown).
Our study also indicates that there is a strong correlation between islet yield and islet function after transplantation. The larger the number of islets transplanted, the greater the likelihood that the patient will be diabetes free after surgery. For example, patients who had TDS/NPS or WB procedures had more islet yields and thus a greater chance to be diabetes free compared with patients whose islet-rich region was removed by a DP or altered by a LPJ procedure before TP-IAT. In contrast, the LPJ and DP surgery groups showed significant reduction of islet yield and thus a lesser chance of insulin independence after surgery. Notably, patients who underwent DP before TP-IAT had the highest HbA1c levels and fewer patients with detectable C-peptide compared with patients from other groups (Fig. 4). Patients undergoing WB procedure received fewer IEQ than patients with TDS/NPS; however, their outcomes are the same or better in terms of insulin requirement, C-peptide, and HbA1c. Thus, it seems that, in general, patients who received greater than 2500 IEQ/kg islets have a better chance to be diabetes free compared with those who received less than 1000 IEQ/kg islets, which has been observed by other groups as well (23, 32).
These data can help physicians identify the most suitable patient population who will benefit the most from TP-IAT and optimize patient selection. Strong evidence on the definitive treatment of CP is elusive (33). It is commonly agreed that the ultimate goal for the treatment of CP is to relieve the intractable pain caused by the disease and to prevent exocrine and endocrine insufficiency (23). Generally, patients with small duct (<7 mm) disease that have failed drainage procedures are first recommended for resectional procedures, including the WB, DP, or total pancreatectomy. These procedures improve pain symptoms in greater than 50% of patients at 5 years after surgery (34–36). Patients with dilated pancreatic duct (> 7 mm) are normally recommended for LPJ. A consensus statement by the American Gastroenterological Association shows that 80% of patients with LPJ had short-term improvement of pain and 60% to 70% achieved continued pain relief 2 years after surgery, with only 0 to 5% morbidity and mortality, subjective improvement of lifestyle, and decreased narcotic use similar to the pain relief outcome as IAT (37–41). Because LPJ has satisfactory outcomes assessed by improvement in pain and a lower morbidity than resection procedures, it still has a role in the management of CP today. However, as evidence is obtained from the TP-IAT experience, the role of LPJ may change.
Based on data from other laboratories and our own, pancreatic surgeries are associated with significant islet cell loss and a greater likelihood of reduced islet yield and postoperative diabetes (42). Although our patient number is very limited here, patients who had DP and LPJ preoperatively tend to have lesser islet yield and thus are more likely to develop postoperative diabetes. Therefore, we suggest to perform TP-IAT as early as possible in the patient population that are not likely to respond well to previous procedures to maximally preserve islet mass, to avoid a prolonged period of ineffective treatments, and to minimize the staged approach to patient care represented by reoperative therapy (43).
Nevertheless, our data confirm that even patients with prior surgeries including LPJ do well after TP-IAT as determined by quality of life and diabetes control. For example, although all four patients who had LPJ previously need insulin treatment, one patient only requires an average of 9 U of insulin per day and another patient who requires 13 U of insulin per day at 6 months after transplantation, both with much improved quality of life (data not shown).
In conclusion, TP-IAT is an efficient procedure for pain relief in patients with end-stage CP. Prior surgery, including surgeries other than LPJ, is strongly correlated with islet yield and postoperative insulin requirements in CP patients who had TP-IAT. Islet yield can be compromised by prior surgery due to the fibrotic nature of the respective pancreas, the respective region involved in the resection of the pancreas, and the resulting ductal anatomy. Our data can help to improve patient selection and patient expectations when TP-IAT is considered in patients with intractable pain due to CP and help make decisions regarding the downsides of trying other surgical options before considering TP-IAT.
MATERIALS AND METHODS
Data from 76 CP patients who have undertaken extensive pancreatectomy with IAT at the Medical University of South Carolina between March 2009 and December 2011 were reviewed (3). The mean (standard deviation [SD]) patient age was 42.1 (11.4) years, the mean (SD) duration of symptoms was 7.5 (6.4) years, and the initial mean (SD) body mass index was 27.2 (6.2). The mean follow-up was 18 months, with a range of 6 to 24 months (see Table S1, SDC, http://links.lww.com/TP/A780). Regarding insulin-/diabetes-free rates, only 6-month data were analyzed because the data were insufficient at 24 months.
Patients were divided into four groups based on their previous operations before undergoing TP-IAT. The four groups include TDS/NPS (n=50), WB (n=14), DP (n=8), and LPJ (also called a Puestow procedure; n=4). Patients who underwent no parenchymal resection but TDS and patients who had NPS before TP-IAT were grouped together. The WBs were also grouped together because both involved the removal of the head of the pancreas. This study was approved by the Institutional Review Board at the Medical University of South Carolina and patient consents were obtained.
Each pancreas was weighed and examined for fibrosis by palpation and the extent of fibrosis was confirmed in the pathology laboratory by a histologic fibrosis semiquantitative score system that is based on a 0 to 3 score of interlobular and intralobular fibrosis by microscopy as described (44). Based on the severity of fibrosis, the pancreases were classified into three categories: soft (no obvious fibrotic tissue), moderate (<50% of pancreas with fibrotic tissue), and hard (> 50% of pancreas with fibrotic tissue).
Islet Harvest and Transplantation
Each patient’s pancreas was transferred from the clinic center to the current good manufacturing practice facility at the Medical University of South Carolina in compliance with federal regulations. Islets were harvested from the pancreas using the modified Ricordi method (45). Liberase MTF (Roche, Indianapolis, IN) was infused into the main pancreatic duct or injected directly into the pancreas for distension. Islets were released from other tissues by enzyme digestion and mechanical forces. Islet yield was assessed by the dithizone (Sigma-Aldrich, St. Louis, MO) staining and converted to a standard number of IEQ of islets with diameter standardizing to 150 μM. Islet cell viability was assessed by SytoGreen 13 (25 μM; Invitrogen, Carlsbad, CA) and ethidium bromide (50 μM; Sigma) fluorescent staining based on membrane integrity. Total unpurified islets were resuspended in 5% human albumin with heparin (70 U/kg body weight) for infusion. Endotoxin, Gram staining, and bacterial and fungal cultures were measured in the final products and used as indicators for sterilization. Islets were infused into the portal vein via the mesenteric vein of the patient who was under general anesthesia. Time elapsed from pancreas excision to islet reinfusion into patient was recorded, which included the time needed for tissue transportation and islet preparation.
Measurement of Clinical Outcomes
Average daily oral narcotic requirement standardized as morphine equivalents, average daily insulin requirement, and HbA1c and C-peptide levels were recorded before surgery, on hospital discharge, and at each subsequent postoperative patient encounter as described previously (3). Preoperative C-peptide levels were measured after fasting and C-peptide at 6 months was measured without fasting. Patients with detectable C-peptide value (> 0 ng/mL) were considered C-peptide positive. Study data were managed using REDCap electronic data capture tools hosted at the Medical University of South Carolina.
Data were analyzed by analysis of variance for continuous variables and Fisher’s exact of proportions. Differences between groups were compared. P<0.05 was considered statistically significant. Values are shown as mean±SD. Sample size was considered too low to attempt multivariate modeling, but potential confounding and effect modification was explored with selected subgroup univariate analyses.
The authors thank the Center for Cellular Therapy at the Medical University of South Carolina for performing human islet isolation.
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