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Insulin dependence and pancreatic enzyme replacement therapy are independent prognostic factors for long-term survival after operation for chronic pancreatitis Markus Winny, MD,a Vagia Paroglou,a H€ useyin Bektas, MD,a Alexander Kaltenborn,a,b a,c Benedikt Reichert, MD, Lea Zachau, MD,a Moritz Kleine, MD,a J€ urgen Klempnauer, MD,a and a Harald Schrem, MD, Hannover and Kiel, Germany
Background. This retrospective, single-center, observational study on postoperative long-term results aims to define yet unknown factors for long-term outcome after operation for chronic pancreatitis. Patients and Methods. We analyzed 147 consecutive patients operated for chronic pancreatitis from 2000 to 2011. Mean follow-up was 5.3 years (range, 1 month to 12.7 years). Complete long-term survival data were provided by the German citizen registration authorities for all patients. A quality-oflife questionnaire was sent to surviving patients after a mean follow-up of 5.7 years. Results. Surgical principles were resection (n = 86; 59%), decompression (n = 29; 20%), and hybrid procedures (n = 32; 21%). No significant influences of different surgical principles and operative procedures on survival, long-term quality of life and pain control could be detected. Overall 30-day mortality was 2.7%, 1-year survival 95.9%, and 3-year survival 90.8%. Multivariate Cox regression analysis revealed that only postoperative insulin dependence at the time of hospital discharge (P = .027; Exp(B) = 2.111; 95% confidence interval [CI], 1.089–4.090) and the absence of pancreas enzyme replacement therapy at the time of hospital discharge (P = .039; Exp(B) = 2.102; 95% CI, 1.037– 4.262) were significant, independent risk factors for survival with significant hazard ratios for longterm survival. Long-term improvement in quality of life was reported by 55 of 76 long-term survivors (73%). Conclusion. Pancreatic enzyme replacement should be standard treatment after surgery for chronic pancreatitis at the time of hospital discharge, even when no clinical signs of exocrine pancreatic failure exist. This study underlines the potential importance of early operative intervention in chronic pancreatitis before irreversible endocrine dysfunction is present. (Surgery 2013;j:j-j.) From the General, Visceral and Transplantation Surgery,a Hannover Medical School, and the Federal Armed Forces Medical Center Hannover,b Hannover; and the Department of General and Thoracic Surgery,c Universit€ a tsklinikum Schleswig Holstein, Kiel, Germany
CHRONIC PANCREATITIS is a progressive and painful benign inflammatory process of the pancreas during which pancreatic secretory tissue is destroyed and replaced by fibrous tissue leading to pancreatic exocrine and endocrine insufficiency.1-3 Pain in M.W. and V.P. contributed equally to this paper. Accepted for publication August 12, 2013. Reprint requests: Harald Schrem, MD, Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2013.08.012
the form of recurrent attacks of pancreatitis or constant and disabling pain is usually the main symptom.1-3 Management of pain is mainly empirical, involving analgesics and duct drainage by endoscopic or operative intervention, including partial or total pancreatectomy.2 Medical treatment of intractable pain fails frequently owing to narcotic dependency and failure to control pain effectively.3 The most frequent indication leading to surgery is triggered by otherwise intractable pain.1-3 The main goals of operative intervention for chronic pancreatitis are to relieve pain and preserve pancreatic function.1-3 These 2 goals may be conflicting in cases treated with pancreatic resection. Operative procedures have the known potential to provide SURGERY 1
ARTICLE IN PRESS 2 Winny et al
long-term pain relief and good postoperative quality of life along with less mortality and morbidity compared with nonoperative treatments.1 The differentiation of chronic pancreatitis and pancreatic cancer is crucial for choosing therapies and can be challenging in some cases.4,5 Complications of pancreatic surgery can lead to mortality and substantial morbidity, including insulindependent diabetes and exocrine pancreatic insufficiency. Several studies have reported that local resection of the pancreatic head, with or without duct drainage, and duodenum-preserving pancreatic head resection offer outcomes as effective as pancreatoduodenectomy, with less morbidity and mortality.3 The late incidences of recurrent pain, diabetes, and exocrine insufficiency were reported equivalent for all 3 operative approaches, which include decompression of the diseased and obstructed pancreatic ducts, denervation of the pancreas; resection of the proximal, distal, or total pancreas; and hybrid procedures with combinations of decompression and limited resection.1-3 The current study examines our experience with operative intervention for chronic pancreatitis and aims to define yet unknown factors for longterm survival and quality of life after operation for chronic pancreatitis. PATIENTS AND METHODS The setting of the study is a tertiary referral center in a German university hospital. We included patients operated for chronic pancreatitis at our institution between January 2000 and January 2011. Preoperative symptoms summarized in Table I represent the indications for operation. Therapeutic success was defined as survival with long-term relief of the major symptom pain. The local ethics committee for clinical studies approved the study protocol (reference number: 1,652–2,012). Exclusion criteria were preoperative suspicion of pancreatic cancer or postoperative histopathologic detection of pancreatic cancer in the resection specimen. Data collection. This retrospective, single-center analysis was completed by analysis of survival of the complete cohort in collaboration with the German registration authorities and an additional follow-up survey of long-term survivors. Data were analyzed by chart review. Mean follow-up was 5.3 years (range, 1 month to 12.7 years). Follow-up times were comparable between the 3 main operative interventions (decompression, resection, and hybrid procedures; P = .442). Survival as the major study endpoint was carried out for all patients with complete information
Surgery j 2013
Table I. Preoperative parameters of the study population Parameter Etiology Alcohol abuse Choledocho/cystolithisasis Anatomic pancreatic duct variant Duodenal diverticulum Pancreatic duct stones Unknown Preoperative clinical symptoms Pain Diarrhea Vomiting Weight decrease Night sweating Jaundice Preoperative treatment Insulin dependency Pancreas enzyme substitution Papillotomy Endoscopic bile duct stone removal Bile duct dilatation Bile duct stenting Pancreatic duct stenting Transgastric endoscopic drainage of pseudocyst
n
%
70 7 7 3 2 58
47.5 4.8 4.8 2.1 1.4 39.4
134 16 34 73 8 13
91.2 10.9 23.1 49.7 5.4 8.8
27 72 46 5
18.4 49.0 31.3 3.4
66 31 20 2
44.9 21.1 13.6 1.4
Preoperative laboratory parameters (in serum)
Mean
Range
Amylase (U/L) Lipase (U/L) Bilirubin (mmol/L) Carbohydrate antigen 19-9 (U/mL) Carcinoembryonic antigen (ng/mL)
106 323 16 986 5
4–996 7–6,065 3–505 1–46,600 1–25
from the registration authorities in Germany who provided information on patients’ current addresses and survival status. In Germany, all changes of address and all deaths by law have to be reported to the registration authorities. This information is accessible for our institution within the current legal system in Germany. No patients were lost to follow-up with this approach, at least with respect to their survival status and current addresses, because none of the patients moved abroad to another jurisdiction. For follow-up, an abbreviated and slightly modified version of the chronic pancreatitis module of the European Organization for Research and Treatment quality-of-life questionnaire was sent selectively to the current addresses of known long-term survivors. The questionnaire included questions on their clinical condition, occurrence
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Table II. Overview of the surgical principles and the operative procedures used in this study Operative procedures Decompression (n = 29; 20%) Longitudinal pancreaticojejunostomy Resection of duodenal diverticulum Aneurysm resection of the splenic artery with arterial reanastomoses Duodenotomy and papillotomy with removal of pancreatic ductal stones Resection (n = 86; 59%) Proximal pancreatoduodenectomy Pylorus-preserving pancreatoduodenectomy Distal pancreatectomy Total pancreatectomy Hybrid procedures (n = 32; 22%) Duodenum-preserving pancreatic head resection Local pancreatic head resection with longitudinal pancreaticojejunostomy Proximal pancreatoduodenectomy with longitudinal pancreaticojejunostomy Distal pancreatectomy with longitudinal pancreaticojejunostomy Distal pancreatectomy with resection of duodenal diverticulum Central pancreatectomy with proximal and distal pancreaticojejunostomy Total
of malignant disease, diabetes, diarrhea, analgesic medication, food intolerance, body size and weight, professional reintegration, and improvement of quality of life and pain using visual analog scales (from 1 [no improvement] to 10 [immeasurable improvement]). The questionnaire was sent to 112 long-term surviving patients after a mean time between operation and follow-up of 5.7 years (median, 5.6; range, 0.86–12.7); 76 of 112 patients answered the questionnaire and 35 patients (68%) died during follow-up after a mean time of 3.8 years (range, 1 month to 8.7 years). Clinical, surgical, and demographic characteristics. There were 147 patients (97 males, 50 females) with a mean age of 50.5 years (range, 22–79) who met our inclusion criteria. The etiologies leading to chronic pancreatitis, preoperative clinical symptoms, preoperative treatment, and preoperative laboratory parameters are summarized in Table I. A total of 459 pathologic, anatomic characteristics were detected in 147 patients. Combinations of these characteristics are a frequent observation. The combinations of morphologic changes and their anatomic location more or less dictated the chosen surgical principle and the operative procedure. The presence or absence of a preoperative mass in the pancreatic head influenced the surgical principle and the chosen operative procedure (Table II). Taken together, 56 of 60 patients with a mass in the pancreatic head were treated with a resection either alone or in combination with a decompression procedure (93%)
n
%
25 1 1 2
17.0 0.7 0.7 1.4
59 12 9 6
40.1 8.1 6.1 4.1
18 6 4 1 1 2 147
12.1 4.1 2.8 0.7 0.7 1.4 100
and the remainder by a decompression procedure alone (7%). Patients received pancreas enzyme replacement therapy with Kreon (median dose, 30,000 PhEur Units; range, 0–240,000) after operation and before discharge, depending on the presence of obvious clinical signs for exocrine pancreatic failure. Patients who did not receive pancreas enzyme replacement were believed not to need this therapy. Statistical methods. Kaplan-Meier estimates of survival with log-rank test, univariate and multivariate Cox regression analysis, univariate regression analysis, 2-sided Fisher’s exact tests, Mann–Whitney U tests, receiver operating characteristic (ROC) curve analysis, and chi-square tests were used as appropriate. The SPSS statistics software version 20.0 (IBM, Somers, NY) was used for statistical analysis. RESULTS Preoperative clinical symptoms and etiologies of chronic pancreatitis. Table I summarizes the frequencies of preoperative clinical symptoms, preoperative treatments, and the etiologies of chronic pancreatitis. Preoperative vomiting was associated with duodenal occlusion (P = .011, 2-sided Fisher’s exact test). Preoperative unintended weight decrease (>5 kg in >1one month) was associated with unsuccessful preoperative pain control (P = .002, 2-sided Fisher’s exact test). Preoperative laboratory parameters. Preoperative laboratory parameters are summarized in
ARTICLE IN PRESS 4 Winny et al
Table I. Preoperative amylase and lipase levels were unable to predict postoperative pain control at the time of hospital discharge or during long-term follow-up (area under the ROC curve .05, univariate regression analysis). Postoperative quality of life. Improvement of quality of life during long-term follow-up was reported by 55 of the 76 patients who answered our questionnaire (73%). The median visual analog scale for improved quality of life was 8.0 points (range, 1–10) with 1 point representing completely absent improvement and 10 points representing an optimal improvement of quality of life. Also, 39 patients reported that they were able to achieve professional reintegration during long-term follow-up (51%). Patients who reported long-term complications were more likely to report failure of professional reintegration (P = .040; 2sided Fisher’s exact test). Questionnaire results on long-term postoperative pain control. The median visual analog scale for pain was 3.0 points (range, 0–10), with 29 patients reporting complete absence of pain (38%), 16 reporting continuous pain (21%), and 31 reporting temporary pain (41%). Chronic pain medication was used by 30 patients (40%), and 20
patients reported regular opioid use (26%). Overall, 41 patients reported improved pain or absent pain (54%) and 11 reported identical or worse pain (15%). Patients who reported postoperative opioid treatment during follow-up (n = 20) were significantly more likely to report lack of professional reintegration (n = 15), whereas patients who were free of opioid medication (n = 51) were more likely to report successful professional reintegration (n = 33; P = .003, Chi-square; P = .004, 2-sided Fisher’s exact test). Freedom from pain was more frequently reported by male patients (48%) compared with female patients (22%; P = .023, 2-sided Fisher’s exact test). Patients with preoperative alcohol abuse had a greater rate of pain (P = .035, Chi-square) and were more likely to use opioids during long-term follow-up (P = .017; Fisher’s exact test). Body weight and body mass index after longterm follow-up. The mean body weight was 70.7 kg (range, 40.0–105.0), with a mean body mass index of 23.5 kg/m2 (range, 14.8–33.9). Classification of body mass index according to the current definition by the World Health Organization shows an underweight classification in 6 patients (8%), normal weight in 50 (66%), a preobese
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classification in 13 (17%), and obese class I classification in 5 (7%). Long-term postoperative endocrine function. Diabetes mellitus was reported by 39 of 76 patients who answered our questionnaire during long-term follow-up (51%), 33 of whom (43%) were insulindependent. This shows an increasing incidence of insulin dependence from the preoperative phase to hospital discharge until the end of follow-up (18%, 22%, and 43%, respectively). Long-term postoperative exocrine function. Diarrhea was reported by 36 of 76 patients (47%) who answered our questionnaire during long-term follow-up, 39 of whom used pancreas enzyme substitution (51%); 36 patients reported food intolerance during long-term follow-up (47%). DISCUSSION The present study identifies significant factors for long-term survival after operative therapy for chronic pancreatitis. Long-term survival after operative intervention for chronic pancreatitis has not been the main focus of previous research so far. This study contains long-term survival data for the whole cohort with a median follow-up of 5.3 years. This is the first study to illustrate statistically influences of preoperative insulin-dependence (Fig 1, A), postoperative insulin dependence (Fig 1, B), and postoperative pancreas enzyme replacement therapy at the time of hospital discharge (Fig 2) on long-term patient survival after operative treatment for chronic pancreatitis. The data from this study demonstrate that insulin dependence at the time of hospital discharge and lack of pancreatic enzyme replacement therapy at the time of hospital discharge both represent significant and independent risk factors for long-term mortality after operative treatment for chronic pancreatitis with significant hazard ratios. We conclude that pancreatic enzyme replacement should be a standard treatment after operative treatment for chronic pancreatitis by the time of discharge regardless of the presence or absence of clinical signs for exocrine pancreatic failure. Furthermore, this study may underline the importance of early operative intervention in chronic pancreatitis before irreversible endocrine dysfunction is present, although our study did not address this question. Clinical studies would be desirable to determine the optimal dosing of pancreatic enzyme replacement therapy in this clinical setting. A recent review describes the detrimental effects of pancreatic exocrine insufficiency in patients with pancreatic diseases including pancreatitis
Winny et al 7
that often result in malnutrition, weight loss, and steatorrhea, which together increase the risk of morbidity and mortality.6 Currently, nutritional interventions including pancreatic enzyme replacement therapy are needed for these patients to improve clinical symptoms and to address the pathophysiology of pancreatic insufficiency.6 This treatment improves associated symptoms and the coefficients of absorption for fat, nitrogen, and liposoluble vitamins without serious adverse events.6 The present study highlights the value of such an approach and shows a significant impact of pancreatic enzyme replacement therapy on long-term patient survival after operative treatment of chronic pancreatitis, although a dose-dependent effect could not be verified. It may be that all patients with chronic pancreatitis may benefit from pancreatic enzyme replacement therapy in this respect, especially in cases with subclinical exocrine pancreatic failure. Further prospective studies with functional physiologic investigations are needed to address this important issue. A comprehensive meta-analysis came to the conclusion that the role of pancreatic enzyme replacement therapy for the treatment of abdominal pain, weight loss, steatorrhea, analgesic use, and quality of life in patients with chronic pancreatitis remains equivocal,7 although Thorat et al8 found recently that pancreatic enzyme replacement therapy leads to an increase in weight gain. The influence of pancreatic enzyme replacement therapy on survival was not evaluated so far owing to lack of published data. Pancreatic diabetes is notoriously difficult to manage and characterized by frequent hypoglycemic events.1,9 Our study demonstrates the prognostic significance of insulin dependence before and after operative intervention for chronic pancreatitis and its influence on long-term patient survival. In this context, a large cohort study from Taiwan demonstrated that the risk of pancreatic cancer is moderately increased in patients with diabetes, especially those using insulin therapy. Interestingly, the risk is greatly increased for diabetic patients with chronic pancreatitis.10 This observation may be relevant for patients with chronic pancreatitis suffering from insulin-dependent pancreatic diabetes. These cases may carry a greater risk of pancreatic carcinoma within morphologic changes within the pancreas that may otherwise be attributed to chronic pancreatitis. These patients may profit from a more aggressive operative approach. Some groups consider that resection for chronic pancreatitis is frequently assumed to be
ARTICLE IN PRESS 8 Winny et al
more likely to result in endocrine and exocrine insufficiency and should thus be avoided in cases that could also be treated with an organ-preserving decompression procedure. This view is prevalent, although a significant negative influence of resectional procedures on short- or long-term endocrine and/or exocrine pancreatic function could not be demonstrated.1,3,11,12 Our present study does not support such a notion. In this context it is interesting to note that Andersen and Frey3 favor local resection or excavation of the pancreatic head, because they believe that this approach lessens the risk for early postoperative diabetes, although they were unable to demonstrate data to support this view. We believe that the operative procedures seem to be equivalent in their longterm effect as long as they are applied correctly based on the anatomic findings of the individual patient. The present study seems to underline this notion. Our study also shows that preoperative alcohol abuse had no statistical influence on long-term survival. Alcohol abuse was the most frequent etiology for chronic pancreatitis in this cohort. Similar observations were also described by other authors.11,13,14 The 30-day mortality was largely in line with other published series.12,15,16 In our study, the principle of operative decompression had no effect on long-term survival compared with resection and hybrid principles. Other authors, however, have refuted this concept.1,17,18 In the current study, the necessity of reoperation had no influence on long-term patient survival. In our study, the surgical principle adopted (decompression versus resection versus hybrid procedures) and the operative procedure itself had no influence on improvement of long-term quality of life or on the absence or improvement of pain during long-term follow-up. Aimoto et al1 and van der Gaag et al12 have reported recently similar observations. In this context, several prospective, randomized trials that compared 2 different operative approaches to chronic pancreatitis were unable to demonstrate statistically significant advantages of 1 method over the other in respect to clinical outcome, including quality of life, morbidity, recurrent pain, diabetes, exocrine pancreatic function, and mortality.1,3,11,14-16,18-23 In our opinion, the combination of morphologic changes within the pancreas and their anatomic location dictate the operative principle and the operative procedure. This view is shared by several other authors.1,12,14,24 The results of an older, large, retrospective analysis including 504 patients with excellent
Surgery j 2013
long-term follow-up (maximum, 14 years; 1972– 1998) from Germany reported improvement of quality of life for 72% of patients,15 which is in line with ours, although professional reintegration was somewhat less in the current cohort. This latter observation may be influenced to some degree by societal changes in Germany within the last 40 years. A recent study from The Netherlands found that full professional reintegration with paid work could only be achieved by 34% of patients during long-term follow-up.12 The frequency of full professional reintegration during follow-up varies greatly in different publications, from 25% to 80%.11-13,15,16,20-22 We believe that this variation is likely influenced by the age of the analyzed patients, different durations of follow-up, and national differences in social systems with different attitudes toward definitions of disability among young, chronically ill patients. Our data failed to demonstrate a significant influence of any specific operative approaches on long-term professional rehabilitation.11-13,15,16,20-22 Patients who reported postoperative opioid use during follow-up were significantly more likely to report lack of professional reintegration. Preoperative amylase and lipase levels were of no use in predicting postoperative pain control at the time of hospital discharge or during long-term follow-up.25,26 Successful long-term pain control in this series could not be attributed to a specific surgical principle or a specific operative procedure as reported in previous publications.11-13,15,16,20-22,27 Interestingly, the present study shows that male patients achieved better long-term freedom from pain than females, in line with the greater pain prevalence in women, which is consistently observed but not well understood.28 Illegal (eg, psychostimulants, opioids, cannabinoids) and legal (alcohol, nicotine) drugs of abuse create a complex behavioral pattern composed of drug intake, withdrawal, seeking, and relapse.29 This concept may explain our findings that patients with preoperative alcohol abuse had a greater rate of subjective pain during long-term follow-up and were more likely to use opioids during long-term follow-up.
REFERENCES 1. Aimoto T, Uchida E, Nakamura Y, et al. Current surgical treatment for chronic pancreatitis. J Nihon Med Sch 2011; 78:352-9. 2. Braganza JM, Lee SH, McCloy RF, et al. Chronic pancreatitis. Lancet 2011;377:1184-97. 3. Andersen DK, Frey CF. The evolution of the surgical treatment of chronic pancreatitis. Ann Surg 2010;251:18-32.
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4. Liao Q, Zhao YP, Yang YC, et al. Combined detection of serum tumor markers for differential diagnosis of solid lesions located at the pancreatic head. Hepatobiliary Pancreat Dis Int 2007;6:641-5. 5. Brimiene_ V, Brimas G, Strupas K. Differential diagnosis between chronic pancreatitis and pancreatic cancer: a prospective study of 156 patients. Medicina (Kaunas) 2011;47: 154-62. 6. Nakajima K, Oshida H, Toshitaka M, et al. Pancrelipase: an evidence-based review of its use for treating pancreatic exocrine insufficiency. Core Evidence 2012;7:77-91. 7. Shafiq N, Rana S, Bhasin D, et al. Pancreatic enzymes for chronic pancreatitis. Cochrane Database Syst Rev 2009;7: CD006302. 8. Thorat V, Reddy N, Bhatia S, et al. Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis-a doubleblind, placebo-controlled study. Aliment Pharmacol Ther 2012;36:426-36. 9. Sasikala M, Talukdar R, Pavan Kumar P, et al. b-Cell dysfunction in chronic pancreatitis. Dig Dis Sci 2012;57:1764-72. 10. Lai HC, Tsai IJ, Chen PC, et al. Gallstones, a cholecystectomy, chronic pancreatitis, and the risk of subsequent pancreatic cancer in diabetic patients: a population-based cohort study. J Gastroenterol 2013;48:721-7. 11. B€ uchler MW, Friess H, Bittner R, et al. Duodenum-preserving pancreatic head resection: long-term results. J Gastrointest Surg 1997;1:13-9. 12. van der Gaag NA, van Gulik TM, Busch ORC, et al. Functional and medical outcomes after tailored surgery for pain due to chronic pancreatitis. Ann Surg 2012;255:763-70. 13. R€ uckert F, Distler M, Hoffmann S, et al. Quality of life in patients after pancreaticoduodenectomy for chronic pancreatitis. J Gastrointest Surg 2011;15:1143-50. 14. Keck T, Wellner UF, Riediger H, et al. Long-term outcome after 92 duodenum-preserving pancreatic head resections for chronic pancreatitis: comparison of Beger and Frey Procedures. J Gastrointest Surg 2010;14:549-56. 15. Beger HG, Schlossser W, Friess H, et al. Duodenum-preserving head resection in chronic pancreatitis changes the natural course of the disease. A single-center 26-year experience. Ann Surg 1999;230:512-23. 16. Izbicki JR, Bloechle C, Broering DC, et al. Extended drainage versus resection in surgery for chronic pancreatitis. A prospective randomized trial comparing the longitudinal pancreaticojejunostomy combined with local pancreatic head excision with the pylorus-preserving pancreatoduodenectomy. Ann Surg 1998;228:771-9.
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17. Yin Z, Sun J, Yin D, et al. Surgical treatment strategies in chronic pancreatitis. A meta-analysis. Arch Surg 2012;147: 961-8. 18. Zheng Z, Xiang G, Tan C, et al. Pancreaticoduodenectomy versus duodenum-preserving pancreatic head resection for the treatment of chronic pancreatitis. Pancreas 2012;41: 147-52. 19. K€ oninger J, Seiler CM, Sauerland S, et al. Duodenum-preserving pancreatic head resection: a randomized controlled trial comparing the original Beger procedure with the Berne modification. J Surg 2008;143:490-8. 20. Farkas G, Leindler L, Daroczi M, et al. Prospective randomised comparison of organ-preserving pancreatic head resection with pylorus-preserving pancreaticoduodenectomy. Langenbecks Arch Surg 2006;391:338-42. 21. Izbicki JR, Bloechle C, Knoefel WT, et al. Drainage versus Resektion in der chirurgischen Therapie der chronischen Pankreatitis: eine randomisierte Studie. Chirurg 1997;68: 369-77. 22. Izbicki JR, Bloechle C, Knoefel WT, et al. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized trial. Ann Surg 1995;221:350-8. 23. Klempa I, Spatny M, Menzel J. Pancreatic function and quality of life after resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized comparative study after duodenum preserving resection of the head of the pancreas versus Whipple’s operation. Chirurg 1995;66:350-9. 24. Riediger H, Adam U, Fischer E, et al. Long-term outcome after resection for chronic pancreatitis in 224 patients. J Gastrointest Surg 2007;11:949-60. 25. Halm U, Rohde N, Klapdor R, et al. Improved sensitivity of fuzzy logic based tumor marker profiles for diagnosis of pancreatic carcinoma versus benign pancreatic disease. Anticancer Res 2000;20:4957-60. 26. Donnely JG, Ooi DS, Burns BF, et al. Chronic increased serum lipase without evidence of pancreatitis: tumorderived lipase? Clin Chem 1996;42:462-4. 27. B€ uchler MW, Friess H, M€ uller MW, et al. Randomized trial of duodenum-preserving pancreatic head resection versus pylorus-preserving Whipple in chronic pancreatitis. Am J Surg 1995;169:65-70. 28. Leresche L. Defining gender disparities in pain management. Clin Orthop Relat Res 2011;469:1871-7. 29. Filip M, Zaniewska M, Frankowska M, et al. The importance of the adenosine A(2A) receptor-dopamine D(2) receptor interaction in drug addiction. Curr Med Chem 2012;19: 317-55.
Insulin dependence and pancreatic enzyme replacement therapy are independent prognostic factors for long-term survival after operation for chronic pancreatitis Markus Winny, MD,a Vagia Paroglou,a H€ useyin Bektas, MD,a Alexander Kaltenborn,a,b a,c Benedikt Reichert, MD, Lea Zachau, MD,a Moritz Kleine, MD,a J€ urgen Klempnauer, MD,a and a Harald Schrem, MD, Hannover and Kiel, Germany
Background. This retrospective, single-center, observational study on postoperative long-term results aims to define yet unknown factors for long-term outcome after operation for chronic pancreatitis. Patients and Methods. We analyzed 147 consecutive patients operated for chronic pancreatitis from 2000 to 2011. Mean follow-up was 5.3 years (range, 1 month to 12.7 years). Complete long-term survival data were provided by the German citizen registration authorities for all patients. A quality-oflife questionnaire was sent to surviving patients after a mean follow-up of 5.7 years. Results. Surgical principles were resection (n = 86; 59%), decompression (n = 29; 20%), and hybrid procedures (n = 32; 21%). No significant influences of different surgical principles and operative procedures on survival, long-term quality of life and pain control could be detected. Overall 30-day mortality was 2.7%, 1-year survival 95.9%, and 3-year survival 90.8%. Multivariate Cox regression analysis revealed that only postoperative insulin dependence at the time of hospital discharge (P = .027; Exp(B) = 2.111; 95% confidence interval [CI], 1.089–4.090) and the absence of pancreas enzyme replacement therapy at the time of hospital discharge (P = .039; Exp(B) = 2.102; 95% CI, 1.037– 4.262) were significant, independent risk factors for survival with significant hazard ratios for longterm survival. Long-term improvement in quality of life was reported by 55 of 76 long-term survivors (73%). Conclusion. Pancreatic enzyme replacement should be standard treatment after surgery for chronic pancreatitis at the time of hospital discharge, even when no clinical signs of exocrine pancreatic failure exist. This study underlines the potential importance of early operative intervention in chronic pancreatitis before irreversible endocrine dysfunction is present. (Surgery 2013;j:j-j.) From the General, Visceral and Transplantation Surgery,a Hannover Medical School, and the Federal Armed Forces Medical Center Hannover,b Hannover; and the Department of General and Thoracic Surgery,c Universit€ a tsklinikum Schleswig Holstein, Kiel, Germany
CHRONIC PANCREATITIS is a progressive and painful benign inflammatory process of the pancreas during which pancreatic secretory tissue is destroyed and replaced by fibrous tissue leading to pancreatic exocrine and endocrine insufficiency.1-3 Pain in M.W. and V.P. contributed equally to this paper. Accepted for publication August 12, 2013. Reprint requests: Harald Schrem, MD, Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2013.08.012
the form of recurrent attacks of pancreatitis or constant and disabling pain is usually the main symptom.1-3 Management of pain is mainly empirical, involving analgesics and duct drainage by endoscopic or operative intervention, including partial or total pancreatectomy.2 Medical treatment of intractable pain fails frequently owing to narcotic dependency and failure to control pain effectively.3 The most frequent indication leading to surgery is triggered by otherwise intractable pain.1-3 The main goals of operative intervention for chronic pancreatitis are to relieve pain and preserve pancreatic function.1-3 These 2 goals may be conflicting in cases treated with pancreatic resection. Operative procedures have the known potential to provide SURGERY 1
ARTICLE IN PRESS 2 Winny et al
long-term pain relief and good postoperative quality of life along with less mortality and morbidity compared with nonoperative treatments.1 The differentiation of chronic pancreatitis and pancreatic cancer is crucial for choosing therapies and can be challenging in some cases.4,5 Complications of pancreatic surgery can lead to mortality and substantial morbidity, including insulindependent diabetes and exocrine pancreatic insufficiency. Several studies have reported that local resection of the pancreatic head, with or without duct drainage, and duodenum-preserving pancreatic head resection offer outcomes as effective as pancreatoduodenectomy, with less morbidity and mortality.3 The late incidences of recurrent pain, diabetes, and exocrine insufficiency were reported equivalent for all 3 operative approaches, which include decompression of the diseased and obstructed pancreatic ducts, denervation of the pancreas; resection of the proximal, distal, or total pancreas; and hybrid procedures with combinations of decompression and limited resection.1-3 The current study examines our experience with operative intervention for chronic pancreatitis and aims to define yet unknown factors for longterm survival and quality of life after operation for chronic pancreatitis. PATIENTS AND METHODS The setting of the study is a tertiary referral center in a German university hospital. We included patients operated for chronic pancreatitis at our institution between January 2000 and January 2011. Preoperative symptoms summarized in Table I represent the indications for operation. Therapeutic success was defined as survival with long-term relief of the major symptom pain. The local ethics committee for clinical studies approved the study protocol (reference number: 1,652–2,012). Exclusion criteria were preoperative suspicion of pancreatic cancer or postoperative histopathologic detection of pancreatic cancer in the resection specimen. Data collection. This retrospective, single-center analysis was completed by analysis of survival of the complete cohort in collaboration with the German registration authorities and an additional follow-up survey of long-term survivors. Data were analyzed by chart review. Mean follow-up was 5.3 years (range, 1 month to 12.7 years). Follow-up times were comparable between the 3 main operative interventions (decompression, resection, and hybrid procedures; P = .442). Survival as the major study endpoint was carried out for all patients with complete information
Surgery j 2013
Table I. Preoperative parameters of the study population Parameter Etiology Alcohol abuse Choledocho/cystolithisasis Anatomic pancreatic duct variant Duodenal diverticulum Pancreatic duct stones Unknown Preoperative clinical symptoms Pain Diarrhea Vomiting Weight decrease Night sweating Jaundice Preoperative treatment Insulin dependency Pancreas enzyme substitution Papillotomy Endoscopic bile duct stone removal Bile duct dilatation Bile duct stenting Pancreatic duct stenting Transgastric endoscopic drainage of pseudocyst
n
%
70 7 7 3 2 58
47.5 4.8 4.8 2.1 1.4 39.4
134 16 34 73 8 13
91.2 10.9 23.1 49.7 5.4 8.8
27 72 46 5
18.4 49.0 31.3 3.4
66 31 20 2
44.9 21.1 13.6 1.4
Preoperative laboratory parameters (in serum)
Mean
Range
Amylase (U/L) Lipase (U/L) Bilirubin (mmol/L) Carbohydrate antigen 19-9 (U/mL) Carcinoembryonic antigen (ng/mL)
106 323 16 986 5
4–996 7–6,065 3–505 1–46,600 1–25
from the registration authorities in Germany who provided information on patients’ current addresses and survival status. In Germany, all changes of address and all deaths by law have to be reported to the registration authorities. This information is accessible for our institution within the current legal system in Germany. No patients were lost to follow-up with this approach, at least with respect to their survival status and current addresses, because none of the patients moved abroad to another jurisdiction. For follow-up, an abbreviated and slightly modified version of the chronic pancreatitis module of the European Organization for Research and Treatment quality-of-life questionnaire was sent selectively to the current addresses of known long-term survivors. The questionnaire included questions on their clinical condition, occurrence
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Table II. Overview of the surgical principles and the operative procedures used in this study Operative procedures Decompression (n = 29; 20%) Longitudinal pancreaticojejunostomy Resection of duodenal diverticulum Aneurysm resection of the splenic artery with arterial reanastomoses Duodenotomy and papillotomy with removal of pancreatic ductal stones Resection (n = 86; 59%) Proximal pancreatoduodenectomy Pylorus-preserving pancreatoduodenectomy Distal pancreatectomy Total pancreatectomy Hybrid procedures (n = 32; 22%) Duodenum-preserving pancreatic head resection Local pancreatic head resection with longitudinal pancreaticojejunostomy Proximal pancreatoduodenectomy with longitudinal pancreaticojejunostomy Distal pancreatectomy with longitudinal pancreaticojejunostomy Distal pancreatectomy with resection of duodenal diverticulum Central pancreatectomy with proximal and distal pancreaticojejunostomy Total
of malignant disease, diabetes, diarrhea, analgesic medication, food intolerance, body size and weight, professional reintegration, and improvement of quality of life and pain using visual analog scales (from 1 [no improvement] to 10 [immeasurable improvement]). The questionnaire was sent to 112 long-term surviving patients after a mean time between operation and follow-up of 5.7 years (median, 5.6; range, 0.86–12.7); 76 of 112 patients answered the questionnaire and 35 patients (68%) died during follow-up after a mean time of 3.8 years (range, 1 month to 8.7 years). Clinical, surgical, and demographic characteristics. There were 147 patients (97 males, 50 females) with a mean age of 50.5 years (range, 22–79) who met our inclusion criteria. The etiologies leading to chronic pancreatitis, preoperative clinical symptoms, preoperative treatment, and preoperative laboratory parameters are summarized in Table I. A total of 459 pathologic, anatomic characteristics were detected in 147 patients. Combinations of these characteristics are a frequent observation. The combinations of morphologic changes and their anatomic location more or less dictated the chosen surgical principle and the operative procedure. The presence or absence of a preoperative mass in the pancreatic head influenced the surgical principle and the chosen operative procedure (Table II). Taken together, 56 of 60 patients with a mass in the pancreatic head were treated with a resection either alone or in combination with a decompression procedure (93%)
n
%
25 1 1 2
17.0 0.7 0.7 1.4
59 12 9 6
40.1 8.1 6.1 4.1
18 6 4 1 1 2 147
12.1 4.1 2.8 0.7 0.7 1.4 100
and the remainder by a decompression procedure alone (7%). Patients received pancreas enzyme replacement therapy with Kreon (median dose, 30,000 PhEur Units; range, 0–240,000) after operation and before discharge, depending on the presence of obvious clinical signs for exocrine pancreatic failure. Patients who did not receive pancreas enzyme replacement were believed not to need this therapy. Statistical methods. Kaplan-Meier estimates of survival with log-rank test, univariate and multivariate Cox regression analysis, univariate regression analysis, 2-sided Fisher’s exact tests, Mann–Whitney U tests, receiver operating characteristic (ROC) curve analysis, and chi-square tests were used as appropriate. The SPSS statistics software version 20.0 (IBM, Somers, NY) was used for statistical analysis. RESULTS Preoperative clinical symptoms and etiologies of chronic pancreatitis. Table I summarizes the frequencies of preoperative clinical symptoms, preoperative treatments, and the etiologies of chronic pancreatitis. Preoperative vomiting was associated with duodenal occlusion (P = .011, 2-sided Fisher’s exact test). Preoperative unintended weight decrease (>5 kg in >1one month) was associated with unsuccessful preoperative pain control (P = .002, 2-sided Fisher’s exact test). Preoperative laboratory parameters. Preoperative laboratory parameters are summarized in
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Table I. Preoperative amylase and lipase levels were unable to predict postoperative pain control at the time of hospital discharge or during long-term follow-up (area under the ROC curve .05, univariate regression analysis). Postoperative quality of life. Improvement of quality of life during long-term follow-up was reported by 55 of the 76 patients who answered our questionnaire (73%). The median visual analog scale for improved quality of life was 8.0 points (range, 1–10) with 1 point representing completely absent improvement and 10 points representing an optimal improvement of quality of life. Also, 39 patients reported that they were able to achieve professional reintegration during long-term follow-up (51%). Patients who reported long-term complications were more likely to report failure of professional reintegration (P = .040; 2sided Fisher’s exact test). Questionnaire results on long-term postoperative pain control. The median visual analog scale for pain was 3.0 points (range, 0–10), with 29 patients reporting complete absence of pain (38%), 16 reporting continuous pain (21%), and 31 reporting temporary pain (41%). Chronic pain medication was used by 30 patients (40%), and 20
patients reported regular opioid use (26%). Overall, 41 patients reported improved pain or absent pain (54%) and 11 reported identical or worse pain (15%). Patients who reported postoperative opioid treatment during follow-up (n = 20) were significantly more likely to report lack of professional reintegration (n = 15), whereas patients who were free of opioid medication (n = 51) were more likely to report successful professional reintegration (n = 33; P = .003, Chi-square; P = .004, 2-sided Fisher’s exact test). Freedom from pain was more frequently reported by male patients (48%) compared with female patients (22%; P = .023, 2-sided Fisher’s exact test). Patients with preoperative alcohol abuse had a greater rate of pain (P = .035, Chi-square) and were more likely to use opioids during long-term follow-up (P = .017; Fisher’s exact test). Body weight and body mass index after longterm follow-up. The mean body weight was 70.7 kg (range, 40.0–105.0), with a mean body mass index of 23.5 kg/m2 (range, 14.8–33.9). Classification of body mass index according to the current definition by the World Health Organization shows an underweight classification in 6 patients (8%), normal weight in 50 (66%), a preobese
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classification in 13 (17%), and obese class I classification in 5 (7%). Long-term postoperative endocrine function. Diabetes mellitus was reported by 39 of 76 patients who answered our questionnaire during long-term follow-up (51%), 33 of whom (43%) were insulindependent. This shows an increasing incidence of insulin dependence from the preoperative phase to hospital discharge until the end of follow-up (18%, 22%, and 43%, respectively). Long-term postoperative exocrine function. Diarrhea was reported by 36 of 76 patients (47%) who answered our questionnaire during long-term follow-up, 39 of whom used pancreas enzyme substitution (51%); 36 patients reported food intolerance during long-term follow-up (47%). DISCUSSION The present study identifies significant factors for long-term survival after operative therapy for chronic pancreatitis. Long-term survival after operative intervention for chronic pancreatitis has not been the main focus of previous research so far. This study contains long-term survival data for the whole cohort with a median follow-up of 5.3 years. This is the first study to illustrate statistically influences of preoperative insulin-dependence (Fig 1, A), postoperative insulin dependence (Fig 1, B), and postoperative pancreas enzyme replacement therapy at the time of hospital discharge (Fig 2) on long-term patient survival after operative treatment for chronic pancreatitis. The data from this study demonstrate that insulin dependence at the time of hospital discharge and lack of pancreatic enzyme replacement therapy at the time of hospital discharge both represent significant and independent risk factors for long-term mortality after operative treatment for chronic pancreatitis with significant hazard ratios. We conclude that pancreatic enzyme replacement should be a standard treatment after operative treatment for chronic pancreatitis by the time of discharge regardless of the presence or absence of clinical signs for exocrine pancreatic failure. Furthermore, this study may underline the importance of early operative intervention in chronic pancreatitis before irreversible endocrine dysfunction is present, although our study did not address this question. Clinical studies would be desirable to determine the optimal dosing of pancreatic enzyme replacement therapy in this clinical setting. A recent review describes the detrimental effects of pancreatic exocrine insufficiency in patients with pancreatic diseases including pancreatitis
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that often result in malnutrition, weight loss, and steatorrhea, which together increase the risk of morbidity and mortality.6 Currently, nutritional interventions including pancreatic enzyme replacement therapy are needed for these patients to improve clinical symptoms and to address the pathophysiology of pancreatic insufficiency.6 This treatment improves associated symptoms and the coefficients of absorption for fat, nitrogen, and liposoluble vitamins without serious adverse events.6 The present study highlights the value of such an approach and shows a significant impact of pancreatic enzyme replacement therapy on long-term patient survival after operative treatment of chronic pancreatitis, although a dose-dependent effect could not be verified. It may be that all patients with chronic pancreatitis may benefit from pancreatic enzyme replacement therapy in this respect, especially in cases with subclinical exocrine pancreatic failure. Further prospective studies with functional physiologic investigations are needed to address this important issue. A comprehensive meta-analysis came to the conclusion that the role of pancreatic enzyme replacement therapy for the treatment of abdominal pain, weight loss, steatorrhea, analgesic use, and quality of life in patients with chronic pancreatitis remains equivocal,7 although Thorat et al8 found recently that pancreatic enzyme replacement therapy leads to an increase in weight gain. The influence of pancreatic enzyme replacement therapy on survival was not evaluated so far owing to lack of published data. Pancreatic diabetes is notoriously difficult to manage and characterized by frequent hypoglycemic events.1,9 Our study demonstrates the prognostic significance of insulin dependence before and after operative intervention for chronic pancreatitis and its influence on long-term patient survival. In this context, a large cohort study from Taiwan demonstrated that the risk of pancreatic cancer is moderately increased in patients with diabetes, especially those using insulin therapy. Interestingly, the risk is greatly increased for diabetic patients with chronic pancreatitis.10 This observation may be relevant for patients with chronic pancreatitis suffering from insulin-dependent pancreatic diabetes. These cases may carry a greater risk of pancreatic carcinoma within morphologic changes within the pancreas that may otherwise be attributed to chronic pancreatitis. These patients may profit from a more aggressive operative approach. Some groups consider that resection for chronic pancreatitis is frequently assumed to be
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more likely to result in endocrine and exocrine insufficiency and should thus be avoided in cases that could also be treated with an organ-preserving decompression procedure. This view is prevalent, although a significant negative influence of resectional procedures on short- or long-term endocrine and/or exocrine pancreatic function could not be demonstrated.1,3,11,12 Our present study does not support such a notion. In this context it is interesting to note that Andersen and Frey3 favor local resection or excavation of the pancreatic head, because they believe that this approach lessens the risk for early postoperative diabetes, although they were unable to demonstrate data to support this view. We believe that the operative procedures seem to be equivalent in their longterm effect as long as they are applied correctly based on the anatomic findings of the individual patient. The present study seems to underline this notion. Our study also shows that preoperative alcohol abuse had no statistical influence on long-term survival. Alcohol abuse was the most frequent etiology for chronic pancreatitis in this cohort. Similar observations were also described by other authors.11,13,14 The 30-day mortality was largely in line with other published series.12,15,16 In our study, the principle of operative decompression had no effect on long-term survival compared with resection and hybrid principles. Other authors, however, have refuted this concept.1,17,18 In the current study, the necessity of reoperation had no influence on long-term patient survival. In our study, the surgical principle adopted (decompression versus resection versus hybrid procedures) and the operative procedure itself had no influence on improvement of long-term quality of life or on the absence or improvement of pain during long-term follow-up. Aimoto et al1 and van der Gaag et al12 have reported recently similar observations. In this context, several prospective, randomized trials that compared 2 different operative approaches to chronic pancreatitis were unable to demonstrate statistically significant advantages of 1 method over the other in respect to clinical outcome, including quality of life, morbidity, recurrent pain, diabetes, exocrine pancreatic function, and mortality.1,3,11,14-16,18-23 In our opinion, the combination of morphologic changes within the pancreas and their anatomic location dictate the operative principle and the operative procedure. This view is shared by several other authors.1,12,14,24 The results of an older, large, retrospective analysis including 504 patients with excellent
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long-term follow-up (maximum, 14 years; 1972– 1998) from Germany reported improvement of quality of life for 72% of patients,15 which is in line with ours, although professional reintegration was somewhat less in the current cohort. This latter observation may be influenced to some degree by societal changes in Germany within the last 40 years. A recent study from The Netherlands found that full professional reintegration with paid work could only be achieved by 34% of patients during long-term follow-up.12 The frequency of full professional reintegration during follow-up varies greatly in different publications, from 25% to 80%.11-13,15,16,20-22 We believe that this variation is likely influenced by the age of the analyzed patients, different durations of follow-up, and national differences in social systems with different attitudes toward definitions of disability among young, chronically ill patients. Our data failed to demonstrate a significant influence of any specific operative approaches on long-term professional rehabilitation.11-13,15,16,20-22 Patients who reported postoperative opioid use during follow-up were significantly more likely to report lack of professional reintegration. Preoperative amylase and lipase levels were of no use in predicting postoperative pain control at the time of hospital discharge or during long-term follow-up.25,26 Successful long-term pain control in this series could not be attributed to a specific surgical principle or a specific operative procedure as reported in previous publications.11-13,15,16,20-22,27 Interestingly, the present study shows that male patients achieved better long-term freedom from pain than females, in line with the greater pain prevalence in women, which is consistently observed but not well understood.28 Illegal (eg, psychostimulants, opioids, cannabinoids) and legal (alcohol, nicotine) drugs of abuse create a complex behavioral pattern composed of drug intake, withdrawal, seeking, and relapse.29 This concept may explain our findings that patients with preoperative alcohol abuse had a greater rate of subjective pain during long-term follow-up and were more likely to use opioids during long-term follow-up.
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4. Liao Q, Zhao YP, Yang YC, et al. Combined detection of serum tumor markers for differential diagnosis of solid lesions located at the pancreatic head. Hepatobiliary Pancreat Dis Int 2007;6:641-5. 5. Brimiene_ V, Brimas G, Strupas K. Differential diagnosis between chronic pancreatitis and pancreatic cancer: a prospective study of 156 patients. Medicina (Kaunas) 2011;47: 154-62. 6. Nakajima K, Oshida H, Toshitaka M, et al. Pancrelipase: an evidence-based review of its use for treating pancreatic exocrine insufficiency. Core Evidence 2012;7:77-91. 7. Shafiq N, Rana S, Bhasin D, et al. Pancreatic enzymes for chronic pancreatitis. Cochrane Database Syst Rev 2009;7: CD006302. 8. Thorat V, Reddy N, Bhatia S, et al. Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis-a doubleblind, placebo-controlled study. Aliment Pharmacol Ther 2012;36:426-36. 9. Sasikala M, Talukdar R, Pavan Kumar P, et al. b-Cell dysfunction in chronic pancreatitis. Dig Dis Sci 2012;57:1764-72. 10. Lai HC, Tsai IJ, Chen PC, et al. Gallstones, a cholecystectomy, chronic pancreatitis, and the risk of subsequent pancreatic cancer in diabetic patients: a population-based cohort study. J Gastroenterol 2013;48:721-7. 11. B€ uchler MW, Friess H, Bittner R, et al. Duodenum-preserving pancreatic head resection: long-term results. J Gastrointest Surg 1997;1:13-9. 12. van der Gaag NA, van Gulik TM, Busch ORC, et al. Functional and medical outcomes after tailored surgery for pain due to chronic pancreatitis. Ann Surg 2012;255:763-70. 13. R€ uckert F, Distler M, Hoffmann S, et al. Quality of life in patients after pancreaticoduodenectomy for chronic pancreatitis. J Gastrointest Surg 2011;15:1143-50. 14. Keck T, Wellner UF, Riediger H, et al. Long-term outcome after 92 duodenum-preserving pancreatic head resections for chronic pancreatitis: comparison of Beger and Frey Procedures. J Gastrointest Surg 2010;14:549-56. 15. Beger HG, Schlossser W, Friess H, et al. Duodenum-preserving head resection in chronic pancreatitis changes the natural course of the disease. A single-center 26-year experience. Ann Surg 1999;230:512-23. 16. Izbicki JR, Bloechle C, Broering DC, et al. Extended drainage versus resection in surgery for chronic pancreatitis. A prospective randomized trial comparing the longitudinal pancreaticojejunostomy combined with local pancreatic head excision with the pylorus-preserving pancreatoduodenectomy. Ann Surg 1998;228:771-9.
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17. Yin Z, Sun J, Yin D, et al. Surgical treatment strategies in chronic pancreatitis. A meta-analysis. Arch Surg 2012;147: 961-8. 18. Zheng Z, Xiang G, Tan C, et al. Pancreaticoduodenectomy versus duodenum-preserving pancreatic head resection for the treatment of chronic pancreatitis. Pancreas 2012;41: 147-52. 19. K€ oninger J, Seiler CM, Sauerland S, et al. Duodenum-preserving pancreatic head resection: a randomized controlled trial comparing the original Beger procedure with the Berne modification. J Surg 2008;143:490-8. 20. Farkas G, Leindler L, Daroczi M, et al. Prospective randomised comparison of organ-preserving pancreatic head resection with pylorus-preserving pancreaticoduodenectomy. Langenbecks Arch Surg 2006;391:338-42. 21. Izbicki JR, Bloechle C, Knoefel WT, et al. Drainage versus Resektion in der chirurgischen Therapie der chronischen Pankreatitis: eine randomisierte Studie. Chirurg 1997;68: 369-77. 22. Izbicki JR, Bloechle C, Knoefel WT, et al. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized trial. Ann Surg 1995;221:350-8. 23. Klempa I, Spatny M, Menzel J. Pancreatic function and quality of life after resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized comparative study after duodenum preserving resection of the head of the pancreas versus Whipple’s operation. Chirurg 1995;66:350-9. 24. Riediger H, Adam U, Fischer E, et al. Long-term outcome after resection for chronic pancreatitis in 224 patients. J Gastrointest Surg 2007;11:949-60. 25. Halm U, Rohde N, Klapdor R, et al. Improved sensitivity of fuzzy logic based tumor marker profiles for diagnosis of pancreatic carcinoma versus benign pancreatic disease. Anticancer Res 2000;20:4957-60. 26. Donnely JG, Ooi DS, Burns BF, et al. Chronic increased serum lipase without evidence of pancreatitis: tumorderived lipase? Clin Chem 1996;42:462-4. 27. B€ uchler MW, Friess H, M€ uller MW, et al. Randomized trial of duodenum-preserving pancreatic head resection versus pylorus-preserving Whipple in chronic pancreatitis. Am J Surg 1995;169:65-70. 28. Leresche L. Defining gender disparities in pain management. Clin Orthop Relat Res 2011;469:1871-7. 29. Filip M, Zaniewska M, Frankowska M, et al. The importance of the adenosine A(2A) receptor-dopamine D(2) receptor interaction in drug addiction. Curr Med Chem 2012;19: 317-55.
