Niels A. van der Gaag

Preoperative biliary drainage for cancer of the head of the pancreas

BACKGROUND The benefits of preoperative biliary drainage, which was introduced to improve the postoperative outcome in patients with obstructive jaundice caused by a tumor of the pancreatic head, are unclear. METHODS In this multicenter, randomized trial, we compared preoperative biliary drainage with surgery alone for patients with cancer of the pancreatic head. Patients with obstructive jaundice and a bilirubin level of 40 to 250 micromol per liter (2.3 to 14.6 mg per deciliter) were randomly assigned to undergo either preoperative biliary drainage for 4 to 6 weeks, followed by surgery, or surgery alone within 1 week after diagnosis. Preoperative biliary drainage was attempted primarily with the placement of an endoprosthesis by means of endoscopic retrograde cholangiopancreatography. The primary outcome was the rate of serious complications within 120 days after randomization. RESULTS We enrolled 202 patients; 96 were assigned to undergo early surgery and 106 to undergo preoperative biliary drainage; 6 patients were excluded from the analysis. The rates of serious complications were 39% (37 patients) in the early-surgery group and 74% (75 patients) in the biliary-drainage group (relative risk in the early-surgery group, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). Preoperative biliary drainage was successful in 96 patients (94%) after one or more attempts, with complications in 47 patients (46%). Surgery-related complications occurred in 35 patients (37%) in the early-surgery group and in 48 patients (47%) in the biliary-drainage group (relative risk, 0.79; 95% CI, 0.57 to 1.11; P=0.14). Mortality and the length of hospital stay did not differ significantly between the two groups. CONCLUSIONS Routine preoperative biliary drainage in patients undergoing surgery for cancer of the pancreatic head increases the rate of complications. (Current Controlled Trials number, ISRCTN31939699.)

High expression of the bile salt‐homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis

Fibroblast growth factor 19 (FGF19) is an endocrine factor produced by the small intestine in response to uptake of luminal bile salts. In the liver, FGF19 binds to FGF receptor‐4, resulting in down‐regulation of cytochrome P (CYP) 7A1 and reduced bile salt synthesis. Down‐regulation of CYP7A1 under cholestatic conditions has been attributed to bile salt–mediated induction of the transcriptional repressor short heterodimer partner (SHP), because the interrupted enterohepatic cycle of bile salts is thought to abrogate intestinal FGF19 production and thus result in lowering of plasma FGF19 levels. Unexpectedly, we observed marked elevation of plasma FGF19 in patients with extrahepatic cholestasis caused by a pancreatic tumor (2.3 ± 2.3 in cholestatic versus 0.40 ± 0.25 ng/mL and 0.29 ± 0.12 ng/mL in postcholestatic patients who received preoperative drainage by biliary stenting, P = 0.004, and noncholestatic control patients, P = 0.04, respectively). Although FGF19 messenger RNA (mRNA) is virtually absent in normal liver, FGF19 mRNA was strongly increased (31‐fold to 374‐fold, P < 0.001) in the liver of cholestatic patients in comparison with drained and control patients. In the absence of changes in SHP mRNA, CYP7A1 mRNA was strongly reduced (7.2‐fold to 24‐fold, P < 0.005) in the liver of cholestatic patients in comparison with drained and control patients, indicating an alternative regulatory pathway. Alterations in transcripts encoding hepatobiliary transporters [adenosine triphosphate–binding cassette, subfamily C, member 3 (ABCC3)/multidrug resistance protein 3 (MRP3), organic solute transporter α/β (OSTα/β), organic anion‐transporting polypeptide (OATP1B1)] further suggest that bile salts are secreted via a nonbiliary route in patients with extrahepatic cholestasis. Conclusion: The liver expresses FGF19 under conditions of extrahepatic cholestasis. This is accompanied by a number of adaptations aimed at protecting the liver against bile salt toxicity. FGF19 signaling may be involved in some of these adaptations. (HEPATOLOGY 2009.)

Therapeutic delay and survival after surgery for cancer of the pancreatic head with or without preoperative biliary drainage.

Objective:To evaluate the relation between delay in surgery because of preoperative biliary drainage (PBD) and survival in patients scheduled for surgery for pancreatic head cancer. Background:Patients with obstructive jaundice due to pancreatic head cancer can undergo PBD. The associated delay of surgery can lead to more advanced cancer stages at surgical exploration, affecting resection rate and survival. Methods:We conducted a multicenter, randomized controlled clinical trial to compare PBD with early surgery (ES) for pancreatic head cancer for complications. We obtained Kaplan-Meier estimates of overall survival for patients with pathology-proven malignancy and compared survival functions of ES and PBD groups using log-rank test statistics. Multivariable Cox regression analyses were performed to evaluate the prognostic role of time to surgery for overall survival. Results:Mean times from randomization to surgery were 1.2 (0.9-1.5) and 5.1 (4.8-5.5) weeks in the ES and PBD groups, respectively (P < 0.001). In the ES group, 60 (67%) of 89 patients underwent resection, versus 53 (58%) of 91 patients in the PBD group (P = 0.20). Median survival after randomization was 12.2 (9.1-15.4) months in the ES group versus 12.7 (8.9-16.6) months in the PBD group (P = 0.91). A longer time to surgery was significantly associated with slightly lower mortality rate after surgery (hazard ratio = 0.90, 95% CI, 0.83-0.97), when taking into account resection, bilirubin, complications, pancreatic adenocarcinoma, tumor-positive lymph nodes, and microscopically residual disease. Conclusions:In patients with pancreatic head cancer, the delay in surgery associated with PBD does not impair or benefit survival rate.

Chylous Ascites after Pancreaticoduodenectomy: Introduction of a Grading System

BACKGROUND Chylous ascites (CA) is a complication that follows thoracic and abdominal surgery, recognized after provocation by enteral feeding and characterized by its milky appearance from an elevated triglyceride level. The aim of this study was to evaluate incidence, management, and predisposing factors of CA and its impact on outcomes after pancreaticoduodenectomy. STUDY DESIGN Between 1996 and 2007, 609 consecutive patients underwent pancreaticoduodenectomy. Patients having a drain output with a milky appearance, and with a triglyceride level greater than 1.2 mmol/L, were compared with patients without significant drain production or with a low triglyceride level. Management of CA was reviewed. RESULTS Sixty-six patients had isolated CA (11%) of any measurable volume, 440 patients (72%) had no CA, and 109 patients (16%) were excluded from analysis. CA was diagnosed on postoperative day 6 (median; interquartile range 5 to 8), generally after introduction of a normal (polymeric low-chain-triglyceride) diet. Female gender (odds ratio, 1.79; 95% CI, 1.05 to 3.03) and chronic pancreatitis at pathology (odds ratio, 2.52; 95% CI, 1.19 to 5.32) were independently associated with development of isolated CA. A low-chain-triglyceride-restricted diet was initiated in 47 patients, 3 were started on total parenteral nutrition, and an expectative approach was followed in 16 patients. CA resolved after 3.5 days (median; interquartile range, 2 to 5). Isolated CA was significantly associated with prolonged hospital stay (p=0.002). CONCLUSIONS We propose a novel definition and grading system for CA after pancreaticoduodenectomy, according to which the incidence is 9%, with clinically significant CA occurring in 4% (grades B and C). Although female gender and (focal) chronic pancreatitis were associated with development of isolated CA, no predisposing factors that could readily anticipate CA were identified. Isolated CA was associated with prolonged hospital stay.

A comparative study of intraductal papillary neoplasia of the biliary tract and pancreas.

Intraductal papillary mucinous neoplasm of the pancreas is a rare but well-established entity in contrast to intraductal papillary mucinous neoplasm of the biliary tract. The aim of this study was to compare the clinicopathologic features of intraductal papillary mucinous neoplasms of the biliary tract and of the pancreas. Twenty patients who underwent resection for intraductal papillary mucinous neoplasm of the biliary tract were compared with 29 cases resected for intraductal papillary mucinous neoplasm of the pancreas. Clinicopathologic characteristics and resection specimens of all patients were reassessed and immunohistochemically screened for expression of a distinct set of tumor markers. Median ages of patients with intraductal papillary mucinous neoplasms of the biliary tract and of the pancreas were 66 and 62 years, respectively (P < .05). Twelve patients with intraductal papillary mucinous neoplasm of the biliary tract (60%) had neoplasms with infiltrating carcinoma, compared with 6 patients with intraductal papillary mucinous neoplasm of the pancreas (21%, P < .05). Cytokeratin 7 and 20 expressions were equal in biliary and pancreatic intraductal papillary mucinous neoplasms. Cytokeratin 20 expression was mainly found in intestinal-type tumors. Gastric, pancreaticobiliary, and oncocytic subtypes were all observed in the intraductal papillary mucinous neoplasm of the biliary tract group. The distribution was significantly different from the intraductal papillary mucinous neoplasm of the pancreas group. The 3-year overall survival rate of malignant biliary and pancreatic intraductal papillary mucinous neoplasm was 63% and 65%, respectively (P = .798). Positive lymph nodes and a high expression of membranous mucin were associated with a significantly shorter overall survival in patients with malignant intraductal papillary mucinous neoplasm. Finally, p53 and Ki67 proliferation index were both associated with the carcinogenesis of intraductal papillary mucinous neoplasm, whereas DPC4 and CDX2 were not. Clinicopathologic features of intraductal papillary mucinous neoplasm of the biliary tract largely resemble those of intraductal papillary mucinous neoplasm of the pancreas, although intraductal papillary mucinous neoplasm of the biliary tract was associated with a higher malignancy rate at the time of surgical treatment. The level of membranous mucin expression and positive lymph nodes are significant prognosticators in patients with malignant intraductal papillary mucinous neoplasm.

Functional and medical outcomes after tailored surgery for pain due to chronic pancreatitis

Objective:We measured a comprehensive set of outcome measures after different surgical procedures for painful chronic pancreatitis (CP) at long-term follow-up. Background:Pain caused by CP can be alleviated through operative intervention with type of procedure depending on anatomical abnormalities. Outcome measures include functional (pain relief, quality of life [QoL]), medical (endo- and exocrine function), and clinical (reoperation) results reported by patient. Methods:A cross-sectional cohort of 223 consecutive patients who underwent surgical drainage, head resection, or left-sided pancreas resection, depending on anatomical abnormalities, was analyzed. Participating patients were reassessed during a prospectively scheduled outpatient clinic visit. Results:At follow-up, 44 patients had died; 146 of 179 living patients consented to participate in the study. After 63 months (range: 14–268), 68% reported no or little pain, 19% reported intermediate pain, and 12% reported severe pain. Preoperative daily opioid use (OR: 3.04; 95% confidence interval [CI]: 1.09–8.49) and high numbers of preceding endoscopic procedures (OR [odds ratio]: 3.89; 95% CI: 1.01–14.9) were associated with persistent severe pain. Compared with the general population, physical more than mental QoL remained impaired (P < 0.05). At follow-up, endocrine insufficiency was present in 57% of patients and exocrine insufficiency was present in 77%. Independently, a head resection and a reoperation for any cause were moderately associated with new-onset diabetes (P < 0.1). Compared with patients who underwent left-sided resection, the risk of developing exocrine insufficiency after surgery was higher after drainage or head resection. After 20 months (interquartile range: 10–51) after surgery, 26 (12%) of 223 patients underwent 1 or more elective reoperations. Conclusions:Operative intervention for painful CP, tailored to anatomical abnormalities, results in excellent to fair long-term pain relief, but approximately 10% of patients do not respond. QoL scores remained slightly compromised. High preoperative pain levels, suggested through daily opioid use and high numbers of endoscopic procedures, are associated with less favorable outcome.

Effect of preoperative biliary drainage on coagulation and fibrinolysis in severe obstructive cholestasis.

Goals To evaluate the function of coagulation and fibrinolysis in cholestatic patients before and after preoperative biliary drainage (PBD). Background Cholestasis owing to an obstructive biliary malignancy is associated with postoperative complications related to a proinflammatory state, an impaired hepatic synthesis function, and a potential derangement of hemostasis. Hence, PBD is advocated for cholestatic patients undergoing major surgery. Study Plasma coagulation and fibrinolytic parameters were assessed in 24 cholestatic patients and 10 controls. In 9 cholestatic patients, the parameters were reassessed at least 4 weeks after PBD. Results Compared with controls, cholestatic patients showed lower concentrations (P<0.001) of plasma vitamin K-dependent factors II and VII, whereas prothrombin time, activated partial thromboplastin time, and factor V were unaltered. Thrombin generation was increased in cholestatic patients, as reflected by higher plasma concentrations of thrombin-antithrombin complexes and D-dimers. Fibrinolysis was significantly impaired as evidenced by low plasminogen activator activity (PAA) owing to an increase in plasminogen activator inhibitor -1). Elevated markers for thrombin generation thrombin-antithrombin decreased after PBD from 10.7±1.2 to 5.7±0.7 ng/mL (P<0.05). Additionally, impairment of fibrinolysis in cholestatic patients resolved after PBD (plasminogen activator inhibitor-1 levels decreased from 19±1 to 10±1 IU/mL and plasminogen activator activity increased from 82±3 to 110±4%, respectively). D-dimers remained unaltered after PBD, likely because of normalization of coagulation and fibrinolytic activity. Conclusions Obstructive cholestasis is associated with a procoagulant state, despite an impaired vitamin K-dependent coagulation factor synthesis. Virtually all alterations in coagulation and fibrinolysis were reversed by biliary drainage.

The quandary of preresection biliary drainage for pancreatic cancer.

Abstract Surgery in patients with obstructive jaundice caused by a tumor in the pancreatic head area is associated with a higher risk of postoperative complications. Preoperative biliary drainage was introduced in an attempt to improve the general condition and reduce morbidity and mortality. Extensive experimental studies have been performed to analyze the beneficial effect of biliary drainage and showed improvement in liver function, nutritional status, and cell-mediated immune function as well as reduction in mortality. However, despite the results seen in the experimental studies, clinical studies reported both beneficial and adverse effects, and most studies advised against routinely performing preoperative biliary drainage. To add clarity to the ongoing controversy, a recent randomized controlled trial was performed and reported more overall complications in patients with jaundice who underwent preoperative biliary drainage followed by surgery compared to those who underwent surgery alone. Many of these complications were stent related. Like most clinical studies, a plastic stent was used to initiate biliary drainage. Patients with jaundice because of a tumor in the pancreatic head area without locoregional irresectability or metastases should be candidates for early surgery. Preoperative biliary drainage should not be performed routinely. However, some selected patients might benefit from preoperative biliary drainage, in cases of severe jaundice, neoadjuvant therapy, or postponed surgery due to logistics. In these cases, the use of metal biliary stents is indicated.

Quality of life and functional outcome after resection of pancreatic cystic neoplasm

Objectives The objectives of this study were to assess the long-term quality of life (QOL) after the resection of a primary pancreatic cyst and to determine predictors of outcome. Secondary outcomes were pancreatic function and survival. Methods One hundred eight consecutive patients, who underwent resection between 1992 and 2007 and had nearly 60 months follow-up, were reviewed. Questionnaires and function tests were collected during scheduled outpatient clinic visits. Results At follow-up, 20 patients had died. Five-year overall survival was 94% for benign and 62% for malignant neoplasia. Of 88 living patients, 65 (74%) returned questionnaires. Generic physical and mental QOL scores were equal or better compared with healthy references. None of the disease-specific symptom scales were above mean 50, implicating none to mild complaints. Independent predictors for good generic QOL were young age (P < 0.05) and resected malignancy (P < 0.05); predictors for good gastrointestinal QOL were male sex (P < 0.1), limited resection (P < 0.05), endocrine insufficiency (P < 0.05), and employment (P < 0.05). Endocrine insufficiency prevalence was 40%, and 59% for exocrine insufficiency. Conclusions After cyst resection, long-term QOL is equal to healthy references, pancreatic insufficiency is prevalent but does not impair QOL, and survival relates positive compared with solid pancreatic adenocarcinoma. The excellent long-term outcome justifies proceeding with surgery once a medical indication for resection has been established.

Role of preoperative biliary drainage in jaundiced patients who are candidates for pancreatoduodenectomy or hepatic resection.

To the editor: W ith interest, we read the review article by Iacono et al1 concerning the role of preoperative biliary drainage (PBD) for pancreatic (middle or distal bile duct obstruction) or hepatic (proximal obstruction) resection. We encourage the subject to be discussed, but we feel that several major misconceptions in their criticism of our randomized trial on PBD for pancreatic cancer should be corrected.2 We will discuss the author’s criticism to our study in corresponding numbers.