Koert F. D. Kuhlmann

Hospital volume and mortality after pancreatic resection - A systematic review and an evaluation of intervention in The Netherlands

Objectives:To evaluate the best available evidence on volume-outcome effect of pancreatic surgery by a systematic review of the existing data and to determine the impact of the ongoing plea for centralization in The Netherlands. Summary Background Data:Centralization of pancreatic resection (PR) is still under debate. The reported impact of hospital volume on the mortality rate after PR varies. Since 1994, there has been a continuous plea for centralization of PR in The Netherlands, based on repetitive analysis of the volume-outcome effect. Methods:A systematic search for studies comparing hospital mortality rates after PR between high- and low-volume hospitals was used. Studies were reviewed independently for design features, inclusion and exclusion criteria, cutoff values for high and low volume, and outcome. Primary outcome measure was hospital or 30-day mortality. Data were obtained from the Dutch nationwide registry on the outcome of PR from 1994 to 2004. Hospitals were divided into 4 volume categories based on the number of PRs performed per year. Interventions and their effect on mortality rates and centralization were analyzed. Results:Twelve observational studies with a total of 19,688 patients were included. The studies were too heterogeneous to allow a meta-analysis; therefore, a qualitative analysis was performed. The relative risk of dying in a high-volume hospital compared with a low-volume hospital was between 0.07 and 0.76, and was inversely proportional to the volume cutoff values arbitrarily defined. In 5 evaluations within a decade, hospital mortality rates were between 13.8% and 16.5% in hospitals with less than 5 PRs per year, whereas hospital mortality rates were between 0% and 3.5% in hospitals with more than 24 PRs per year. Despite the repetitive plea for centralization, no effect was seen. During 2001, 2002, and 2003, 454 of 792 (57.3%) patients underwent surgery in hospitals with a volume of less than 10 PRs per year, compared with 280 of 428 (65.4%) patients between 1994 and 1996. Conclusions:The data on hospital volume and mortality after PR are too heterogeneous to perform a meta-analysis, but a systematic review shows convincing evidence of an inverse relation between hospital volume and mortality and enforces the plea for centralization. The 10-year lasting plea for centralization among the surgical community did not result in a reduction of the mortality rate after PR or change in the referral pattern in The Netherlands.

Quality of life after curative or palliative surgical treatment of pancreatic and periampullary carcinoma

Quality of life (QOL) is an important outcome measure after treatment of pancreatic and periampullary carcinoma. The aim of this prospective longitudinal study was to analyse QOL after surgery for resectable pancreatic or periampullary carcinoma.

Incidence and management of biliary leakage after hepaticojejunostomy

This study analyzes the change in the management of biliary leakage after hepaticojejunostomy. Between 1993 and 2003 all patients (n = 1033) were studied with a hepaticojejunostomy as part of a pancreatoduodenectomy (n = 486), proximal bile duct resection (without liver resection) (n = 35), and biliodigestive bypass for malignant (n = 302) and benign (n = 210) disease. Biliary leakage was defined as the presence of bile-stained fluid (>50 mL) in the abdominal drain more than 24 hours after surgery, proven radiologically or at relaparotomy. The studied patients were divided into two equal periods to analyze the change in management. Overall, 24 of 1033 patients (2.3%) had biliary leakage. In multivariate analysis, a body mass index greater than 35 kg/m2 (P = .012), endoscopic biliary drainage (P = .044), and an anastomosis on the segmental bile ducts (P < .001) were independent predictors of leakage. Management in the first half of the study period (1993-1998) versus the second half (1999–2003) was maintenance of operatively placed drains (18% vs. 15%, respectively, P = 1.000), percutaneous transhepatic biliary drainage (18% vs. 69%, respectively, P = .012), surgical drainage (55% vs. 8%, respectively, P = .023), and re-hepaticojejunostomy (9% vs. 8%, respectively, P = 1.000). There was no mortality in the patients with biliary leakage. Leakage after a hepaticojejunostomy is a relatively rare complication without mortality and can safely be managed with percutaneous transhepatic biliary drainage.

Recurrent disease after microscopically radical (R0) resection of periampullary adenocarcinoma in patients without adjuvant therapy

The survival rate after microscopically radical resection of pancreatic duct adenocarcinoma is still poor. Patients with ampulla of Vater and distal common bile duct adenocarcinoma indicate a much more favorable prognosis. Controversy exists as to whether adjuvant therapy could improve the outcome in these patients after resection. The aim of the present study was to analyze the pattern of recurrence in patients with periampullary adenocarcinoma after pancreatoduodenectomy. Between January 1992 and December 2002, all patients with an R0 resection were identified and used for this analysis. A total of 190 patients underwent a microscopically radical resection and received no adjuvant therapy. Of those, 72 patients were diagnosed with pancreatic duct adenocarcinoma, 86 patients were diagnosed with ampulla of Vater adenocarcinoma, and 31 patients were diagnosed with distal common bile duct adenocarcinoma. Recurrent disease was indicated in 81% of the patients with pancreatic duct adenocarcinoma, 50% of the patients with ampulla of Vater adenocarcinoma, and in 74% of the patients with bile duct adenocarcinoma. Multivariate analysis revealed that lymph node metastases were prognostic for recurrent disease in patients with pancreatic duct adenocarcinoma (P = 0.038). The depth of invasion (T4, P < 0.032) and lymph node metastases (P < 0.001) were prognostic in patients with ampulla of Vater adenocarcinoma. Poor tumor differentiation (P < 0.001) was prognostic in patients with distal bile duct adenocarcinoma. Selected patients with periampullary malignancies exhibited a high recurrence rate and should be encouraged to enroll in clinical trials for adjuvant treatment including local therapy (radiotherapy) according to the identified prognostic factors.

Evaluation of Matrix Metalloproteinase 7 in Plasma and Pancreatic Juice as a Biomarker for Pancreatic Cancer

Differentiating between periampullary carcinoma and chronic pancreatitis with an inflammatory mass is difficult. Consequently, 6% to 9% of pancreatic resections for suspected carcinoma are done inappropriately for chronic pancreatitis. Here, we test if matrix metalloproteinase 7 (MMP-7), a secreted protease frequently expressed in pancreatic carcinoma, can be measured in plasma, pancreatic, and duodenal juice, and if it can distinguish between periampullary carcinoma and chronic pancreatitis. Ninety-four patients who underwent pancreatic surgery for a (peri)pancreatic neoplasm (n = 63) or chronic pancreatitis (n = 31) were analyzed. Median plasma MMP-7 levels were significantly higher in carcinoma (1.95 ng/mL; interquartile range, 0.81-3.22 ng/mL) compared with chronic pancreatitis and benign disease (0.83 ng/mL; interquartile range, 0.25-1.21 ng/mL; P < 0.01). MMP-7 levels in pancreatic juice were higher, although not significantly, in carcinoma (62 ng/mg protein; interquartile range, 18-241 ng/mg protein) compared with chronic pancreatitis and benign disease (23 ng/mg protein; interquartile range, 8.5-99 ng/mg protein; P = 0.17). MMP-7 levels in duodenal juice were universally low. At an arbitrary cutoff of 1.5 ng/mL in plasma, positive and negative predictive values were 83% and 57%, respectively, values comparable to those of todays most common pancreatic tumor marker, carbohydrate antigen 19-9 (CA19-9; 83% and 53%, respectively). Positive and negative likelihood ratios for plasma MMP-7 were 3.35 and 0.52, respectively. The area under the receiver operating characteristic curve for MMP-7 was 0.73 (95% confidence interval, 0.63-0.84) and for CA19-9, 0.75 (95% confidence interval, 0.64-0.85). Combined MMP-7 and CA19-9 assessment gave a positive predictive value of 100%. Thus, plasma MMP-7 levels discriminated between patients with carcinoma and those with chronic pancreatitis or benign disease. The diagnostic accuracy of plasma MMP-7 alone is not sufficient to determine treatment strategy in patients with a periampullary mass, but combined evaluation of plasma MMP-7 with CA19-9 and other markers may be clinically useful. (Cancer Epidemiol Biomarkers Prev 2007;16(5):886–91)

Adenoviral gene therapy for pancreatic cancer: Where do we stand?

Background: The prognosis of patients with pancreatic cancer is poor. This is mainly caused by the late diagnosis, the aggressive biology and the lack of effective treatment modalities. Adenoviral gene therapy has the potential to selectively treat both primary tumor and (micro)metastatic tissue. Methods: This review provides an overview of what has been achieved so far in the field of adenoviral gene therapy for pancreatic cancer. Results: Transductional targeting allows decreased toxicity due to vector dissemination to non-target cells and permits delivery with a lower viral dose. It can evade or diminish the immune response, which remains a major problem. Transcriptional targeting evolves quickly but essential drawbacks such as the lack of an efficient animal model delay clinical application. Few clinical trials utilizing adenoviruses have been performed in patients with pancreatic cancer today. Worldwide, only seven phase III trials are being performed investigating adenoviral vectors in cancer patients. Conclusion: A clear therapeutic effect of adenoviral gene therapy in pancreatic cancer has not yet been achieved, because the step from bench to bedside has encountered drawbacks. Combinations of the different targeting strategies and techniques to evade the immune system harbor the future for adenoviral gene therapy in patients with pancreatic cancer.

Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma

Survival of patients with pancreatic cancer is poor. Adenoviral (Ad) gene therapy employing the commonly used serotype 5 reveals limited transduction efficiency due to the low amount of coxsackie-adenovirus receptor on pancreatic cancer cells. To identify fiber-chimeric adenoviruses with improved gene transfer, a library of Ad vectors based on Ad5 and carrying fiber molecules consisting of 16 other serotypes were transduced to human pancreatic carcinoma cell lines. Adenoviruses containing fibers from serotype 16 and 50 showed increased gene transfer and were further analyzed. In a gene-directed prodrug activation system using cytosine deaminase, these adenoviruses proved to be effective in eradicating primary pancreatic tumor cells. Fiber-chimeric Ad5 containing fiber 16 and wild-type Ad5 were also transduced ex vivo to slices of normal human pancreatic tissue and pancreatic carcinoma tissue obtained during surgery. It was shown that fiber-chimeric Ad5 with fiber 16 revealed an improved gene delivery to primary pancreatic tumor tissue compared to Ad5. In conclusion, fiber-chimeric adenoviruses carrying fiber 16 and 50 reveal a significantly enhanced gene transfer and an increased specificity to human pancreatic adenocarcinoma compared to Ad5, whereas transduction to normal pancreatic tissue was decreased. These findings expand the therapeutic window of Ad gene therapy for pancreatic cancer.

778. A Novel Genetically Modified Adenovirus Vector Shows Enhanced Infectivity towards Ex Vivo Pancreatic Cancer

Top of pageAbstract Conditionally replicating adenovirus (CRAd) represents a potential therapeutic option for pancreatic cancer (PC). Clinical trials have shown safety and specificity of such adenovirus (Ad) vectors. However, transduction of tumor cells is limited by the low expression of the primary Adenovirus Receptor (CAR) on PC. To overcome this problem, Ad vectors were developed with peptides in the fiber that should allow targeting to PC. A peptide ligand for the Ephrin A2 receptor was incorporated and this vector (Ad-YSA) showed an increase of tumor cell transduction in vitro. Ad-RGD served as a positive control. Since animal models have proven to be of little value in predicting the outcome of oncolytic virotherapy, we used the tissue slice system to explore modified Ad behavior in human tissue. Fresh tissue from normal pancreas and pancreatic adenocarcinoma was obtained from surgical specimens (Whipple procedure). Slices, generated with the Krumdieck tissue slicer, were cultured in medium supplemented with growth factors in a 5/95% CO2/O2 environment. The slices were infected with 1e8 to 5e8 viral particles (wildtype and fiber modified virus harboring the green fluorescent reporter protein (GFP) gene under control of a CMV promoter (Ad.CMV.GFP). As an internal control, to correct for slice size, viability and CAR expression, an equivalent amount of wildtype Ad.CMV.dsRED per slice was added. Three days later reporter protein production was measured by fluorimetry. Morphologic features were determined by HE-staining. These experiments were performed both with primary pancreatic tissue and with tumor tissue. According to morphology, pancreas and tumor tissue could be kept alive for at least three days. Normal pancreas did not show increased transduction efficacy with Ad-RGD or Ad-YSA. Compared to wildtype Ad, Ad-RGD and Ad-YSA revealed a 1.5 to 8.6 and 1.8 to 7.6-fold increase in transduction of pancreatic cancer, respectively (n=7). We observed persistent interpatient variability of infection profiles, which may be related to differential receptor expression. We currently examine CAR, integrin and EphA2 receptor expression in the tissue slices. Our results demonstrate that targeting to the ephrin A2 receptor can augment pancreatic cancer transduction. The tissue slicer technology appears to be of great value to study host-virus interactions. (See Figure)