title: Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer.
abstract: BACKGROUND
  The potential prognostic value of several commonly investigated immunohistochemical markers in resected pancreatic cancer is variably reported. The objective of this study was to conduct a systematic review of literature evaluating p53, p16, smad4, bcl-2, bax, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression as prognostic factors in resected pancreatic adenocarcinoma and to conduct a subsequent meta-analysis to quantify the overall prognostic effect.
  
  
  METHODS
  Relevant literature was identified using Medline, EMBASE and ISI Web of Science. The primary end point was overall survival assessed on univariate analysis. Only studies analysing resected pancreatic adenocarcinoma were eligible for inclusion and the summary log(e) hazard ratio (logHR) and variance were pooled using an inverse variance approach. Evidence of heterogeneity was evaluated using the χ(2) test for heterogeneity and its impact on the meta-analysis was assessed by the I(2) statisic. Hazard ratios greater than one reflect adverse survival associated with positive immunostaining.
  
  
  RESULTS
  Vascular endothelial growth factor emerged as the most potentially informative prognostic marker (11 eligible studies, n=767, HR=1.51 (95% confidence interval, CI=1.18-1.92)) with no evidence of any significant publication bias (Egger's test, P=0.269). Bcl-2 (5 eligible studies, n=314, HR=0.51 (95% CI=0.38-0.68)), bax (5 studies, n=274, HR=0.63 (95% CI=0.48-0.83)) and p16 (3 studies, n=229, HR=0.63 (95% CI=0.43-0.92)) also returned significant overall survival differences, but in smaller patient series due to a lack of evaluable literature. Neither p53 (17 studies, n=925, HR=1.22 (95% CI=0.96-1.56)), smad4 (5 studies, n=540, HR=0.88 (95% CI=0.61-1.27)) nor EGFR (4 studies, n=250, HR=1.35 (95% CI=0.80-2.27)) was found to represent significant prognostic factors when analysing the pooled patient data. There was evidence of significant heterogeneity in four of the seven study groups.
  
  
  CONCLUSIONS
  These results support the case for immunohistochemical expression of VEGF representing a significant and reproducible marker of adverse prognosis in resected pancreatic cancer.
authors: Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Royal Liverpool University Hospital, 5th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK.
authors: R A
authors: RA
authors: Smith
authors: J
authors: J
authors: Tang
authors: C
authors: C
authors: Tudur-Smith
authors: J P
authors: JP
authors: Neoptolemos
authors: P
authors: P
authors: Ghaneh
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000473:pathology* / Q000601:surgery; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000276:immunology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D066246:ErbB Receptors / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000032:analysis; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000473:pathology* / Q000601:surgery; D011237:Predictive Value of Tests; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051901:Smad4 Protein / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: C494826:BAX protein, human; D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016159:Tumor Suppressor Protein p53; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; C512478:EGFR protein, human; D066246:ErbB Receptors