title: High expression of delta-like ligand 4 predicts poor prognosis after curative resection for pancreatic cancer.
abstract: BACKGROUND
  Delta-like ligand 4 (DLL4)-Notch signaling plays a key role in tumor angiogenesis, but its prognostic value in patients with pancreatic ductal adenocarcinoma (PDAC) remains unclear. Our aim was to determine whether high DLL4 expression is correlated with poor prognosis after curative resection for PDAC.
  
  
  METHODS
  Surgical specimens obtained from 89 patients with PDAC were immunohistochemically assessed for DLL4 and vascular endothelial growth factor receptor 2 (VEGFR-2) expression. Prognostic significance of DLL4 expression was evaluated by Kaplan-Meier method and Cox regression. The correlations of DLL4 expression with VEGFR-2 expression, tumor stage, and lymph node metastasis were examined by chi-square test and multivariate logistic regression.
  
  
  RESULTS
  There were 38 (42.7%) and 51 patients who showed high and low DLL4 expression, respectively. Survival curves showed that patients with low DLL4 expression had a significantly better survival than those with high DLL4 expression (P < .001). Multivariate survival analysis demonstrated that high DLL4 expression was independently associated with both reduced overall survival (hazard ratio [HR] 2.24; 95% confidence interval [95% CI] 1.14-4.38) and reduced progression-free survival (HR 2.37; 95% CI 1.22-4.60). Multivariate logistic regression analyses showed that high DLL4 expression was independently associated with both advanced tumor stage (odds ratio [OR] 6.84; 95% CI 2.42-9.36) and lymph node metastasis (OR 3.27; 95% CI 1.04-10.34). We also found a positive correlation between DLL4 and VEGFR-2 expression (P < .001).
  
  
  CONCLUSIONS
  High DLL4 expression is significantly associated with poor prognosis for surgically resected PDAC, advanced tumor stage, and lymph node metastasis. Application of adjuvant therapy targeting DLL4-Notch signaling may improve prognosis.
authors.affiliation: Center for Clinical Epidemiology and Evidence-Based Medicine, Second Military Medical University, Shanghai, China.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Chen
authors.forename: Quan-Cai
authors.initials: QC
authors.lastname: Cai
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Zheng
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Man
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.forename: Gang
authors.initials: G
authors.lastname: Jin
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Zhao-Shen
authors.initials: ZS
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000378:metabolism* / Q000556:secondary / Q000601:surgery; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D018655:Lymphocyte Count; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009504:Neutrophils; D010190:Pancreatic Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D010976:Platelet Count; D016016:Proportional Hazards Models; D012372:ROC Curve; D047368:Tumor Burden; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C064045:delta protein; D040301:Vascular Endothelial Growth Factor Receptor-2