title: The novel tumor angiogenic factor, adrenomedullin-2, predicts survival in pancreatic adenocarcinoma.
abstract: BACKGROUND
  Tumor angiogenesis has been demonstrated to have an important role in the development, progression, and metastasis of pancreas cancer. Adrenomedullin-2 (ADM2) is a calcitonin gene-related peptide that has recently been shown to be a novel tumor angiogenesis factor, acting via mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/Akt, and vascular endothelial growth factor/vascular endothelial growth factor-2 signaling pathways. Through the use of tissue microarray (TMA) technology, we hypothesize that ADM2 is an important tumor angiogenesis factor in pancreatic cancer.
  
  
  METHODS
  Multiple TMAs were created using tissue from pancreatic cancer patients resected between January 1996 and December 2006. Core tissue samples of formalin-fixed, paraffin-embedded blocks of pancreatic cancer tissue were collected through an institutional review board-approved protocol and linked to available clinicopathologic data. Two TMAs consisting of 112 and 60 patients with pancreatic adenocarcinoma were studied for ADM2 protein expression using a quantitative, automated immunofluorescent microscopy system, a technology that removes potential observer bias in TMA analysis. The results were analyzed using independent Student t-test, chi-square, log-rank regression, and Kaplan-Meier methods.
  
  
  RESULTS
  One hundred sixteen patients were identified for complete analysis, and 56 patients had complete survival data. Median follow-up for survivors was 14.5 mo. Total cellular levels of ADM2 were found to be a predictor of survival in pancreatic cancer. Low ADM2 levels were associated with a higher 5-y survival compared with high ADM2 levels (18% versus 6%, P = 0.05). Median survival was also worse in high ADM2 expressers (18.7 versus 8.6 mo). In accordance with prior-published pancreatic cancer data, a worse histologic grade (P = 0.001), tumor (T) stage (P = 0.009), and overall disease stage (P = 0.004), all portended a worse survival.
  
  
  CONCLUSIONS
  For the first time, we have demonstrated that high levels of ADM2 expression predict a poorer survival in patients with pancreatic adenocarcinoma. This suggests a possible role of ADM2 in pancreas cancer and as a novel biomarker that predicts poorer survival. Additional study of ADM2 in pancreatic cancer will help reveal its true angiogenic role in pancreas cancer and its potential role as a novel therapeutic target.
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut.
authors.forename: Lindsay L
authors.initials: LL
authors.lastname: Hollander
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Salem
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut. Electronic address: Charles.cha@yale.edu.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Cha
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D036361:Peptide Hormones / Q000378:metabolism*; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: C484330:ADM2 protein, human; D014408:Biomarkers, Tumor; D036361:Peptide Hormones
keywords: Adrenomedullin-2; Biomarker; Intermedin; Pancreatic adenocarcinoma; Therapeutic target; Tissue microarray; Tumor angiogenesis