title: Absence of FLICE-inhibitory protein is a novel independent prognostic marker for very short survival in pancreatic ductal adenocarcinoma.
abstract: OBJECTIVE
  Evading apoptosis is a hallmark of pancreatic cancer. In pancreatic cancer models, chemotherapy down-regulates the antiapoptotic protein cellular FLICE inhibitory protein (c-FLIP), which renders cells sensitive to apoptosis. Currently, the relevance of c-FLIP expression as a biomarker in pancreatic cancer is unknown, and here we assessed the prognostic significance of the c-FLIP expression status in a large cohort of pancreatic cancer patients with clinical follow-up.
  
  
  METHODS
  Cellular FLICE inhibitory protein expression levels were determined by immunohistochemistry in 120 surgically resected ductal pancreatic adenocarcinomas. Survival analysis by c-FLIP status was compared with established clinicopathologic biomarkers as well as Ki-67 and cyclooxygenase 2 expression levels as 2 other established independent prognostic biomarkers in pancreatic cancer.
  
  
  RESULTS
  Of 120 tumors, 111 (91%) were c-FLIP positive, whereas 9 (9%) were completely c-FLIP negative. Cyclooxygenase 2 was positive in 59 cases (52%), and Ki-67 was positive in more than 10% of tumor cells in 51 cases (44%). Univariate and multivariate survival analysis (correcting for stage, grade, and proliferation index) showed that c-FLIP is an independent prognostic factor. Specifically, c-FLIP negativity identifies 9% of patients with a highly aggressive disease course (P = 0.0001).
  
  
  CONCLUSIONS
  Cellular FLICE inhibitory protein expression status is a valuable prognostic biomarker in pancreatic cancer.
authors.affiliation: From the *Department of Pathology, †Comprehensive Cancer Center Ulm, and Departments of ‡General, Visceral and Transplantation Surgery and §Internal Medicine, University Hospital Ulm, Germany; and ∥Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Germany.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Schmid
authors.forename: Marie-Charlotte
authors.initials: MC
authors.lastname: Glatzel
authors.forename: Claudia
authors.initials: C
authors.lastname: Welke
authors.forename: Marko
authors.initials: M
authors.lastname: Kornmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Kleger
authors.forename: Thomas F E
authors.initials: TF
authors.lastname: Barth
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Lennerz
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D019394:Ki-67 Antigen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human