title: Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma.
abstract: BACKGROUND
  Mixed lineage kinase domain-like protein (MLKL) is a necrosome component mediating programmed necrosis that may be an important determinant of cancer cell death. The goal of the current study was to evaluate the prognostic value of MLKL expression in patients with pancreatic adenocarcinoma (PAC).
  
  
  METHODS
  Tissue from 80 patients was collected from a prospectively maintained database of patients with PAC who underwent pancreaticoduodenectomy between January 2000 and October 2008. Immunohistochemistry analysis was performed and scored using an established scoring system. Kaplan-Meier survival curves were generated for recurrence-free survival (RFS) and overall survival (OS) for all patients and for patients receiving adjuvant chemotherapy. MLKL scores were correlated with RFS and OS using univariate and multivariate Cox regression analyses incorporating clinically relevant covariates.
  
  
  RESULTS
  The median age of the patients was 63 years and 53% were men. Low MLKL expression was associated with decreased OS (6 months vs 17 months; P = .006). In the subset of 59 patients who received adjuvant chemotherapy, low MLKL expression was associated with decreased RFS (5 months vs 15 months; P = .006) and decreased OS (6 months vs 19 months; P < .0001). On multivariate analysis, low MLKL expression was associated with poor OS in all patients (hazards ratio, 4.6 [95% confidence interval, 1.6-13.8]; P = .006) and in patients receiving adjuvant chemotherapy (hazards ratio, 8.1 [95% confidence interval, 2.2-29.2]; P = .002).
  
  
  CONCLUSIONS
  Low expression of MLKL is associated with decreased OS in patients with resected PAC and decreased RFS and OS in the subset of patients with resected PAC who receive adjuvant chemotherapy. The use of this biomarker in patients with PAC may provide important prognostic information.
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Colbert
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Fisher
authors.forename: Claire W
authors.initials: CW
authors.lastname: Hardy
authors.forename: William A
authors.initials: WA
authors.lastname: Hall
authors.forename: Burcu
authors.initials: B
authors.lastname: Saka
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Shelton
authors.forename: Aleksandra V
authors.initials: AV
authors.lastname: Petrova
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Warren
authors.forename: Brooke G
authors.initials: BG
authors.lastname: Pantazides
authors.forename: Khanjan
authors.initials: K
authors.lastname: Gandhi
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kowalski
authors.forename: David A
authors.initials: DA
authors.lastname: Kooby
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
authors.forename: Charles A
authors.initials: CA
authors.lastname: Staley
authors.forename: N Volkan
authors.initials: NV
authors.lastname: Adsay
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Landry
authors.forename: Shishir K
authors.initials: SK
authors.lastname: Maithel
authors.forename: David S
authors.initials: DS
authors.lastname: Yu
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011494:Protein Kinases / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; C570693:MLKL protein, human; D011494:Protein Kinases
keywords: biomarker; mixed lineage kinase domain-like protein (MLKL); necroptosis; necrosis; pancreatic cancer