title: Immunohistochemical expression of phospho-mTOR is associated with poor prognosis in patients with gallbladder adenocarcinoma.
abstract: BACKGROUND
  Advanced gallbladder carcinoma (GBC) is a highly fatal disease with poor prognosis and few therapeutic alternatives. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a central role in cell growth and homeostasis. Its regulation is frequently altered in various tumors and is an attractive target for cancer therapy; however, its status in GBC remains unclear.
  
  
  OBJECTIVE
  To characterize immunohistochemical expression and prognostic significance of phospho-mTOR in advanced gallbladder carcinoma.
  
  
  METHODS
  Phospho-mTOR expression was examined by immunohistochemistry in tissue microarrays containing 128 advanced GBCs and 99 cases of chronic cholecystitis, which were divided into 2 groups according to the presence or absence of metaplasia. To evaluate the association of the level of phospho-mTOR expression with clinical variables and patient survival, the advanced GBCs were classified as having low or high expression. Statistical analysis was performed by using a significance level of P < .05, and Kaplan-Meier curves were constructed for survival analysis.
  
  
  RESULTS
  Immunostaining for phospho-mTOR was positive in 82 of 128 tumors (64.1%) and in 24% of chronic cholecystitis cases (16% nonmetaplasia and 32% with metaplasia) (P < .001). Survival analysis indicated that a high phospho-mTOR immunohistochemical expression was associated with poorer prognosis in patients with advanced GBC (P = .02).
  
  
  CONCLUSIONS
  Metaplasia is a common finding in chronic cholecystitis and is considered a precursor lesion of dysplasia. Our results suggest that the activation of mTOR occurs very early during the development of GBC, contributing to the carcinogenesis process. Phospho-mTOR expression is correlated with poor survival, supporting the potential of mTOR for targeted therapy.
authors.affiliation: Department of Pathology, School of Medicine, CEGINBIOREN, University of La Frontera, Temuco, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Leal
authors.forename: Patricia
authors.initials: P
authors.lastname: García
authors.forename: Alejandra
authors.initials: A
authors.lastname: Sandoval
authors.forename: Pablo
authors.initials: P
authors.lastname: Letelier
authors.forename: Priscilla
authors.initials: P
authors.lastname: Brebi
authors.forename: Carmen
authors.initials: C
authors.lastname: Ili
authors.forename: Héctor
authors.initials: H
authors.lastname: Álvarez
authors.forename: Oscar
authors.initials: O
authors.lastname: Tapia
authors.forename: Juan C
authors.initials: JC
authors.lastname: Roa
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002677:Chile / Q000453:epidemiology; D002763:Cholecystectomy; D002764:Cholecystitis / Q000175:diagnosis / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D005706:Gallbladder Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D008297:Male; D008679:Metaplasia; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases