title: Prognostic significance of Ki67 proliferation index, HIF1 alpha index and microvascular density in patients with non-small cell lung cancer brain metastases.
abstract: BACKGROUND
  Survival upon diagnosis of brain metastases (BM) in patients with non-small cell lung cancer (NSCLC) is highly variable and established prognostic scores do not include tissue-based parameters.
  
  
  METHODS
  Patients who underwent neurosurgical resection as first-line therapy for newly diagnosed NSCLC BM were included. Microvascular density (MVD), Ki67 tumor cell proliferation index and hypoxia-inducible factor 1 alpha (HIF-1 alpha) index were determined by immunohistochemistry.
  
  
  RESULTS
  NSCLC BM specimens from 230 patients (151 male, 79 female; median age 56 years; 199 nonsquamous histology) and 53/230 (23.0%) matched primary tumor samples were available. Adjuvant whole-brain radiation therapy (WBRT) was given to 153/230 (66.5%) patients after neurosurgical resection. MVD and HIF-1 alpha indices were significantly higher in BM than in matched primary tumors. In patients treated with adjuvant WBRT, low BM HIF-1 alpha expression was associated with favorable overall survival (OS), while among patients not treated with adjuvant WBRT, BM HIF-1 alpha expression did not correlate with OS. Low diagnosis-specific graded prognostic assessment score (DS-GPA), low Ki67 index, high MVD, low HIF-1 alpha index and administration of adjuvant WBRT were independently associated with favorable OS. Incorporation of tissue-based parameters into the commonly used DS-GPA allowed refined discrimination of prognostic subgroups.
  
  
  CONCLUSIONS
  Ki67 index, MVD and HIF-1 alpha index have promising prognostic value in BM and should be validated in further studies.
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: A S
authors.initials: AS
authors.lastname: Berghoff
authors.forename: A
authors.initials: A
authors.lastname: Ilhan-Mutlu
authors.forename: A
authors.initials: A
authors.lastname: Wöhrer
authors.forename: M
authors.initials: M
authors.lastname: Hackl
authors.forename: G
authors.initials: G
authors.lastname: Widhalm
authors.forename: J A
authors.initials: JA
authors.lastname: Hainfellner
authors.forename: K
authors.initials: K
authors.lastname: Dieckmann
authors.forename: T
authors.initials: T
authors.lastname: Melchardt
authors.forename: B
authors.initials: B
authors.lastname: Dome
authors.forename: H
authors.initials: H
authors.lastname: Heinzl
authors.forename: P
authors.initials: P
authors.lastname: Birner
authors.forename: M
authors.initials: M
authors.lastname: Preusser
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism*; D008297:Male; D055806:Microvessels / Q000473:pathology*; D008875:Middle Aged; D015995:Prevalence; D011379:Prognosis; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen