title: Intracellular signalling via the AKT axis and downstream effectors is active and prognostically significant in cancer of unknown primary (CUP): a study of 100 CUP cases.
abstract: BACKGROUND
  Hypothesising that cancer of unknown primary (CUP) may harbour unique characteristics, we present a translational study of the immunohistochemical expression and clinical correlation of key PTEN/AKT pathway molecules.
  
  
  METHODS
  We collected 100 paraffin-embedded CUP tissue blocks. We studied using tissue microarrays the expression of PTEN, phospho-AKT, Cyclin D1, p21, phospho-RPS6. From the percentage of staining tumour cells and the literature, we selected cut-offs to classify the expression of each biomolecule. We correlated IHC expression with clinical data.
  
  
  RESULTS
  PTEN, pAKT, and pRPS6 showed frequent expression. At univariate analysis, high IHC expression of pAKT and pRPS6 displayed statistically significant association with worse survival. Prognosis was worse upon concurrent high IHC expression of pMAPK and pAKT {median overall survival = 8 months [95% confidence interval (CI) 5.3-10.7] versus 17 months [95% CI 13.1-20.9]}. In multivariate analysis, high p21 was associated with better survival (risk ratio [RR] = 0.34 [95% CI 0.16-0.73], P = 0.005). High expression of pAKT (RR = 2.39 [95% CI 1.23-4.66], P = 0.01) or pRPS6 (RR = 2.76 [95% CI 1.31-5.84], P = 0.008) was associated with worse survival.
  
  
  CONCLUSIONS
  p21 expression conferred favourable prognosis, while high pAKT or pRPS6 expression predicted worse prognosis. Concurrent MAPK and pAKT expression had a marked adverse impact on survival.
authors.affiliation: Department of Medical Oncology, Ioannina University Hospital, Ioannina; Clinical Trial and Applied Research in Oncology Group (CARING), University of Ioannina, Ioannina; Hellenic Cooperative Oncology Group (HeCOG), Athens.
authors.forename: V
authors.initials: V
authors.lastname: Golfinopoulos
authors.affiliation: Department of Medical Oncology, Ioannina University Hospital, Ioannina; Clinical Trial and Applied Research in Oncology Group (CARING), University of Ioannina, Ioannina; Hellenic Cooperative Oncology Group (HeCOG), Athens.
authors.forename: G
authors.initials: G
authors.lastname: Pentheroudakis
authors.affiliation: Clinical Trial and Applied Research in Oncology Group (CARING), University of Ioannina, Ioannina; Department of Pathology, Medical School, University of Ioannina, Ioannina.
authors.forename: A
authors.initials: A
authors.lastname: Goussia
authors.affiliation: Clinical Trial and Applied Research in Oncology Group (CARING), University of Ioannina, Ioannina; Department of Pathology, Medical School, University of Ioannina, Ioannina.
authors.forename: V
authors.initials: V
authors.lastname: Siozopoulou
authors.affiliation: Department of Pathology, Medical School, Aristotle University of Thessaloniki, Thessaloniki.
authors.forename: M
authors.initials: M
authors.lastname: Bobos
authors.affiliation: Department of Medical Oncology, Medical School, Aristotle University of Thessaloniki, Thessaloniki; Papageorgiou General Hospital, Thessaloniki, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Krikelis
authors.affiliation: Department of Medical Oncology, Institute of Health Research Hospital Clinic of Valencia (INCLIVA), University of Valencia, Valencia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Oncological Institute Ion Chiricuta, Cluj, Romania.
authors.forename: T
authors.initials: T
authors.lastname: Ciuleanu
authors.affiliation: Clinical Trial and Applied Research in Oncology Group (CARING), University of Ioannina, Ioannina; Department of Pharmacology, Medical School, University of Ioannina, Ioannina, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Marselos
authors.affiliation: Hellenic Cooperative Oncology Group (HeCOG), Athens; Department of Medical Oncology, Medical School, Aristotle University of Thessaloniki, Thessaloniki; Papageorgiou General Hospital, Thessaloniki, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Fountzilas
authors.affiliation: Clinical Trial and Applied Research in Oncology Group (CARING), University of Ioannina, Ioannina; Department of Pathology, Medical School, University of Ioannina, Ioannina.
authors.forename: V
authors.initials: V
authors.lastname: Malamou-Mitsi
authors.affiliation: Department of Medical Oncology, Ioannina University Hospital, Ioannina; Clinical Trial and Applied Research in Oncology Group (CARING), University of Ioannina, Ioannina; Hellenic Cooperative Oncology Group (HeCOG), Athens. Electronic address: npavlid@uoi.gr.
authors.forename: N
authors.initials: N
authors.lastname: Pavlidis
mesh_terms: D006801:Humans; D009382:Neoplasms, Unknown Primary / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D046888:Tissue Array Analysis
chemical_list: D051057:Proto-Oncogene Proteins c-akt