title: Klotho is a novel biomarker for good survival in resected large cell neuroendocrine carcinoma of the lung.
abstract: BACKGROUND
  In terms of prognosis, large cell neuroendocrine carcinoma (LCNEC) differs distinctively from other non-small cell lung cancers, with the prognosis of LCNEC being poor, even for early-stage disease. Improvements in survival require a biomarker capable of defining a subset of patients destined to do poorly so that these patients can be targeted for additional therapies, including chemotherapy. In this study, we focused on the Klotho gene, which is an anti-aging gene known to be a potential tumor suppressor. We investigated whether the immunohistochemical expression of Klotho can predict survival patients with resected LCNEC.
  
  
  METHODS
  The histological characteristics of patients receiving an initial diagnosis of LCNEC (n=30) at Tokyo Medical University Hospital were retrospectively reviewed, and multiple variables including stage, lymphangioinvasion, lymph node status and the expression of Klotho as identified using an immunohistochemical analysis, were assessed.
  
  
  RESULTS
  Immunostaining for Klotho was mostly cytoplasmic, and Klotho expression was seen in 10 patients (33.3%) but not in 20 patients (66.7%). The expression of Klotho was significantly associated with a good outcome of resected patients with LCNEC and Klotho(-) was associated with increased LCNEC risk by multivariate analysis (hazard ratio 4.92, 95% confidence interval 1.04-23.24, p=0.044). Neither lymph node status nor lymphangioinvasion were significantly associated with a poor survival. However, among patients without lymph node metastasis or angioinvasion, the survival benefit of Klotho expression in the primary tumor was significantly higher, compared with that of patients without Klotho expression.
  
  
  CONCLUSIONS
  Klotho staining provides a new biomarker for a good outcome in patients with LCNEC, especially among patients without lymph node metastasis or lymphangioinvasion.
authors.affiliation: Division of Thoracic Surgery 1, Department of Surgery 1, Tokyo Medical University, 6-7-1, Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. jusuda@tokyo-med.ac.jp
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Usuda
authors.forename: Shuji
authors.initials: S
authors.lastname: Ichinose
authors.forename: Taichirou
authors.initials: T
authors.lastname: Ishizumi
authors.forename: Keishi
authors.initials: K
authors.lastname: Ohtani
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Inoue
authors.forename: Hisashi
authors.initials: H
authors.lastname: Saji
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kakihana
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kajiwara
authors.forename: Osamu
authors.initials: O
authors.lastname: Uchida
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nomura
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ohira
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ikeda
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018287:Carcinoma, Large Cell / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D018278:Carcinoma, Neuroendocrine / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D005260:Female; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D000090265:Klotho Proteins; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D005966:Glucuronidase; D000090265:Klotho Proteins