title: Diagnostic and prognostic role of plasma levels of two forms of cytokeratin 18 in patients with non-small-cell lung cancer.
abstract: OBJECTIVE
  Cytokeratin 18 (CK18) can be used as a serum biomarker for carcinoma cell death, whereas caspase-cleaved (ccCK18) fragments reflect tumour apoptosis. We explored the potential diagnostic and prognostic role of circulating CK18 and ccCK18 in patients with non-small-cell lung cancer (NSCLC) in comparison with Cyfra 21.1, a fragment of cytokeratin 19.
  
  
  METHODS
  Subject cohorts consisted of 200 healthy blood donors (HBD), 113 patients with benign lung diseases (BLD) and 179 NSCLC cases. Plasma levels of ccCK18, total CK18 and Cyfra 21.1 were determined with ELISA assays.
  
  
  RESULTS
  Plasma levels of ccCK18 and total CK18 were higher in the NSCLC group compared to the HBD and BLD cohorts (p<0.0001). Using a cut-off of 104 U/L for ccCK18 and 302 U/L for total CK18 (95% specificity in the HBD group) the diagnostic accuracy of both CK18 forms to distinguish between NSCLC and BLD cases was 56%, whereas it was 94% for Cyfra 21.1. Multivariate survival analysis showed that total CK18 was a stronger prognostic factor than both ccCK18 and Cyfra 21.1 (HR 0.64 for low versus high total CK18 levels, 95% confidence interval (CI) 0.50-0.82; p=0.0004) in the entire NSCLC cohort and in 78 patients with locally advanced or metastatic disease treated with chemoradiotherapy or first-line chemotherapy (HR 0.70 95% CI 0.52-0.94; p=0.018).
  
  
  CONCLUSIONS
  Cyfra 21.1 is a useful diagnostic biomarker for NSCLC. Total CK18 shows a promising potential as prognostic marker in NSCLC patients, independently of the therapeutical intervention. In contrast, ccCK18 was not of prognostic value in NSCLC, suggesting that tumour necrosis is of particular importance in this disease.
authors.affiliation: Clinical Proteomics, Karolinska Biomics Center, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. luigi.depetris@ki.se
authors.forename: Luigi
authors.initials: L
authors.lastname: De Petris
authors.forename: Eva
authors.initials: E
authors.lastname: Brandén
authors.forename: Richard
authors.initials: R
authors.lastname: Herrmann
authors.forename: Betzabe Chavez
authors.initials: BC
authors.lastname: Sanchez
authors.forename: Hirsh
authors.initials: H
authors.lastname: Koyi
authors.forename: Barbro
authors.initials: B
authors.lastname: Linderholm
authors.forename: Rolf
authors.initials: R
authors.lastname: Lewensohn
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtiö
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000401:mortality; D003937:Diagnosis, Differential; D004797:Enzyme-Linked Immunosorbent Assay / Q000592:standards; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D053538:Keratin-18 / Q000737:chemistry / Q000378:metabolism*; D053539:Keratin-19 / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011379:Prognosis; D012680:Sensitivity and Specificity
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D053538:Keratin-18; D053539:Keratin-19; D010446:Peptide Fragments; C102012:antigen CYFRA21.1