title: Circulating cell death products predict clinical outcome of colorectal cancer patients.
abstract: BACKGROUND
  Tumor cell death generates products that can be measured in the circulation of cancer patients. CK18-Asp396 (M30 antigen) is a caspase-degraded product of cytokeratin 18 (CK18), produced by apoptotic epithelial cells, and is elevated in breast and lung cancer patients.
  
  
  METHODS
  We determined the CK18-Asp396 and total CK18 levels in plasma of 49 colorectal cancer patients, before and after surgical resection of the tumor, by ELISA. Correlations with patient and tumor characteristics were determined by Kruskal-Wallis H and Mann-Whitney U tests. Disease-free survival was determined using Kaplan-Meier methodology with Log Rank tests, and univariate and multivariate Cox proportional hazard analysis.
  
  
  RESULTS
  Plasma CK18-Asp396 and total CK18 levels in colorectal cancer patients were related to disease stage and tumor diameter, and were predictive of disease-free survival, independent of disease-stage, with hazard ratios (HR) of patients with high levels (> median) compared to those with low levels (< or = median) of 3.58 (95% CI: 1.17-11.02) and 3.58 (95% CI: 0.97-7.71), respectively. The CK18-Asp396/CK18 ratio, which decreased with tumor progression, was also predictive of disease-free survival, with a low ratio (< or = median) associated with worse disease-free survival: HR 2.78 (95% CI: 1.06-7.19). Remarkably, the plasma CK18-Asp396 and total CK18 levels after surgical removal of the tumor were also predictive of disease-free survival, with patients with high levels having a HR of 3.78 (95% CI: 0.77-18.50) and 4.12 (95% CI: 0.84-20.34), respectively, indicating that these parameters can be used also to monitor patients after surgery.
  
  
  CONCLUSIONS
  CK18-Asp396 and total CK18 levels in the circulation of colorectal cancer patients are predictive of tumor progression and prognosis and might be helpful for treatment selection and monitoring of these patients.
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Centre, C4-P, P,O, Box 9600, 2300 RC Leiden, The Netherlands. P.J.Koelink@lumc.nl
authors.forename: Pim J
authors.initials: PJ
authors.lastname: Koelink
authors.forename: Cornelis Bhw
authors.initials: CB
authors.lastname: Lamers
authors.forename: Daan W
authors.initials: DW
authors.lastname: Hommes
authors.forename: Hein W
authors.initials: HW
authors.lastname: Verspaget
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020169:Caspases / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000097:blood* / Q000473:pathology / Q000601:surgery*; D004797:Enzyme-Linked Immunosorbent Assay / Q000706:statistics & numerical data; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D053538:Keratin-18 / Q000097:blood* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D013997:Time Factors
chemical_list: D053538:Keratin-18; D020169:Caspases