title: Minimal residual disease in gastric cancer: evidence of an independent prognostic relevance of urokinase receptor expression by disseminated tumor cells in the bone marrow.
abstract: OBJECTIVE
  To study the invasion-related molecule urokinase-type plasminogen activator receptor (u-PAR) expressed by disseminated tumor cells as a biologic predictor of poor survival in a large prospective series of patients with gastric cancer.
  
  
  METHODS
  In 156 gastric cancer patients (prospective series), disseminated tumor cells in the bone marrow and the u-PAR expressed by these tumor cells were determined by cytokeratin (CK) 18 immunocytochemistry and u-PAR/CK18 double immunocytochemistry.
  
  
  RESULTS
  In contrast to the mere detection of disseminated tumor cells at primary surgery, the additional evidence of u-PAR on these cells correlated significantly with pathologic T stage (P =.0474) and the expression of u-PAR (P =.0093) and plasminogen-activator inhibitor 1 (P =.0145) in the primary tumor (immunohistochemistry, chi(2)). Kaplan-Meier analysis revealed no association with prognosis for the mere detection of disseminated tumor cells. In contrast, a significant association was seen between detection of u-PAR on these cells and shorter disease-free (P <.0001) and overall survival (P <.0001). Multivariate analysis revealed that u-PAR on disseminated tumor cells at the time of primary surgery is an independent prognostic factor for disease-free (95% confidence interval [CI], 1.72 to 3.21; P =.024) and overall survival (P =.0049; relative risk, 2.89; 95% CI, 1.92 to 4.30).
  
  
  CONCLUSIONS
  This is the first large study to show that u-PAR, detected on disseminated tumor cells in the bone marrow, is an independent prognostic parameter in gastric cancer, in contrast to the mere detection of minimal residual disease (MRD). u-PAR may be a promising marker to define a critical subpopulation of disseminated tumor cells and a target to eliminate MRD. Molecular phenotyping of MRD is critical for defining its individual clinical relevance.
authors.affiliation: Department of Surgery, Klinikum Grosshadern, Ludwig Maximilians University of Munich, Munich, Germany.
authors.forename: Markus Maria
authors.initials: MM
authors.lastname: Heiss
authors.forename: Erich H
authors.initials: EH
authors.lastname: Simon
authors.forename: Bianca C M
authors.initials: BC
authors.lastname: Beyer
authors.forename: Klaus Uwe
authors.initials: KU
authors.lastname: Gruetzner
authors.forename: Anwar
authors.initials: A
authors.lastname: Tarabichi
authors.forename: Rudolf
authors.initials: R
authors.lastname: Babic
authors.forename: Friedrich Wilhelm
authors.initials: FW
authors.lastname: Schildberg
authors.forename: Heike
authors.initials: H
authors.lastname: Allgayer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D019046:Bone Marrow Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000556:secondary*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D018365:Neoplasm, Residual / Q000175:diagnosis; D015849:Plasminogen Inactivators / Q000378:metabolism; D011379:Prognosis; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D016019:Survival Analysis; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C524898:PLAUR protein, human; D015849:Plasminogen Inactivators; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D007633:Keratins; D014568:Urokinase-Type Plasminogen Activator