title: P-glycoprotein expression at diagnosis may not be a primary mechanism of therapeutic failure in childhood rhabdomyosarcoma.
abstract: OBJECTIVE
  To evaluate the prognostic significance of tumor cell P-glycoprotein (Pgp) expression at diagnosis in children with rhabdomyosarcoma.
  
  
  METHODS
  A panel of three anti-Pgp monoclonal antibodies (mAb) (C219, C494, and JSB-1) that recognize different Pgp epitopes was used to measure Pgp expression in rhabdomyosarcoma specimens obtained at diagnosis from 76 patients treated at St Jude Children's Research Hospital from 1969 to 1991. Two separate experiments using different immunohistochemical methods (immune alkaline phosphatase and immunoperoxidase) were performed to evaluate Pgp expression. The immunostaining was graded using a semiquantitative scale corresponding to the percentage of tumor cells with detectable staining. The influence of Pgp expression on outcome was assessed by the Kaplan-Meier method and Cox regression analysis with stepwise selection. The relationship between Pgp expression and clinical features was assessed using the Mantel-Haenszel method.
  
  
  RESULTS
  Pgp expression at diagnosis did not predict worse overall survival or progression-free survival when tested in either experiment with C219, C494, or JSB-1 separately. No association was shown between Pgp expression and clinical features (clinical group, primary site, or histology) or response. However, in the immune alkaline phosphatase experiment, patients whose tumors had more than 10% tumor cell staining with all three mAbs had a significantly higher rate of estimated 5-year survival (78% +/- 10%) than did all other patients (38% +/- 8%; P = .025). In this instance, Pgp expression had independent prognostic value after adjusting for clinical group.
  
  
  CONCLUSIONS
  We found no strong association between Pgp expression at diagnosis and clinical features or extent of disease in pediatric rhabdomyosarcoma. Depending on the criteria used to define it, high Pgp expression at diagnosis does not predict poor outcome. Although a large prospective study is needed to provide definitive conclusions, our findings suggest that Pgp-mediated multidrug resistance may not be a primary mechanism of therapeutic failure in rhabdomyosarcoma.
authors.affiliation: Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Kuttesch
authors.forename: D M
authors.initials: DM
authors.lastname: Parham
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.forename: W H
authors.initials: WH
authors.lastname: Meyer
authors.forename: L
authors.initials: L
authors.lastname: Bowman
authors.forename: D N
authors.initials: DN
authors.lastname: Shapiro
authors.forename: A S
authors.initials: AS
authors.lastname: Pappo
authors.forename: W M
authors.initials: WM
authors.lastname: Crist
authors.forename: W T
authors.initials: WT
authors.lastname: Beck
authors.forename: P J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000032:analysis; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor / Q000032:analysis*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D015999:Multivariate Analysis; D012208:Rhabdomyosarcoma / Q000737:chemistry* / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality / Q000601:surgery; D017211:Treatment Failure; D014407:Tumor Cells, Cultured / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D000469:Alkaline Phosphatase