title: Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma.
abstract: Pediatric ependymomas are enigmatic tumors, and their clinical management remains one of the more difficult in pediatric oncology. The identification of biological correlates of outcome and therapeutic targets remains a significant challenge in this disease. We therefore analyzed a panel of potential biological markers to determine optimal prognostic markers. We constructed a tissue microarray from 97 intracranial tumors from 74 patients (WHO grade II-III) and analyzed the candidate markers nucleolin, telomerase catalytic subunit (hTERT; antibody clone 44F12), survivin, Ki-67, and members of the receptor tyrosine kinase I (RTK-I) family by immunohistochemistry. Telomerase activity was determined using the in vitro-based telomere repeat amplification protocol assay, and telomere length was measured using the telomere restriction fragment assay. Primary tumors with low versus high nucleolin protein expression had a 5-year event-free survival of 74%+/-13% and 31%+/-7%, respectively. Multivariate analysis identified low nucleolin expression to be independently associated with a more favorable prognosis (hazard ratio=6.25; 95% confidence interval, 1.6-24.2; p=0.008). Ki-67 and survivin correlated with histological grade but not with outcome. Immunohistochemical detection of the RTK-I family did not correlate with grade or outcome. Telomerase activity was evident in 19 of 22 primary tumors, with telomere lengthening and/or maintenance occurring in five of seven recurrent cases. Low nucleolin expression was the single most important biological predictor of outcome in pediatric intracranial ependymoma. Furthermore, telomerase reactivation and maintenance of telomeric repeats appear necessary for childhood ependymoma progression. These findings require corroboration in a clinical trial setting.
authors.affiliation: Children's Brain Tumor Research Centre, University of Nottingham, Nottingham, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Ridley
authors.forename: Ruman
authors.initials: R
authors.lastname: Rahman
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Brundler
authors.forename: David
authors.initials: D
authors.lastname: Ellison
authors.forename: James
authors.initials: J
authors.lastname: Lowe
authors.forename: Keith
authors.initials: K
authors.lastname: Robson
authors.forename: Emma
authors.initials: E
authors.lastname: Prebble
authors.forename: Inga
authors.initials: I
authors.lastname: Luckett
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Sheila
authors.initials: S
authors.lastname: Parkes
authors.forename: Vikki
authors.initials: V
authors.lastname: Rand
authors.forename: Beth
authors.initials: B
authors.lastname: Coyle
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000032:analysis*; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004806:Ependymoma / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D010750:Phosphoproteins / Q000096:biosynthesis*; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000096:biosynthesis*; D019098:Telomerase / Q000096:biosynthesis; D016615:Telomere / Q000378:metabolism; D046888:Tissue Array Analysis; D000097796:Nucleolin
chemical_list: D014408:Biomarkers, Tumor; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D019098:Telomerase; D000097796:Nucleolin