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Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma

Children's Brain Tumor Research Centre, University of Nottingham, Nottingham, UK (L.R., R.R., J.L., K.R., V.R., B.C., R.G.G.); Department of Pathology (M.-A.B.) and West Midlands Regional Children's Tumor Registry (S.P.), Birmingham Children's Hospital, Birmingham, UK; St. Jude Children's Research Hospital, Memphis, TN, USA (D.E., I.L., R.J.G.); Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham, UK (E.P.); Department of Neuropathology, Nottingham University Hospital, Queens Medical Centre, Nottingham, UK (J.L., K.R.)

Address correspondence to Richard Grundy, Children's Brain Tumor Research Centre, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK (richard.grundy{at}nottingham.ac.uk).

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 telo mere 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, telo merase reactivation and maintenance of telomeric repeats appear necessary for childhood ependymoma progression. These findings require corroboration in a clinical trial setting.

Key Words: ependymoma • nucleolin • pediatric • telomerase • telomere

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				J.-P. Kilday, R. Rahman, S. Dyer, L. Ridley, J. Lowe, B. Coyle, and R. Grundy Pediatric Ependymoma: Biological Perspectives Mol. Cancer Res., June 1, 2009; 7(6): 765 - 786. [Abstract] [Full Text] [PDF]