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Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation

Authors

  • Eduard H. Panosyan MD,

    1. Department of Pediatrics, University of California Los Angeles (UCLA), Los Angeles, California
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  • Dan R. Laks MS,

    1. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
    2. Department of Psychiatry, UCLA, Los Angeles, California
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  • Michael Masterman-Smith MS,

    1. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
    2. Department of Psychiatry, UCLA, Los Angeles, California
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  • Jack Mottahedeh PhD,

    1. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
    2. Department of Psychiatry, UCLA, Los Angeles, California
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  • William H. Yong MD,

    1. Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California
    2. The Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
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  • Timothy F. Cloughesy MD,

    1. The Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
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  • Jorge A. Lazareff MD,

    1. The Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
    2. Department of Neurosurgery, UCLA, Los Angeles, California
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  • Paul S. Mischel MD,

    1. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
    2. Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California
    3. The Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
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  • Theodore B. Moore MD,

    1. Department of Pediatrics, University of California Los Angeles (UCLA), Los Angeles, California
    2. The Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
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  • Harley I. Kornblum MD, PhD

    Corresponding author
    1. Department of Pediatrics, University of California Los Angeles (UCLA), Los Angeles, California
    2. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
    3. The Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California
    4. The Intellectual and Developmental Disabilities Research Center, UCLA, Los Angeles, California
    • Departments of Psychiatry, Pharmacology, and Pediatrics, David Geffen School of Medicine at UCLA, Neuroscience Research Center, Suite 379, 635 Charles E. Young Dr. South, Los Angeles, CA 90095.
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  • Conflict of interest: Nothing to declare.

Abstract

Background

Cultured brain tumors can form neurospheres harboring tumorigenic cells with self renewal and differentiation capacities. Renewable neurosphere formation has clinical predictive value in adult malignant gliomas, yet its prognostic role for pediatric brain tumors is unknown.

Methods

Established neurosphere conditions were used for culturing samples from glial, embryonal and mixed glioneuronal tumors from 56 pediatric patients. Potential associations between neurosphere formation and clinical outcome were analyzed retrospectively.

Results

Thirty-seven percent of all samples formed renewable neurospheres. Analysis of available clinical outcome data from 51 patients demonstrated significantly increased hazard ratios (HR) for both disease progression (HR = 9.9, P < 0.001) and death (HR = 16.6, P < 0.01) in the neurosphere forming group. Furthermore, neurosphere formation correlated with adverse progression free survival (PFS) in glial and embryonal tumors, but not in mixed glioneuronal tumors. Overall survival (OS) was significantly worse for neurosphere-forming patients with embryonal tumors, as a group and amongst the subgroup with medulloblastoma, but not in the glial group. Multivariate analysis showed that neurosphere formation was associated with diminished PFS and OS independent of age, gender, or treatment. Neurosphere formation was an independent predictor of diminished PFS of glial tumors after adjusting for grade. Multivariate analysis, adjusting for both Ki67 staining and neurosphere formation, demonstrated that neurosphere formation remained predictive of progression whereas Ki67 did not.

Conclusions

Neurosphere formation is more predictive of pediatric brain tumor progression than semi-quantitative Ki67 staining. Pediatric brain tumor derived neurospheres may provide a predictive model for preclinical explorations. Pediatr Blood Cancer. 2010;55:644–651. © 2010 Wiley-Liss, Inc.

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