Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation.
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.
Panosyan
Eduard H
EH
Department of Pediatrics, University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
Laks
Dan R
DR
Masterman-Smith
Michael
M
Mottahedeh
Jack
J
Yong
William H
WH
Cloughesy
Timothy F
TF
Lazareff
Jorge A
JA
Mischel
Paul S
PS
Moore
Theodore B
TB
Kornblum
Harley I
HI
D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D005910:Glioma / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007223:Infant; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D016016:Proportional Hazards Models