Prognostic marker analysis in pediatric intracranial ependymomas.

Histologic grading methods dependent upon H&E staining review have not been shown to reliably predict survival in children with intracranial ependymomas due to the subjectivity of the analytical methods. We hypothesized that the immunohistochemical detection of MIB-1, Tenascin C, CD34, VEGF, and CA IX may represent objective markers of post-operative survival (Progression Free and Overall Survival; PFS, OS) in these patients. Intracranial ependymomas from patients aged 22 years or less were studied. The original histologic grade was recorded, H&E sections were reviewed for vascular proliferation status, and immunohistochemistry was used to determine MIB-1, Tenascin C, CD34, VEGF, and CA IX status. Based upon the World Health Organization (WHO) grading system, 3 Grade I, 18 Grade II and 9 Grade III ependymomas were studied. Median follow-up time was 9.0 years; median PFS was, 6.1 years. Original WHO grade did not correlate with PFS or OS. Peri-necrotic CA IX localization correlated with PFS (Log rank = 0.0181) and OS (Log rank p = 0.0015). All patients with a CA IX ≤ 5 % total area localization were alive at last follow-up. Perinecrotic CA IX staining was also associated with vascular proliferation (p = 0.006), though not with VEGF expression score. MIB-1 labeling index (LI) correlated with OS (HR 1.06, 95 % CI 1.01, 1.12) and PFS (HR 1.08, 95 % CI 1.02, 1.14). MIB-1 LI and perinecrotic CA IX individually correlated with PFS. The effect of perinecrotic CA IX remained when grade was added to a Cox model predicting PFS. Immunodetection of CA IX and MIB-1 expression are predictive biomarkers for survival in children with posterior fossa ependymomas. These markers represent objective indicators of survival that supplement H&E grading alone.

Validation of an Immunohistochemistry Assay for Detection of CD155, the Poliovirus Receptor, in Malignant Gliomas.

CONTEXT: - The oncolytic polio-rhinovirus recombinant (PVSRIPO) has demonstrated promise in currently ongoing phase I/II clinical trials against recurrent glioblastoma and was granted breakthrough therapy designation by the Food and Drug Administration/Center for Biologics Evaluation and Research. A reliable clinical assay to document expression of the poliovirus receptor, CD155, in routinely available patient tumor samples is needed for continued clinical development of PVSRIPO oncolytic immunotherapy in primary brain tumors and beyond. OBJECTIVES: - To validate a novel anti-CD155 antibody for immunohistochemistry and develop a robust, reliable, and specific protocol for detecting CD155 expression in glioblastoma formalin-fixed, paraffin-embedded (FFPE) tissue samples. To characterize the expression of CD155 in human glioblastoma cells as well as to evaluate the influence of CD155 expression levels on tumor cell susceptibility to PVSRIPO infection and killing. DESIGN: - Immunohistochemical staining on glioblastoma FFPE tissue sections and immunoblot of corresponding frozen tissues were performed. Positive controls were confirmed sites of poliovirus propagation, spinal cord anterior horn, and tonsils; negative controls were vascular smooth muscle in patient samples and FFPE sections from a confirmed CD155-negative Burkitt lymphoma line (Raji). RESULTS: - We succeeded in developing a reliable assay to specifically detect CD155 by immunohistochemistry in glioblastoma FFPE sections. Our data suggest widespread, virtually universal expression of CD155 in glioblastoma cells at levels commensurate with susceptibility to PVSRIPO infection and killing. CONCLUSIONS: - Anti-CD155 antibody D3G7H achieves monospecific detection of CD155 in immunoblots of tumor homogenates and immunohistochemistry of tumor FFPE sections. Our assay has utility in defining appropriate use of PVSRIPO in oncolytic immunotherapy against malignant glioma and other cancer histotypes.