EGFR amplified and overexpressing glioblastomas and association with better response to adjuvant metronomic temozolomide.

BACKGROUND: Lack of robust predictive biomarkers, other than MGMT promoter methylation, makes temozolomide responsiveness in newly diagnosed glioblastoma (GBM) patients difficult to predict. However, we identified patients with long-term survival (≥35 months) within a group of newly diagnosed GBM patients treated with standard or metronomic adjuvant temozolomide schedules. We thus investigated possible molecular profiles associated with longer survival following temozolomide treatment. METHODS: We investigated the association of molecular features with progression-free (PFS) and overall survival (OS). Human-derived GBM cancer stem cells (CSCs) were used to investigate in vitro molecular mechanisms associated with temozolomide responsiveness. Surgically removed recurrences allowed investigation of molecular changes occurring during therapy in vivo. Statistical analyses included one- and two-way analysis of variance, Student's t test, Cox proportional hazards, and the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: No association was found between survival and gene classifiers associated with different molecular GBM subtypes in the standard-treated group, while in metronomic-treated patients robust association was found between EGFR amplification/overexpression and PFS and OS (OS, EGFR-high vs low: hazard ratiodeath = 0.22, 95% confidence interval = 0.09 to 0.55, P = .001). The result for OS remained statistically significant after Bonferroni correction (P interaction < .0005). Long-term survival following metronomic temozolomide was independent from MGMT and EGFRvIII status and was more pronounced in EGFR-overexpressing GBM patients with PTEN loss. In vitro findings confirmed a selective dose- and time-dependent decrease in survival of temozolomide-treated EGFR+ human-derived glioblastoma CSCs, which occurred through inhibition of NF-κB transcriptional activity. In addition, reduction in EGFR-amplified cells, along with a statistically significant decrease in NF-κB/p65 expression, were observed in specimens from recurrent metronomic-treated EGFR-overexpressing GBM patients. CONCLUSIONS: EGFR-amplified/overexpressing glioblastomas strongly benefit from metronomic temozolomide-based therapies.

Spinal glioneuronal tumor with neuropil-like islands and meningeal dissemination: histopathological and radiological study of a pediatric case.

Cerebral and spinal location of glioneuronal tumors have been recently described as a novel type of primary CNS neoplasia. A distinctive rare form of glioneuronal tumors with neuropil-like islands (GTNI) have been reported to occur in the adult cerebrum, whereas spinal GTNI localization is extremely rare. In the present report we describe a case of a 15-month-old child with a spinal GTNI of the cervical region and meningeal dissemination. Histologically the tumor was composed of round, small neurocytic-like cells arranged around eosinophilic neuropil cores and embedded in a diffuse fibrillar glial component forming prominent "rosetted" neuropil islands displaying strong immunoreactivity for neuronal markers. Cerebral GTNI shows abundant glial components not rarely exhibiting anaplastic features that justify their inclusion within the group of diffuse astrocytomas. In contrast, including our case, spinal GTNI do not show histological evidence of anaplastic features and exhibits a significant neuronal component that may imply considering these lesions in a separate group. Nevertheless, due to their exceptional rarity, the natural history of these lesions is not yet fully understood, but spinal GTNI seems to have an unfavorable clinical course despite their benign histopathological features, which must be taken into account for appropriate treatment and follow-up of the patient.