ZFTA (Zinc Finger Translocation Associated) Fusion in Supratentorial Ependymomas: Low Prevalence in South Asians and No Correlation with Survival.

BACKGROUND: Supratentorial ependymomas (STEs) are an aggressive group of ependymomas, topographically distinct from their posterior fossa and spinal counterparts. Zinc finger translocation associated (ZFTA) fusion-positive cases have been reported to account for the majority of STEs, although data on its association with poorer outcomes are inconsistent. MATERIALS AND METHODS: We assessed the prevalence of the ZFTA fusion by reverse-transcription polymerase chain reaction and fluorescence in situ hybridization in a cohort of 61 patients (68 samples) with STE. Our primary outcome was to determine the role of the ZFTA fusion on progression-free and overall survival of patients with STE. Our secondary objectives were to assess the impact of ZFTA fusion on nuclear factor (NF)-kB pathway signaling via surrogate markers of this pathway, namely COX-2, CCND1, and L1 cell adhesion molecule. RESULTS: ZFTA fusion was noted in 21.3% of STEs in our cohort. The presence of this rearrangement did not significantly impact the progression-free or overall survival of patients with STEs and was not associated with upregulation of markers of the NF-kB pathway. Only gross total resection was significantly associated with better progression-free survival. CONCLUSIONS: In contradiction to previous reports from across the world, the ZFTA fusion is far less prevalent among our population. It does not appear to drive NF-kB signaling or significantly affect outcomes. Gross total resection must be attempted in all cases of STE and adjuvant radiation and/or chemotherapy employed when gross total resection is not achieved.

Predicting the probability of abnormal stimulated growth hormone response in children after radiotherapy for brain tumors.

PURPOSE: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. METHODS AND MATERIALS: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n=72), low-grade glioma (n=28) or craniopharyngioma (n=6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test≥7 ng/mL. RESULTS: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p<0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. CONCLUSIONS: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.

Evaluation of the effects of swainsonine, captopril, tangeretin and nobiletin on the biological behaviour of brain tumour cells in vitro.

Although intrinsic tumours of the brain seldom metastasize to distant sites, their diffuse, infiltrative-invasive growth within the brain generally precludes successful surgical and adjuvant therapy. Hence, attention has now focused on novel therapeutic approaches to combat brain tumours that include the use of anti-invasive and anti-proliferative agents. The effect of four anti-invasive agents, swainsonine (a locoweed alkaloid), captopril (an anti-hypertensive drug), tangeretin and nobiletin (both citrus flavonoids), were investigated on various parameters of brain tumour invasion such as matrix metalloproteinase (MMP) secretion, migration, invasion and adhesion. A standard cytotoxicity assay was used to optimize working concentrations of the drugs on seven human brain tumour-derived cell lines of various histological type and grade of malignancy. A qualitative assessment by gelatin zymography revealed that the effect of these agents varied between the seven cell lines such that the low grade pilocytic astrocytoma was unaffected by three of the agents. In contrast, downregulation of the two gelatinases, MMP-2 and MMP-9 was seen in the grade 3 astrocytoma irrespective of which agent was used. Generally, swainsonine was the least effective whereas the citrus flavonoids, particularly nobiletin, showed the greatest downregulation of secretion of the MMPs. Furthermore, captopril and nobiletin were most efficient at inhibiting invasion, migration and adhesion in four representative cell lines (an ependymoma, a grade II oligoastrocytoma, an anaplastic astrocytoma and a glioblastoma multiforme). Yet again, the effects of the four agents varied between the four cell lines. Nobiletin was, nevertheless, the most effective agent used in these assays. In conclusion, the differential effects seen on the various parameters studied by these putative anti-invasive agents may be the result of interference with MMPs and other mechanisms underlying the invasive phenotype. From these pilot studies, it is possible that these agents, especially the citrus flavonoids, could be of future therapeutic value. However, further work is needed to validate this in a larger study.

The effects of verapamil and flunarizine on epileptiform activity induced by bicuculline and low Mg2+ in neocortical tissue of epileptic and primary non-epileptic patients.

In human neocortical slices the specific L-type calcium channel blocker verapamil had been shown to be antiepileptic in the low Mg(2+)-model of epilepsy. The present investigation demonstrated: (1) verapamil exerted also an antiepileptic effect on epileptiform field potentials (EFP) induced by the GABAA-antagonist bicuculline. (2) The unspecific calcium channel modulator flunarizine, which in contrast to verapamil penetrates the blood-brain barrier, depressed EFP in the low Mg(2+)-model and in the bicuculline model. (3) There was no significant difference in the antiepileptic efficacy of verapamil and flunarizine in epileptic (epilepsy surgery) and primary non-epileptic (tumor surgery) neocortical slices.