2-Hydroxyglutarate as a biomarker in glioma patients

Background: mutation of IDH1 gene is a prognostic factor and a diagnostic hallmark of gliomas. Mutant IDH1 enzyme can convert α-KG into 2-Hydroxyglutarate (2HG) and mutated gliomas have elevated amounts of intracellular 2HG. Since 2HG is a small molecule it seems possible that it could reach the systemic circulation and to be excreted by urine. And so, we analyzed 2HG concentration in plasma and urine in glioma patients to identify a surrogate biomarker of IDH1 gene mutation. Materials and Methods: All patients had a prior histological confirmation of glioma, a recent brain MRI (within 2 weeks) showing the neoplastic lesions. The exclusion criteria were any chemotherapy performed within 28 days prior, other neoplastic and metabolic diseases. Plasma and urine samples were taken from all patients and 2HG concentrations determined by liquid chromatography tandem mass spectrometry; exon 4 of IDH1 genes were analyzed by Sanger sequencing; differences in metabolite concentrations between mutant and wild-type IDH1 patients were examined with the Mann-Whitney U test for non-parametric data; Student’s t-test was used to compare parametric data. ROC curve was used to evaluate the cut off value of the 2HG biomarker. Results: 84 patients were enrolled: 38 with IDH1 mutated and 46 IDH1 wild-type. All the mutations were R132H. Among patients with mutant IDH1 we had 21 highgrade gliomas (HGG) and 17 low-grade gliomas (LGG); among patients with IDH wild-type we had 35 HGG and 11 LGG.. In all patients we analyzed the mean 2HG concentration in plasma (P_2HG), in urine (U_2HG) and the ratio between P_2HG and U_2HG (R_2HG). We found an important significant difference in R_2HG between glioma patients with and without IDH1 mutation (22.2 versus 15.6, respectively, p<0.0001). The optimal cut-off value of R_2HG to identify glioma patients with and without IDH mutation was 19 (sensitivity 63%, specificity 76%, accuracy 70%); in only PTS with HGG the optimal cut-off value was 20 (sensitivity 76%, specificity 89%, accuracy 84%, positive predictive value 80%, negative predictive value 86%). No associations between the grade or size of tumor and R_2HG were found. In 7 patients with highgrade gliomas we found a correlation between R_2HG value and response to treatment. Conclusions: analyzing R_2HG derived from individual plasma and urine 2HG levels is possible discriminate glioma patients with and without IDH mutation, in particular in high grade gliomas. Moreover, a larger samples need to be analyzed to investigate this method in patients follow-up for recurrence detection and to monitor treatment efficacy

Getting the best outcomes from epilepsy surgery.

Neurosurgery is an underutilized treatment that can potentially cure drug-refractory epilepsy. Careful, multidisciplinary presurgical evaluation is vital for selecting patients and to ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guided surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies. Ann Neurol 2018;83:676-690

Brain tumor related-epilepsy

Introduction Gliomas are commonly associated with the development of epilepsy; in some cases the two conditions share common pathogenic mechanisms and may influence each other. Brain tumor related-epilepsy (BTRE) complicates the clinical management of gliomas and can substantially affect daily life. State of the art The incidence of seizures is high in patients with slow growing tumors located in the frontotemporal regions. However, recent studies suggest that epileptogenesis may be more associated with tumor molecular genetic markers than tumor grade or location. Although the exact mechanism of epileptogenesis in glioma is incompletely understood, glutamate-induced excitotoxicity and disruption of intracellular communication have garnered the most attention. Clinical management Management of BTRE requires a multidisciplinary approach involving the use of antiepileptic drugs (AEDs), surgery aided by electrocorticography, and adjuvant chemoradiation. Future directions Insight into the mechanisms of glioma growth and epileptogenesis is essential to identify new treatment targets and to develop effective treatment for both conditions. Selecting AEDs tailored to act against known tumor molecular markers involved in the epileptogenesis could enhance treatment value and help inform individualized medicine in BRTE