Object. This study was performed to evaluate the complications of invasive subdural grid monitoring during epilepsy surgery in children. Methods. The authors retrospectively reviewed the records of 35 consecutive children with intractable localization-related epilepsy who underwent invasive video electroencephalography (EEG) with subdural grid electrodes at The Hospital for Sick Children between 1996 and 2001. After subdural grid monitoring and identification of the epileptic regions, cortical excisions and/or multiple subpial transections (MSTs) were performed. Complications after these procedures were then categorized as either surgical or neurological. There were 17 male and 18 female patients whose mean age was 11.7 years. The duration of epilepsy before surgery ranged from 2 to 17 years (mean 8.3 years). Fifteen children (43%) had previously undergone surgical procedures for epilepsy. The number of electrodes on the grids ranged from 40 to 117 (mean 95). During invasive video EEG, cerebrospinal fluid leaks occurred in seven patients. Also, cerebral edema (five patients), subdural hematoma (five patients), and intracerebral hematoma (three patients) were observed on postprocedural imaging studies but did not require surgical intervention. Hypertrophic scars on the scalp were observed in nine patients. There were three infections, including one case of osteomyelitis and two superficial wound infections. Blood loss and the amounts of subsequent transfusions correlated directly with the size and number of electrodes on the grids (p < 0.001). Twenty-eight children derived significant benefit from cortical resections and MSTs, with a more than 50% reduction of seizures and a mean follow-up period of 30 months. Conclusions. The results of this study indicate that carefully selected pediatric patients with intractable epilepsy can benefit from subdural invasive monitoring procedures that entail definite but acceptable risks.

Malignant astrocytomas are highly invasive neoplasms infiltrating diffusely into regions of normal brain. Whereas the molecular and cellular mechanisms governing astrocytoma invasion remain poorly understood, evidence in other cell systems has implicated a role for the Rho-GTPases in cell motility and invasion. Here, we examine how the inhibition or activation of Rho-kinase (ROCK) affects astrocytoma morphology, motility, and invasion. ROCK was inhibited in astrocytoma cells by using 5 to 100 μmol/L of Y27632 or by expressing the dominant-negative ROCK mutant, RB/PH TT. ROCK activation was achieved by expressing a constitutively active mutant, CAT. ROCK inhibition led to morphologic and cytoskeletal alterations characterized by an increase in the number and length of cell processes, increased membrane ruffling, and collapse of actin stress fibers. Using two-dimensional radial migration and Boyden chamber assays, we show that astrocytoma migration and invasion were increased at least 2-fold by ROCK inhibition. On the contrary, ROCK activation significantly inhibited migration and invasion of astrocytoma cells. Furthermore, using a Rac-GTP pull-down assay, we show that Rac1 is activated as a consequence of ROCK inhibition. Finally, we show that treatment of astrocytoma cells with small interfering RNA duplexes specific for Rac1-reversed stellation, prevented membrane ruffling formation and abrogated the increased motility observed following treatment with Y27632. Our data show that Rac1 plays a major role in astrocytoma morphology, motility, and invasion. These findings warrant further investigation to determine precisely how the modulation of Rac1 and ROCK can be exploited to inhibit glioma invasion.

Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila. Cancer Res; 76(16); 4708–19. ©2016 AACR.