Seizures and Tumor Progression in Glioma Patients with Uncontrollable Epilepsy Treated with Perampanel.

BACKGROUND/AIM: Excessive extracellular glutamate activates AMPA-type glutamate receptors (AMPA receptors) and induces seizures. Antagonistic activation of AMPA receptors inhibits epilepsy and glioma growth in in vitro and in vivo studies. This study was conducted to evaluate the clinical impacts of perampanel (PER), a novel AMPA receptor antagonist, on seizures and tumor progression in glioma patients with uncontrollable epilepsy. PATIENTS AND METHODS: Twelve glioma patients with uncontrollable epilepsy were treated with PER. Seizure response, PER concentration, and tumor volume were assessed. RESULTS: Obvious seizure control was observed in 10 analyzed patients (100%) and 6 patients (60%) became seizure-free. Median plasma concentrations of PER were 296 ng/ml in those with 4 mg/day PER treatment and 518 ng/ml in those with 8 mg/day PER treatment. High-intensity lesions in fluid-attenuated inversion recovery of magnetic resonance imaging (MRI) were volumetrically assessed to analyze tumor size. Volume reduction was detected within 6 months in correlation with increased plasma levels of PER. CONCLUSION: PER treatment was effective in uncontrollable epilepsy with gliomas. MRI images showed the inhibition of tumor growth.

Efficacy of Combination Therapy with MET and VEGF Inhibitors for MET-overexpressing Glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is a malignant brain tumor with an extremely poor prognosis. GBM tissues frequently express mesenchymal-epithelial transition factor (MET), which induces cell division, growth and migration. In addition, angiogenesis is a significant feature of GBM, attributable to the overexpression of vascular endothelial growth factor (VEGF). Although the VEGF inhibitor bevacizumab was recently highlighted as the second-line drug for GBM treatment, GBMs often recur even with bevacizumab therapy. Based on these findings, we hypothesized that inhibition of both MET and VEGF would exhibit a synergistic effect on MET-overexpressing GBM. MATERIALS AND METHODS: As we observed MET expression at high levels in some patients with GBM, we designed GL261 murine glioma-based experiments. GL261 cells were transfected with siRNAs specific for MET and VEGF in vitro, and the cell growth ratios were evaluated. Simultaneously, transfected GL261 cells were transplanted into the brain of C57BL/6 mice, and their survival was monitored. RESULTS: GBM tissues frequently overexpressed MET protein at high levels compared with lower-grade gliomas. These GBMs at first responded to bevacizumab, but often eventually recurred. When GL261 cells were co-transfected with both MET-specific siRNA and VEGF-specific siRNA, the in vitro tumor cell growth significantly decelerated compared to single siRNA transfection. Consistently, when mice were transplanted with co-transfected GL261 cells, their survival was significantly prolonged compared to those given cells transfected with single siRNA. CONCLUSION: The current data indicate that the inhibition of both MET and VEGF exhibits efficient therapeutic effects of GBM-bearing hosts.

MET Expressed in Glioma Stem Cells Is a Potent Therapeutic Target for Glioblastoma Multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent and the most malignant tumor among adult brain tumors. Previous reports led us to hypothesize that the proto-oncogene mesenchymal-epithelial transition (MET) expressed in glioma stem cell-like cells (GSCs) would be a potent therapeutic target for GBM. PATIENTS AND METHODS: To address this question, we analyzed 113 original samples of tumors from patients based on immunohistochemistry. During this process, we were able to establish GSC lines from patients with GBM that were MET-positive and MET-negative. Using these cells, we tested the therapeutic impact of a MET inhibitor, crizotinib, both in vitro and in vivo. RESULTS: Patients with MET-positive GBM exhibited poor survival. GSC-based experiments revealed that treatment with crizotinib, both in vitro and in vivo, exhibited therapeutic efficacy particularly against MET-positive GSCs. CONCLUSION: Based on these findings, we conclude that MET expressed in GSCs might be a potent therapeutic target for GBM.

Surgical accessibility of the distal internal carotid artery on carotid endarterectomy evaluated using magnetic resonance angiography.

BACKGROUND: Magnetic resonance angiography (MRA) is helpful for preoperatively evaluating the degree of carotid stenosis, although it is not always useful for assessing surgical accessibility to the distal internal carotid artery (ICA) due to the lack of osteological information. OBJECTIVE: To demonstrate a method for evaluating the accessible distal portion of the ICA for carotid endarterectomy (CEA) using MRA. METHODS: As an indicator of the upper limit of the operating field, a line drawn from the C1 transverse process to the hyoid bone (C1-H line) was defined. The cross-point between the C1-H line and distal ICA was delineated on 3-dimensional (3-D) MRA and 3-D tomography angiography (CTA). The distance between the carotid bifurcation and C1-H line was measured in 11 patients. The exposed distal ICA was compared with the extent of intraoperative ICA exposure. RESULTS: The mean vertical distance (27.5 mm) from the carotid bifurcation to the C1-H line measured using 3-D MRA was almost the same as the distance (28 mm) evaluated on 3-D CTA. The discrepancy in distance between the 2 modalities was 1.9 ± 1.7 mm. Furthermore, the point of the ICA across the C1-H line created on 3-D MRA was in accordance with the intraoperative measurement (28.7 mm) of the exposed ICA. CONCLUSION: The C1-H line measured on 3-D MRA is a simple and useful indicator of the distal point of the accessible ICA during CEA, especially in patients with renal dysfunction and allergies to contrast medium.

C1 transverse process-hyoid bone line for preoperative evaluation of the accessible internal carotid artery on carotid endarterectomy: technical note.

BACKGROUND: The preoperative imaging diagnosis of the distal portion of the internal carotid artery (ICA) is extremely important for carotid endarterectomy (CEA). Herein the authors defined a line from the C1 transverse process to the hyoid bone (C1-H line) and evaluated whether the line can be used to predict an accessible ICA in CEA. METHODS: A cross point between the C1-H line and distal ICA was analyzed using three-dimensional computerized tomographic angiography (3D-CTA) in 20 patients. The C1-H line was compared to the line drawn from the mastoid process to the mandible (M-M line). Intraoperative exposure of the distal ICA was evaluated using both lines. Furthermore, the distance of each line from the C2 vertebra was measured to identify the distance difference of each line in relation to the cervical posture. RESULTS: A distal ICA exposed at a cross point of the C1-H line corresponded well with the intraoperative findings. The cross point between the C1-H line and distal ICA was positioned at an average of 7.0 ± 0.7 mm cranially in comparison to the M-M line. The C1-H line showed smaller distance differences at different cervical positions than the M-M line. The C1-H line moved an average of 2.8 ± 2.5 mm from a cervical neutral position to an extensional one in the perpendicular direction. CONCLUSION: The C1-H line measured by 3D-CTA is a simple and useful indicator of the distal ICA exposure in the preoperative diagnosis for CEA.

Novel surgical technique to solidify cyst-type metastatic brain tumors using autologous fibrin glue for complete resection.

BACKGROUND: An outstanding issue regarding the surgical treatment of cyst-type metastatic brain tumors is the incomplete resection of cyst walls. Herein we propose a novel surgical technique that can overcome this issue. During a surgical procedure for cystic tumors, autologous fibrin glue is to be injected into the tumor cysts, which solidifies the cyst lumens and cyst walls en bloc with reducing the tumor size. As a result, tumor masses and cyst walls can be removed completely in an en bloc fashion in all cases. METHODS: The illustrative case presented in this report is a patient with metastatic brain tumors in the frontal lobe. When we reached the tumor wall surgically, we first suctioned out the cyst content and subsequently injected autologous fibrin glue into the cyst lumen. The autologous fibrin glue solidified the tumor en bloc, and we resected the tumor mass and the cyst walls in an en bloc fashion. RESULTS: We have applied this technique to four cases with cyst-type metastatic brain tumors. This approach made it possible to perform ideal en bloc resection in all cases. There were no adverse events due to the autologous fibrin glue. CONCLUSION: We developed a novel surgical technique to solidify cyst-type metastatic brain tumors using autologous fibrin glue, which allows en bloc resection of tumor masses and cyst walls quite safely using inexpensive materials. Given these advantages, it appears a promising surgical strategy for cyst-type metastatic brain tumors.

The chicken egg and skull model of endoscopic endonasal transsphenoidal surgery improves trainee drilling skills.

BACKGROUND: We verified the effectiveness of training in endoscopic endonasal transsphenoidal surgery (eETSS) techniques using chicken eggs and a skull model. METHODS: We verified the area of eggshell removed by drilling when five residents and four experts used the chicken eggs and a skull model. RESULTS: When residents performed drilling on 10 eggs, a mean (± standard deviation [SD]) area of 31.2 ± 17.5 mm2 was removed from the first egg, and 104.8 ± 3.3 mm2 from the tenth and final egg, representing an increase in area and a decrease in SD. The experts performed the same drilling operation on a single egg, and removed a mean area of 257± 31.7 mm2. These results demonstrated that skills improved as a result of this training, and suggested that this method was also capable of overcoming the initial individual differences in the amount of force applied and ability. An obvious difference between residents and experts was seen in the area removed (p = 0.00011); however, this was attributed to differences in endoscopic manipulation, rather than drilling skill. CONCLUSION: Our findings suggest that this training method could be adequate for acquiring eETSS techniques. Although experts showed superior endoscopic manipulation, residents may also be able to acquire adequate endoscopic skills through further training, and our training method appears to offer an effective means of improving eETSS techniques.