Purpose: Glutamatergic neuron–glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability. Experimental Design: An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan–Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry. Results: HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations. Conclusions: Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients.

中文翻译：

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吡仑帕奈对新诊断的高级别胶质瘤周围过度兴奋性的初步试验


目的：谷氨酸能神经元-胶质瘤突触发生和瘤周过度兴奋性在正反馈回路中促进胶质瘤生长。本研究的目的是评估靶向 AMPA 受体拮抗剂吡仑帕奈对瘤周过度兴奋的可行性和估计效应量。实验设计： 进行了一项开放标签试验，比较吡仑帕奈与标准护理 （SOC） 在新诊断的放射学高级别胶质瘤切除术患者中的疗效。吡仑帕奈作为术前负荷剂量给药，随后进行维持治疗直至疾病进展或长达 12 个月。SOC 治疗涉及左乙拉西坦 7 天或根据临床指征。过度兴奋的主要结局由术中皮层电图高频振荡 （HFO） 率定义。通过 Kaplan-Meier 方法估计无癫痫发作和总生存期。通过质谱法测量吡仑帕奈、左乙拉西坦和相关生物标志物的组织浓度。结果： 吡仑帕奈和左乙拉西坦治疗患者的 HFO 发生率相似。该试验在计划的中期分析后提前终止，并评估了 11 例患者 （7 例吡仑帕奈治疗;4 例 SOC 治疗） 的结局。在入组后中位 281 天的随访中，27% 的患者出现癫痫发作，其中 14% 的患者在吡仑帕奈治疗期间维持，50% 的患者接受 SOC 治疗。吡仑帕奈治疗患者的总生存期与胶质母细胞瘤参考队列相似。表面活检中的谷氨酸浓度与相邻电极接触中的 HFO 率呈正相关，与治疗分配或药物浓度无显著相关性。 结论： 胶质瘤瘤周谷氨酸浓度与高 γ 振荡率相关。用吡仑帕奈靶向谷氨酸能活性达到了与左乙拉西坦治疗患者相似的皮层电图过度兴奋水平。