1Departments of Neurosurgery.
2Department of Radiology and Nuclear Medicine, Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
J Neurosurg. 2022 Oct 28;138(5):1263-1272. doi: 10.3171/2022.9.JNS221036. Print 2023 May 1.
Meningiomas are frequently occurring, often benign intracranial tumors. Molecular fluorescence can be used to intraoperatively identify residual meningioma tissue and optimize safe resection; however, currently no clinically approved agent is available for this specific tumor type. In meningiomas, vascular endothelial growth factor α (VEGFα) is upregulated, and this biomarker could be targeted with bevacizumab-IRDye800CW, a fluorescent agent that is already clinically applied for the resection of other tumors and neoplasms. Here, the authors investigated the feasibility of using bevacizumab-IRDye800CW to target VEGFα in a CH-157MN xenografted mouse model.
Five mice with CH-157MN xenografts with volumes of 500 mm3 were administered intravenous bevacizumab-IRDye800CW. Mice were imaged in vivo at 24 hours, 48 hours, and 72 hours after injection with the FMT2500 fluorescence imaging system. Biodistribution was determined ex vivo using the Pearl fluorescent imager at 72 hours after injection. To mimic a clinical scenario, 2 animals underwent postmortem xenograft resection using both white-light and fluorescence guidance. Lastly, fresh and frozen human meningioma specimens were incubated ex vivo with bevacizumab-IRDye800CW, stained with anti-VEGFα, and microscopically examined.
In vivo, tumors fluoresced at all time points after tracer administration and background fluorescence decreased with time. Ex vivo analyses of tracer biodistribution showed the highest fluorescence in resected tumor tissue. Brain, skull, and muscle tissue showed very low fluorescence. Microscopically, fluorescence was observed in the cytoplasm and was correlated with VEGFα expression patterns. During postmortem surgery, both the tumor bulk and a small tumor remnant were detected. Bevacizumab-IRDye800CW bound specifically to all tested human meningioma samples, as indicated by a high fluorescent signal in the tumor bulk compared with the surrounding healthy dura mater.
Bevacizumab-IRDye800CW showed meningioma specificity, as illustrated by high VEGFα-mediated uptake in the meningioma xenograft mouse model. Small tumor lesions were detected using fluorescence guidance. Thus, the next step will be to assess the feasibility of using already available clinical grade bevacizumab-IRDye800CW to optimize meningioma resection in a human trial.
脑膜瘤是一种常见的、常为良性的颅内肿瘤。分子荧光技术可用于术中识别残余脑膜瘤组织并优化安全切除；然而，目前尚无临床批准的用于该特定肿瘤类型的药物。在脑膜瘤中，血管内皮生长因子 α（VEGFα）上调，而bevacizumab-IRDye800CW 可作为一种荧光剂靶向该生物标志物，该荧光剂已临床应用于其他肿瘤和肿瘤的切除。在此，作者研究了在 CH-157MN 异种移植小鼠模型中使用 bevacizumab-IRDye800CW 靶向 VEGFα 的可行性。
将 5 只体积为 500mm3 的 CH-157MN 异种移植小鼠给予静脉注射 bevacizumab-IRDye800CW。注射后 24 小时、48 小时和 72 小时，使用 FMT2500 荧光成像系统进行体内成像。注射后 72 小时，使用 Pearl 荧光成像仪进行离体生物分布测定。为模拟临床情况，2 只动物在进行死后异种移植切除时，同时使用白光和荧光引导。最后，将新鲜和冷冻的人脑膜瘤标本离体孵育 bevacizumab-IRDye800CW，用抗 VEGFα染色，显微镜下观察。
在体内，所有时间点在示踪剂给药后肿瘤均有荧光，背景荧光随时间降低。示踪剂生物分布的离体分析显示，切除的肿瘤组织中荧光最强。脑组织、颅骨和肌肉组织的荧光非常低。显微镜下，细胞质中观察到荧光，并与 VEGFα表达模式相关。在死后手术中，均检测到肿瘤主体和一小部分肿瘤残留。Bevacizumab-IRDye800CW 特异性结合所有测试的人脑膜瘤样本，肿瘤主体的荧光信号明显高于周围健康硬脑膜。
Bevacizumab-IRDye800CW 显示出脑膜瘤特异性，因为在脑膜瘤异种移植小鼠模型中，VEGFα 介导的摄取率高。使用荧光引导检测到小的肿瘤病变。因此，下一步将评估使用现有临床级别的 bevacizumab-IRDye800CW 优化人类脑膜瘤切除术的可行性。
