Department of Neurosurgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Institute of Medical Radiology, University Clinic St. Pölten, Karl Landsteiner University of Health Sciences, St. Pölten, Austria.
Clin Cancer Res. 2021 Mar 15;27(6):1641-1649. doi: 10.1158/1078-0432.CCR-20-3580. Epub 2020 Dec 8.
Insufficient control of infiltrative glioblastoma (GBM) cells is a major cause of treatment failure and tumor recurrence. Hence, detailed insights into pathophysiologic changes that precede GBM recurrence are needed to develop more precise neuroimaging modalities for tailored diagnostic monitoring and therapeutic approaches.
Overall, 168 physiologic MRI follow-up examinations of 56 patients with GBM who developed recurrence after standard therapy were retrospectively evaluated, that is, two post-standard-therapeutic follow-ups before and one at radiological recurrence. MRI biomarkers for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia were determined for brain areas that developed in the further course into recurrence and for the recurrent GBM itself. The temporal pattern of biomarker changes was fitted with locally estimated scatterplot smoothing functions and analyzed for pathophysiologic changes preceding radiological GBM recurrence.
Our MRI approach demonstrated early pathophysiologic changes prior to radiological GBM recurrence in all patients. Analysis of the time courses revealed a model for the pathophysiology of GBM recurrence: 190 days prior to radiological recurrence, vascular cooption by GBM cells induced vessel regression, detected as decreasing vessel density/perfusion and increasing hypoxia. Seventy days later, neovascularization activity was upregulated, which reincreased vessel density and perfusion. Hypoxia, however, continued to intensify for 30 days and peaked 90 days before radiological recurrence.
Hypoxia may represent an early sign for GBM recurrence. This might become useful in the development of new combined diagnostic-therapeutic approaches for tailored clinical management of recurrent GBM. Further preclinical and in-human studies are required for validation and evaluation.
浸润性胶质母细胞瘤（GBM）细胞控制不足是治疗失败和肿瘤复发的主要原因。因此，需要深入了解 GBM 复发前的病理生理变化，以便开发更精确的神经影像学方法，用于针对性的诊断监测和治疗方法。
回顾性评估了 56 例接受标准治疗后复发的 GBM 患者的 168 项生理 MRI 随访检查，即标准治疗后两次随访和一次影像学复发时的检查。为进一步发展为复发的脑区和复发的 GBM 本身确定了用于微血管结构和灌注、新生血管活性、氧代谢和缺氧的 MRI 生物标志物。用局部估计散点平滑函数拟合生物标志物变化的时间模式，并分析影像学 GBM 复发前的病理生理变化。
我们的 MRI 方法在所有患者中均显示出影像学 GBM 复发前的早期病理生理变化。时间过程分析显示了 GBM 复发的病理生理学模型：在影像学复发前 190 天，GBM 细胞的血管选择导致血管退化，表现为血管密度/灌注减少和缺氧增加。70 天后，新生血管活性上调，导致血管密度和灌注增加。然而，缺氧继续加剧 30 天，并在影像学复发前 90 天达到峰值。
缺氧可能是 GBM 复发的早期迹象。这可能有助于开发新的联合诊断-治疗方法，用于对复发性 GBM 进行个体化的临床管理。需要进一步的临床前和人体研究来验证和评估。
