Hypoxia and Microvascular Alterations Are Early Predictors of IDH-Mutated Anaplastic Glioma Recurrence

SIMPLE SUMMARY: Anaplastic gliomas (AGs) are considered the most common and aggressive primary brain tumors of young adults with inevitable recurrence and treatment failure. The aim of this study was to investigate whether the imaging biomarkers of hypoxia, microvascular architecture and neovascularization activity can be of assistance to detect pathophysiological changes in the early developmental stages of isocitrate-dehydrogenase (IDH) mutated AG recurrence. We evaluated 142 physiological magnetic resonance imaging follow-up examinations as a part of the conventional magnetic resonance imaging (MRI) protocol in 60 AG patients after standard therapy. Physiological MRI biomarkers showed intensifying local tissue hypoxia 250 days prior to radiological recurrence with following upregulation of neovascularization activity 50 to 70 days later. Integration of physiological MRI in the monitoring of AG patients may be of clinical significance to make personalized decision of early tumor recurrence without an additional delay for multimodal therapy. ABSTRACT: Anaplastic gliomas (AG) represents aggressive brain tumors that often affect young adults. Although isocitrate-dehydrogenase (IDH) gene mutation has been identified as a more favorable prognostic factor, most IDH-mutated AG patients are confronted with tumor recurrence. Hence, increased knowledge about pathophysiological precursors of AG recurrence is urgently needed in order to develop precise diagnostic monitoring and tailored therapeutic approaches. In this study, 142 physiological magnetic resonance imaging (phyMRI) follow-up examinations in 60 AG patients after standard therapy were evaluated and magnetic resonance imaging (MRI) biomarker maps for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia calculated. From these 60 patients, 34 patients developed recurrence of the AG, and 26 patients showed no signs for AG recurrence during the study period. The time courses of MRI biomarker changes were analyzed regarding early pathophysiological alterations over a one-year period before radiological AG recurrence or a one-year period of stable disease for patients without recurrence, respectively. We detected intensifying local tissue hypoxia 250 days prior to radiological recurrence which initiated upregulation of neovascularization activity 50 to 70 days later. These changes were associated with a switch from an avascular infiltrative to a vascularized proliferative phenotype of the tumor cells another 30 days later. The dynamic changes of blood perfusion, microvessel density, neovascularization activity, and oxygen metabolism showed a close physiological interplay in the one-year period prior to radiological recurrence of IDH-mutated AG. These findings may path the wave for implementing both new MR-based imaging modalities for routine follow-up monitoring of AG patients after standard therapy and furthermore may support the development of novel, tailored therapy options in recurrent AG.