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.
Highlights
Cancers of the central nervous system (CNS) refer to a heterogeneous group of rare tumors [1]
Inclusion criteria were as follows: (i) age ≥18 years; (ii) WHO grading system based histopathological confirmation of an anaplastic glioma (AG, WHO grade III) with mutation of the isocitrate dehydrogenase (IDH) gene as initial diagnosis; (iii) treatment according to the standard of care, i.e., maximal safe and radical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide [23]; (iv) follow-up magnetic resonance imaging (MRI) examinations with the study protocol; (v) no previous diagnosis of Anaplastic glioma (AG) recurrence; (vi) no additional anti-glioma treatment but the standard of care; and (vii) conventional MRI data were evaluated by at least two board-certified radiologists in consensus based on the updated Response Assessment in Neuro-Oncology (RANO) criteria [24,25]
Most radical repeat resection of the tumor is associated with significant survival advantages compared with no surgery or subtotal resection [44], early and reliable recurrence detection, which is an essential requirement for this treatment option, is often challenging even with advanced conventional MRI (cMRI) techniques such as cerebral blood volume (CBV) mapping [45]
Summary
Cancers of the central nervous system (CNS) refer to a heterogeneous group of rare tumors [1]. Gliomas account for 75% of malignant primary CNS tumors in adults and more than the half of these are glioblastoma [4], associated with a poor outcome in terms of median overall survival of 14–17 months [5] and 5-year survival rate of less than 5% [3]. Despite best-practice multimodal treatment including surgical resection, radiotherapy and chemotherapy [10,11], most IDH-mutated AG patients suffer from incurability in due course. This is mainly due to the diffusively infiltration of glioma cells into the brain parenchyma, which makes a complete surgical extraction of the tumor impossible and inevitably leads to recurrence of the tumor eventually combined with likelihood for malignant transformation to glioblastoma
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