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Various Artists - Take Action! This has not only been demonstrated in glioblastoma but also in non-contrast enhancing low grade glioma in which IDH mutated low grade glioma both oligodendroglioma and astrocytoma were more frequently located in the frontal lobes, while non-contrast enhancing IDH wildtype astrocytoma were more frequently located in the basal ganglia of the right hemisphere Therefore, studies must be conducted based on homogeneous tumor populations with respect to IDH mutational status.

This hypothesis was recently supported by Roux et al. Second, the conflicting results in the literature may arise from different statistical methods that were used across studies. Studies often investigated the anatomic localization of glioblastoma with and without MGMT promoter methylation with visual examination, qualitatively, without a statistical, voxel-wise quantitative analysis 7 — 9 , Using similar frequency difference maps, we also found topographical differences, which indicated that when compared with MGMT unmethylated glioblastoma, MGMT methylated glioblastoma were more frequently localized near bifrontal and right occipital periventricular area and less frequently near the right occipital periventricular area.

However, we showed that these apparent differences did not survive rigorous statistical testing. Another methodological difference can be found in the correction for multiple comparisons. Furthermore, the method by Bullmore et al. Our stringent methodology of rigorous statistical testing and applying new insights in glioblastoma molecular subtyping to a large studied patient population are the strengths of our study.

The main limitation of this study is its retrospective design, which may have introduced selection and confounding biases. Selection bias may occur when patients who receive diagnostic biopsies are excluded from analysis, since these tumors are often large, multifocal, located deep within the basal ganglia, or crossing midline.

This may skew the results on tumor localization of glioblastoma, which is our main outcome. We have therefore attempted to limit this bias first by consecutive inclusion of all glioblastoma patients operated upon between and in our cohort, including diagnostic biopsies. In addition, it is known that tumor localization is associated with IDH mutation status, with IDH mutated tumors located more frequently in the frontal lobes, as mentioned earlier Since IDH mutation status is both associated with tumor localization and MGMT methylation status, it may function as a confounding factor.

We therefore have also attempted to limit this potential bias by excluding all IDH mutated tumors. Another limitation is that we included patients from two medical centers from a period of over seven years. This introduced variation of MRI scan protocols such as magnet strength, voxel size, and slice thickness, which consequently may have negatively influenced registration accuracy and anatomical localization.

Such registration inaccuracies can however be considered minor relative to the size of the tumor, and it is therefore unlikely that our results were significantly impacted by scanner variations. Additionally, tumor volume assessment on these MRI scans were performed by one observer without confirmation of a second, independent assessor. This may have introduced some degree of information bias. We have attempted to limit this bias during volumetric assessment by blinding the assessor for patients' clinical and molecular characteristics.

Also, it is known that both the inter- and intraobserver agreement for preoperative tumor volumes in glioblastoma is relatively high, while small variations in segmentation will probably have only a very limited effect on determining gross tumor localization Finally, it should be noted that the known intertest variability is a limitation of MGMT analyses, as assays used in other studies may produce slightly different MGMT methylation results This may partially explain the variety in the proportion of MGMT methylated tumors reported in literature.

To conclude, in the largest homogenous IDH wildtype glioblastoma population to date, we showed that visual appearance of differences could not be confirmed with rigorous voxel-wise statistical testing and thus that there is no statistical difference in anatomical localization between IDH wildtype glioblastoma with vs. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.

The studies involving human participants were reviewed and approved by MEC Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors would like to thank Claudine Nogarede-Bloemendaal for assistance with data collection at the Haaglanden MC.

Supplementary Video S9. P value map methylated GBM T1w. Supplementary Video S P value map methylated GBM T2w. P value map unmethylated GBM T1w. P value map unmethylated GBM T2w. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. Surgery for glioblastoma in light of molecular markers: impact of resection and MGMT promoter methylation in newly diagnosed IDH-1 wild-type glioblastomas.

MGMT gene silencing and benefit from temozolomide in glioblastoma. Smits M, van den Bent MJ. Imaging correlates of adult glioma genotypes. Anatomic localization of O6-methylguanine DNA methyltransferase MGMT promoter methylated and unmethylated tumors: a radiographic study in de novo human glioblastomas. Anatomical specificity of O6-methylguanine DNA methyltransferase protein expression in glioblastomas.

J Neurooncol. Clin Cancer Res. Structural and advanced imaging in predicting MGMT promoter methylation of primary glioblastoma: a region of interest based analysis. BMC Cancer. The World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. SimpleElastix: a user-friendly, multi-lingual library for medical image registration.

Las Vegas, NV Interlaboratory comparison of IDH mutation detection. Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC brain tumor group phase III trial. Neuro Oncol. Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference.

Permutation inference for the general linear model. Probabilistic radiographic atlas of glioblastoma phenotypes. Am J Neuroradiol. An analysis of image texture, tumor location, and MGMT promoter methylation in glioblastoma using magnetic resonance imaging. Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin.

J Clin Oncol. Factors involved in maintaining prolonged functional independence following supratentorial glioblastoma resection: Clinical article. J Neurosurg. MRI atlas of IDH wild-type supratentorial glioblastoma: probabilistic maps of phenotype, management, and outcomes. Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain. Intraobserver and interobserver agreement in volumetric assessment of glioblastoma multiforme resection.

MGMT testing—the challenges for biomarker-based glioma treatment. Nat Rev Neurol. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

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