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In Vivo Molecular Profiling of Human Glioma

Cross-Sectional Observational Study Using Dynamic Susceptibility Contrast Magnetic Resonance Perfusion Imaging

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Abstract

Purpose

To assess the diagnostic performance of dynamic susceptibility contrast perfusion magnetic resonance perfusion imaging (DSC-MRI) for in vivo human glioma molecular profiling.

Methods

In this study 100 patients with histopathologically confirmed glioma who provided written informed consent were retrospectively assessed between January 2016 and February 2017 in two prospective trials that were approved by the local institutional review board. Cerebral blood volume (CBV) measurements from DSC-MRI were assessed, and histogram parameters of relative CBV (rCBV) results were compared among World Health Organization (WHO) 2016 based histological findings and molecular characteristics. A classification and regression tree (CART) algorithm with 10-fold cross-validation was used to calculate the diagnostic accuracy.

Results

The 90th percentile (C90) of rCBV was significantly lower in patients with the isocitrate dehydrogenase 1/2 (IDH1/2) mutation (2.86 ± 1.21; p < 0.001) and loss of alpha-thalassemia mental retardation syndrome X‑linked (ATRX) expression (2.23 ± 0.91; p < 0.001) than in those with the IDH1/2 wild type (4.78 ± 2.34) and maintained ATRX expression (4.30 ± 2.02). The standard deviation (SD) of rCBV was significantly higher in glioblastoma (GBM) with methylated O6-methylguanine DNA methyltransferase (MGMT; 1.99 ± 0.73; p = 0.001) than in those with unmethylated MGMT (1.20 ± 0.45). In CART analysis, rCBV predicted the molecular subgroup in 76.3% of astroglial tumors; however, the diagnostic performance was reduced to 48.1% by including oligodendrogliomas with chromosome 1p/19q co-deletion in the analysis due to substantial overlap of rCBV values between OD1p/19q-LOH and IDHwt GBM.

Conclusion

The DSC-MRI procedure may provide insight into the IDH1/2 mutation and ATRX expression status and MGMT methylation profile of diffuse glioma; however, taking integrated oligodendroglioma into account limits the diagnostic performance of rCBV in non-invasively predicting the molecular subtype.

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Funding

JS was supported by the Else-Übelmesser Foundation (grant no. 30.19845). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Johann-Martin Hempel.

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J.-M. Hempel, J. Schittenhelm, U. Klose, B. Bender, G. Bier, M. Skardelly, G. Tabatabai, S. Castaneda Vega, U. Ernemann and C. Brendle declare that they have no competing interests.

Caption Electronic Supplementary Material

62_2018_676_MOESM1_ESM.pdf

Supplementary Fig. 1. Histogram parameters of rCBV values in WHO 2016-based tumor grading. Boxplots illustrate the 90th percentile of rCBV values in glioma grading according to the individual WHO 2016 glioma grades. Significant p values at α = 0.0083 are highlighted in yellow. rCBV is dimensionless.

62_2018_676_MOESM2_ESM.pdf

Supplementary Fig. 2. Area under the ROC curves in differentiation of IDH1/2 mutation status in astroglial tumors. The AUC of ROC curves for differentiating between the IDH1/2 mutation and IDH wild type in astroglial brain tumors excluding OD, based on histogram parameters of rCBV values.

62_2018_676_MOESM3_ESM.pdf

Supplementary Fig. 3. Multivariate CART analysis. Decision trees from multivariate CART analysis with 10-fold cross-validation demonstrating the diagnostic performance of rCBV histogram parameters in non-invasive glioma classification according to their integrated molecular profile.

62_2018_676_MOESM4_ESM.docx

Supplementary Table 1. Diagnostic performance of rCBV histogram parameters in stratifying astroglial brain tumors according to IDH1/2 mutation status.

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Hempel, JM., Schittenhelm, J., Klose, U. et al. In Vivo Molecular Profiling of Human Glioma. Clin Neuroradiol 29, 479–491 (2019). https://doi.org/10.1007/s00062-018-0676-2

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