Integrated MRI-Immune-Genomic Features Enclose a Risk Stratification Model in Patients Affected by Glioblastoma

Giulia Mazzaschi; Alessandro Olivari; Antonio Pavarani; Costanza Anna Maria Lagrasta; Caterina Frati; Denise Madeddu; Bruno Lorusso; Silvia Dallasta; Chiara Tommasi; Antonino Musolino; Marcello Tiseo; Maria Michiara; Federico Quaini; Pellegrino Crafa

doi:10.3390/cancers14133249

Integrated MRI-Immune-Genomic Features Enclose a Risk Stratification Model in Patients Affected by Glioblastoma

Cancers (Basel). 2022 Jul 1;14(13):3249. doi: 10.3390/cancers14133249.

Authors

Giulia Mazzaschi^{1

2}, Alessandro Olivari^{1

2}, Antonio Pavarani³, Costanza Anna Maria Lagrasta⁴, Caterina Frati⁴, Denise Madeddu⁴, Bruno Lorusso⁴, Silvia Dallasta⁵, Chiara Tommasi^{1

2}, Antonino Musolino^{1

2}, Marcello Tiseo^{1

2}, Maria Michiara¹, Federico Quaini², Pellegrino Crafa^{2

4}

Affiliations

¹ Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy.
² Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
³ Neuroradiology Unit, University Hospital of Parma, 43126 Parma, Italy.
⁴ Pathology Unit, University Hospital of Parma, 43126 Parma, Italy.
⁵ Geriatric Department, University of Genoa, 16132 Genova, Italy.

Abstract

Background: The aim of the present study was to dissect the clinical outcome of GB patients through the integration of molecular, immunophenotypic and MR imaging features.

Methods: We enrolled 57 histologically proven and molecularly tested GB patients (5.3% IDH-1 mutant). Two-Dimensional Free ROI on the Biggest Enhancing Tumoral Diameter (TDFRBETD) acquired by MRI sequences were used to perform a manual evaluation of multiple quantitative variables, among which we selected: SD Fluid Attenuated Inversion Recovery (FLAIR), SD and mean Apparent Diffusion Coefficient (ADC). Characterization of the Tumor Immune Microenvironment (TIME) involved the immunohistochemical analysis of PD-L1, and number and distribution of CD3+, CD4+, CD8+ Tumor Infiltrating Lymphocytes (TILs) and CD163+ Tumor Associated Macrophages (TAMs), focusing on immune-vascular localization. Genetic, MR imaging and TIME descriptors were correlated with overall survival (OS).

Results: MGMT methylation was associated with a significantly prolonged OS (median OS = 20 months), while no impact of p53 and EGFR status was apparent. GB cases with high mean ADC at MRI, indicative of low cellularity and soft consistency, exhibited increased OS (median OS = 24 months). PD-L1 and the overall number of TILs and CD163+TAMs had a marginal impact on patient outcome. Conversely, the density of vascular-associated (V) CD4+ lymphocytes emerged as the most significant prognostic factor (median OS = 23 months in V-CD4^high vs. 13 months in V-CD4^low, p = 0.015). High V-CD4+TILs also characterized TIME of MGMT^meth GB, while p53^mut appeared to condition a desert immune background. When individual genetic (MGMT^unmeth), MR imaging (mean ADC^low) and TIME (V-CD4+TILs^low) negative predictors were combined, median OS was 21 months (95% CI, 0-47.37) in patients displaying 0-1 risk factor and 13 months (95% CI 7.22-19.22) in the presence of 2-3 risk factors (p = 0.010, HR = 3.39, 95% CI 1.26-9.09).

Conclusion: Interlacing MRI-immune-genetic features may provide highly significant risk-stratification models in GB patients.

Keywords: glioblastoma; magnetic resonance imaging (MRI); tumor immune microenvironment (TIME).

Grants and funding

This research received no external funding.