Tailored Intraoperative MRI Strategies in High-Grade Glioma Surgery: A Machine Learning-Based Radiomics Model Highlights Selective Benefits.

BACKGROUND AND OBJECTIVES: In high-grade glioma (HGG) surgery, intraoperative MRI (iMRI) has traditionally been the gold standard for maximizing tumor resection and improving patient outcomes. However, recent Level 1 evidence juxtaposes the efficacy of iMRI and 5-aminolevulinic acid (5-ALA), questioning the continued justification of iMRI because of its associated costs and extended surgical duration. Nonetheless, drawing from our clinical observations, we postulated that a subset of intricate HGGs may continue to benefit from the adjunctive application of iMRI. METHODS: In a prospective study of 73 patients with HGG, 5-ALA was the primary technique for tumor delineation, complemented by iMRI to detect residual contrast-enhanced regions. Suboptimal 5-ALA efficacy was defined when (1) iMRI detected contrast-enhanced remnants despite 5-ALA's indication of a gross total resection or (2) surgeons observed residual fluorescence, contrary to iMRI findings. Radiomic features from preoperative MRIs were extracted using a U2-Net deep learning algorithm. Binary logistic regression was then used to predict compromised 5-ALA performance. RESULTS: Resections guided solely by 5-ALA achieved an average removal of 93.14% of contrast-enhancing tumors. This efficacy increased to 97% with iMRI integration, albeit not statistically significant. Notably, for tumors with suboptimal 5-ALA performance, iMRI's inclusion significantly improved resection outcomes (P-value: .00013). The developed deep learning-based model accurately pinpointed these scenarios, and when enriched with radiomic parameters, showcased high predictive accuracy, as indicated by a Nagelkerke R2 of 0.565 and a receiver operating characteristic of 0.901. CONCLUSION: Our machine learning-driven radiomics approach predicts scenarios where 5-ALA alone may be suboptimal in HGG surgery compared with its combined use with iMRI. Although 5-ALA typically yields favorable results, our analyses reveal that HGGs characterized by significant volume, complex morphology, and left-sided location compromise the effectiveness of resections relying exclusively on 5-ALA. For these intricate cases, we advocate for the continued relevance of iMRI.

TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAFV600E/TERT promoter double-mutated glioma.

The BRAF gene and the TERT promoter are among the most frequently altered genomic loci in low-grade (LGG) and high-grade-glioma (HGG), respectively. The coexistence of BRAF and TERT promoter aberrations characterizes a subset of aggressive glioma. Therefore, we investigated interactions between those alterations in malignant glioma. We analyzed co-occurrence of BRAFV600E and TERT promoter mutations in our clinical data (n = 8) in addition to published datasets (n = 103) and established a BRAFV600E-positive glioma cell panel (n = 9) for in vitro analyses. We investigated altered gene expression, signaling events and TERT promoter activity upon BRAF- and E-twenty-six (ETS)-factor inhibition by qRT-PCR, chromatin immunoprecipitation (ChIP), Western blots and luciferase reporter assays. TERT promoter mutations were significantly enriched in BRAFV600E-mutated HGG as compared to BRAFV600E-mutated LGG. In vitro, BRAFV600E/TERT promoter double-mutant glioma cells showed exceptional sensitivity towards BRAF-targeting agents. Remarkably, BRAF-inhibition attenuated TERT expression and TERT promoter activity exclusively in double-mutant models, while TERT expression was undetectable in BRAFV600E-only cells. Various ETS-factors were broadly expressed, however, only ETS1 expression and phosphorylation were consistently downregulated following BRAF-inhibition. Knock-down experiments and ChIP corroborated the notion of a functional role for ETS1 and, accordingly, all double-mutant tumor cells were highly sensitive towards the ETS-factor inhibitor YK-4-279. In conclusion, our data suggest that concomitant BRAFV600E and TERT promoter mutations synergistically support cancer cell proliferation and immortalization. ETS1 links these two driver alterations functionally and may represent a promising therapeutic target in this aggressive glioma subgroup.

TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma.

Background: Meningiomas are mostly benign tumors tending to progress to higher-grade lesions. Mutations in the telomerase reverse transcriptase (TERT) gene promoter are comparably rare in meningioma, but were recently suggested to predict risk of recurrence and progression. Here we have analyzed a cohort of World Health Organization grades I-III meningiomas regarding the impact of TERT promoter mutations on patient prognosis and in vitro cell propagation feasibility. Methods: From 110 meningioma patients, 128 tissue samples were analyzed for the TERT promoter mutations C228T and C250T by direct sequencing. Of the 128 samples, 121 were tested for cell propagation in vitro. Telomerase activity, TERT mRNA expression, and telomere lengths were investigated by telomeric repeat amplification protocol assay, reverse transcription PCR, and quantitative PCR, respectively. Impact of the E-twenty-six (ETS) transcription factor inhibitor YK-4-279 on cell viability and TERT promoter activity was analyzed. Results: TERT promoter mutations were found in 5.5% of all samples analyzed and were associated with a significantly upregulated telomerase activity and TERT mRNA expression (P < 0.0001 both). Regarding telomere lengths, no significant difference between the TERT promoter wild-type and mutated subgroups was detected. Patients with TERT promoter mutated tumors exhibited significantly shorter overall survival (P = 0.0006; 53.8 vs 115.6 mo). The presence of TERT promoter mutations but not telomerase activity or TERT mRNA expression predicted indefinite cell growth in vitro. TERT promoter mutated meningioma cells were hypersensitive against the ETS transcription factor inhibitor YK-4-279, inducing a distinct downregulation of TERT promoter activity. Conclusion: TERT promoter mutations drive meningioma aggressiveness, resulting in reduced patient survival, but might also open novel therapeutic options for progressive disease.