Microenvironmental pressures in glioblastoma select for glioma stem cells (GSCs) subpopulations that are maintained through preferential activation of BMI1 and EZH2 in different niches. Given the high degree of intratumor heterogeneity, combined pharmacological inhibition of Polycomb repressive complexes targets proneural and mesenchynmal GSCs and expands lifespan in mice, warranting the therapeutic evaluation of this approach in patients with glioblastoma. Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.

BACKGROUND AND PURPOSE: MR fingerprinting allows rapid simultaneous quantification of T1 and T2 relaxation times. This study assessed the utility of MR fingerprinting in differentiating common types of adult intra-axial brain tumors. MATERIALS AND METHODS: MR fingerprinting acquisition was performed in 31 patients with untreated intra-axial brain tumors: 17 glioblastomas, 6 World Health Organization grade II lower grade gliomas, and 8 metastases. T1, T2 of the solid tumor, immediate peritumoral white matter, and contralateral white matter were summarized within each ROI. Statistical comparisons on mean, SD, skewness, and kurtosis were performed by using the univariate Wilcoxon rank sum test across various tumor types. Bonferroni correction was used to correct for multiple-comparison testing. Multivariable logistic regression analysis was performed for discrimination between glioblastomas and metastases, and area under the receiver operator curve was calculated. RESULTS: Mean T2 values could differentiate solid tumor regions of lower grade gliomas from metastases (mean, 172 ± 53 ms, and 105 ± 27 ms, respectively; P = .004, significant after Bonferroni correction). The mean T1 of peritumoral white matter surrounding lower grade gliomas differed from peritumoral white matter around glioblastomas (mean, 1066 ± 218 ms, and 1578 ± 331 ms, respectively; P = .004, significant after Bonferroni correction). Logistic regression analysis revealed that the mean T2 of solid tumor offered the best separation between glioblastomas and metastases with an area under the curve of 0.86 (95% CI, 0.69–1.00; P < .0001). CONCLUSIONS: MR fingerprinting allows rapid simultaneous T1 and T2 measurement in brain tumors and surrounding tissues. MR fingerprinting–based relaxometry can identify quantitative differences between solid tumor regions of lower grade gliomas and metastases and between peritumoral regions of glioblastomas and lower grade gliomas.

Glioblastoma is the most lethal brain tumor and harbors glioma stem cells (GSCs) with potent tumorigenic capacity. The function of GSCs in tumor propagation is maintained by several core transcriptional regulators including c-Myc. c-Myc protein is tightly regulated by posttranslational modification. However, the posttranslational regulatory mechanisms for c-Myc in GSCs have not been defined. In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation. In contrast, overexpression of the ubiquitin E3 ligase FBXL14 induced c-Myc degradation, promoted GSC differentiation, and inhibited tumor growth. Ectopic expression of the ubiquitin-insensitive mutant T58A–c-Myc rescued the effects caused by FBXL14 overexpression or USP13 disruption. These data suggest that USP13 and FBXL14 play opposing roles in the regulation of GSCs through reversible ubiquitination of c-Myc.

Background: Brain metastasis is common in patients with malignant mela-noma and represents a significant cause of morbidity and mortality. Nearly 37% of patients with malignant mela-noma eventually develop brain metastasis, and autopsy reports show that 75% of those who died of this disease developed brain metastasis. Methods: We review the level I and level II evidence that guides indications for treatment with surgery, stereotactic radiosurgery, chemotherapy, and immunotherapy for patients with mela-noma brain metastasis. Results: Level I evidence supports the role of whole brain radiotherapy, microsurgery, and radiosurgery alone or in combination for the treatment of patients with mela-noma brain metastasis. Chemotherapy has been ineffective. Ongoing studies continue to assess the effects of immunotherapy and agents in development. Conclusions: Brain metastasis is a common and formidable challenge in patients with malignant melanoma. Although there have been no randomized controlled trials exclusively in patients with mela-noma brain metastasis, care can be guided by the application of level I evidence for the treatment of brain metastasis in general and phase II studies focusing specifically on mela-noma brain metastasis. Promising new agents and approaches are needed and will hopefully be identified in the near future.

BACKGROUND AND PURPOSE: Despite availability of advanced imaging, distinguishing radiation necrosis from recurrent brain tumors noninvasively is a big challenge in neuro-oncology. Our aim was to determine the feasibility of radiomic (computer-extracted texture) features in differentiating radiation necrosis from recurrent brain tumors on routine MR imaging (gadolinium T1WI, T2WI, FLAIR). MATERIALS AND METHODS: A retrospective study of brain tumor MR imaging performed 9 months (or later) post-radiochemotherapy was performed from 2 institutions. Fifty-eight patient studies were analyzed, consisting of a training (n = 43) cohort from one institution and an independent test (n = 15) cohort from another, with surgical histologic findings confirmed by an experienced neuropathologist at the respective institutions. Brain lesions on MR imaging were manually annotated by an expert neuroradiologist. A set of radiomic features was extracted for every lesion on each MR imaging sequence: gadolinium T1WI, T2WI, and FLAIR. Feature selection was used to identify the top 5 most discriminating features for every MR imaging sequence on the training cohort. These features were then evaluated on the test cohort by a support vector machine classifier. The classification performance was compared against diagnostic reads by 2 expert neuroradiologists who had access to the same MR imaging sequences (gadolinium T1WI, T2WI, and FLAIR) as the classifier. RESULTS: On the training cohort, the area under the receiver operating characteristic curve was highest for FLAIR with 0.79; 95% CI, 0.77–0.81 for primary (n = 22); and 0.79, 95% CI, 0.75–0.83 for metastatic subgroups (n = 21). Of the 15 studies in the holdout cohort, the support vector machine classifier identified 12 of 15 studies correctly, while neuroradiologist 1 diagnosed 7 of 15 and neuroradiologist 2 diagnosed 8 of 15 studies correctly, respectively. CONCLUSIONS: Our preliminary results suggest that radiomic features may provide complementary diagnostic information on routine MR imaging sequences that may improve the distinction of radiation necrosis from recurrence for both primary and metastatic brain tumors.

Introduction: Laser Interstitial Thermotherapy (LITT; also known as Stereotactic Laser Ablation or SLA), is a minimally invasive treatment modality that has recently gained prominence in the treatment of malignant primary and metastatic brain tumors and radiation necrosis and studies for treatment of spinal metastasis has recently been reported. Methods: Here we provide a brief literature review of the various contemporary uses for LITT and their reported outcomes. Results: Historically, the primary indication for LITT has been for the treatment of recurrent glioblastoma (GBM). However, indications have continued to expand and now include gliomas of different grades, brain metastasis (BM), radiation necrosis (RN), other types of brain tumors as well as spine metastasis. LITT is emerging as a safe, reliable, minimally invasive clinical approach, particularly for deep seated, focal malignant brain tumors and radiation necrosis. The role of LITT for treatment of other types of tumors of the brain and for spine tumors appears to be evolving at a small number of centers. While the technology appears to be safe and increasingly utilized, there have been few prospective clinical trials and most published studies combine different pathologies in the same report. Conclusion: Well-designed prospective trials will be required to firmly establish the role of LITT in the treatment of lesions of the brain and spine.