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Background: Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting., Methods: The primary endpoint was dose-limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results., Results: Thirty-two patients were enrolled at 9 institutions: 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% White. Treatment was well tolerated with 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 and 16.1 months, respectively., Conclusions: IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant temozolomide for newly diagnosed GBM. Combination IPI + NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in Phase II/III for patients with newly diagnosed GBM., Clinicaltrials.gov Registration: NCT02311920., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM)., Patients and Methods: A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity., Results: Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months [95% confidence interval (CI), 8.2-17.9]. The median PFS was 1.9 months (95% CI, 1.8-3.7). The PFS6 was 10.5% (95% CI, 1.3%-33.1%). Most toxicities were grades 1 and 2, with two grade 3 lymphopenias and one grade 4 thrombocytopenia. Two patients with PFS ≥ 17 months and OS > 32 months were deemed "extended survivors." RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in "extended survivors.", Conclusions: These findings confirm the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways., (©2024 American Association for Cancer Research.)

Purpose: Glioblastoma (GB) is the most common primary malignant brain tumor with the highest incidence occurring in older adults with a median age at diagnosis of 64 years old. While treatment often improves survival it brings toxicities and adverse events (AE). Here we identify sex differences in treatment patterns and AE in individuals ≥ 66 years at diagnosis with GB., Methods: Using the SEER-Medicare dataset sex differences in adverse events were assessed using multivariable logistic regression performed to calculate the male/female odds ratio (M/F OR) and 95% confidence intervals [95% CI] of experiencing an AE adjusted for demographic variables and Elixhauser comorbidity score., Results: Males with GB were more likely to receive standard of care (SOC; Surgery with concurrent radio-chemotherapy) [20%] compared to females [17%], whereas females were more likely to receive no treatment [26%] compared to males [21%]. Females with GB receiving SOC were more likely to develop gastrointestinal disorders (M/F OR = 0.76; 95% CI,0.64-0.91, p = 0.002) or blood and lymphatic system disorders (M/F OR = 0.79; 95% CI,0.66-0.95, p = 0.012). Males with GB receiving SOC were more likely to develop cardiac disorders (M/F OR = 1.21; 95% CI,1.02-1.44, p = 0.029) and renal disorders (M/F OR = 1.65; 95% CI,1.37-2.01, p < 0.001)., Conclusions: Sex differences for individuals, 66 years and older, diagnosed with GB exist in treatment received and adverse events developed across different treatment modalities., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21-CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21-CCR7 axis correlated with KAT5 expression and HMGCS1 K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: While the T2-FLAIR mismatch sign is highly specific for isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted astrocytomas among lower-grade gliomas, its utility in WHO grade 4 gliomas is not well-studied. We derived the partial T2-FLAIR mismatch sign as an imaging biomarker for IDH mutation in WHO grade 4 gliomas., Methods: Preoperative MRI scans of adult WHO grade 4 glioma patients (n = 2165) from the multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium were analyzed. Diagnostic performance of the partial T2-FLAIR mismatch sign was evaluated. Subset analyses were performed to assess associations of imaging markers with overall survival (OS)., Results: One hundred twenty-one (5.6%) of 2165 grade 4 gliomas were IDH-mutant. Partial T2-FLAIR mismatch was present in 40 (1.8%) cases, 32 of which were IDH-mutant, yielding 26.4% sensitivity, 99.6% specificity, 80.0% positive predictive value, and 95.8% negative predictive value. Multivariate logistic regression demonstrated IDH mutation was significantly associated with partial T2-FLAIR mismatch (odds ratio [OR] 5.715, 95% CI [1.896, 17.221], p = 0.002), younger age (OR 0.911 [0.895, 0.927], p < 0.001), tumor centered in frontal lobe (OR 3.842, [2.361, 6.251], p < 0.001), absence of multicentricity (OR 0.173, [0.049, 0.612], p = 0.007), and presence of cystic (OR 6.596, [3.023, 14.391], p < 0.001) or non-enhancing solid components (OR 6.069, [3.371, 10.928], p < 0.001). Multivariate Cox analysis demonstrated cystic components (p = 0.024) and non-enhancing solid components (p = 0.003) were associated with longer OS, while older age (p < 0.001), frontal lobe center (p = 0.008), multifocality (p < 0.001), and multicentricity (p < 0.001) were associated with shorter OS., Conclusion: Partial T2-FLAIR mismatch sign is highly specific for IDH mutation in WHO grade 4 gliomas., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To test the feasibility of using 3D MRF maps with radiomics analysis and machine learning in the characterization of adult brain intra-axial neoplasms., Methods: 3D MRF acquisition was performed on 78 patients with newly diagnosed brain tumors including 33 glioblastomas (grade IV), 6 grade III gliomas, 12 grade II gliomas, and 27 patients with brain metastases. Regions of enhancing tumor, non-enhancing tumor, and peritumoral edema were segmented and radiomics analysis with gray-level co-occurrence matrices and gray-level run-length matrices was performed. Statistical analysis was performed to identify features capable of differentiating tumors based on type, grade, and isocitrate dehydrogenase (IDH1) status. Receiver operating curve analysis was performed and the area under the curve (AUC) was calculated for tumor classification and grading. For gliomas, Kaplan-Meier analysis for overall survival was performed using MRF T1 features from enhancing tumor region., Results: Multiple MRF T1 and T2 features from enhancing tumor region were capable of differentiating glioblastomas from brain metastases. Although no differences were identified between grade 2 and grade 3 gliomas, differentiation between grade 2 and grade 4 gliomas as well as between grade 3 and grade 4 gliomas was achieved. MRF radiomics features were also able to differentiate IDH1 mutant from the wild-type gliomas. Radiomics T1 features for enhancing tumor region in gliomas correlated to overall survival (p < 0.05)., Conclusion: Radiomics analysis of 3D MRF maps allows differentiating glioblastomas from metastases and is capable of differentiating glioblastomas from metastases and characterizing gliomas based on grade, IDH1 status, and survival., Key Points: • 3D MRF data analysis using radiomics offers novel tissue characterization of brain tumors. • 3D MRF with radiomics offers glioma characterization based on grade, IDH1 status, and overall patient survival., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Purpose: Gliomagenesis and resistance of glioblastoma (GBM) are believed to be mediated by glioma stem cells (GSC). Evidence suggests that SHH signaling promotes GSC proliferation and self-renewal., Methods: ABTC-0904 was a two-arm, multicenter phase 0/II study of GDC-0449, an oral inhibitor of Smoothened (SMO) in patients undergoing resection for recurrent GBM. All patients (Arms I and II) had surgery and received drug post-operatively. Only patients in Arm I received drug prior to surgery. The primary objective was to determine 6-month progression free survival (PFS-6). Secondary endpoints include median PFS (mPFS) and overall survival (mOS), response rate, and toxicity. Correlative studies included bioanalysis of GDC-0449, and inhibition of SHH signaling, GSC proliferation and self-renewal., Results: Forty-one patients were enrolled. Pharmacokinetics of GDC-0449 in plasma demonstrated levels within expected therapeutic range in 75% of patients. The proportion of tumorcells producing CD133 + neurospheres, neurosphere proliferation, self-renewal, and expression of the SHh downstream signaling was significantly decreased in Arm I following GDC-0449 treatment (p < 0.005; p < 0.001 respectively) compared to Arm II (no drug pre-op). Treatment was well tolerated. There were no objective responders in either arm. Overall PFS-6 was 2.4% (95% CI 0.9-11.1%). Median PFS was 2.3 months (95% CI 1.9-2.6) and mOS was 7.8 months (95% CI 5.4-10.1)., Conclusions: GDC-0449 was well tolerated, reached tumor, and inhibited CD133 + neurosphere formation, but had little clinical efficacy as a single agent in rGBM. This suggests growth and maintenance of rGBM is not solely dependent on the SHH pathway thus targeting SMO may require combined approaches., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Stereotactic radiosurgery (SRS) has recently emerged as a minimally invasive alternative to resection for treating multiple brain metastases. Given the lack of consensus regarding the application of SRS versus resection for multiple brain metastases, the authors aimed to conduct a systematic literature review of all published work on the topic., Methods: The PubMed, OVID, Cochrane, Web of Science, and Scopus databases were used to identify studies that examined clinical outcomes after resection or SRS was performed in patients with multiple brain metastases. Radiological studies, case series with fewer than 3 patients, pediatric studies, or national database studies were excluded. Data extracted included patient demographics and mean overall survival (OS). Weighted t-tests and ANOVA were performed., Results: A total of 1300 abstracts were screened, 450 articles underwent full-text review, and 129 studies met inclusion criteria, encompassing 20,177 patients (18,852 treated with SRS and 1325 who underwent resection). The OS for the SRS group was 10.2 ± 6 months, and for the resection group it was 6.5 ± 3.8 months. A weighted ANOVA test comparing OS with covariates of age, sex, and publication year revealed that the treatment group (p = 0.045), age (p = 0.034), and publication year (0.0078) were all independently associated with OS (with SRS, younger age, and later publication year being associated with longer survival), whereas sex (p = 0.95) was not., Conclusions: For patients with multiple brain metastases, SRS and resection are effective treatments to prolong OS, with published data suggesting that SRS may have a trend toward lengthened survival outcomes. The authors encourage additional work examining outcomes of treatments for multiple brain metastases.

Introduction: Glioblastoma multiforme (GBM) constitutes one of the deadliest tumors to afflict humans, although it is still considered an orphan disease. Despite testing multiple new and innovative therapies in ongoing clinical trials, the median survival for this type of malignancy is less than two years after initial diagnosis, regardless of therapy. One class of promising new therapies are chimeric antigen receptor T cells or CAR-T which have been shown to be very effective at treating refractory liquid tumors such as B-cell malignancies. However, CAR-T effectivity against solid tumors such as GBM has been limited thus far., Methods: A Pubmed, Google Scholar, Directory of Open Access Journals, and Web of Science literature search using the terms chimeric antigen receptor or CAR-T, GBM, solid tumor immunotherapy, immunotherapy, and CAR-T combination was performed for publication dates between January 1987 and November 2021., Results: In the current review, we present a comprehensive list of CAR-T cells developed to treat GBM, we describe new possible T-cell engineering strategies against GBM while presenting a short introductory history to the reader regarding the origin(s) of this cutting-edge therapy. We have also compiled a unique list of anti-GBM CAR-Ts with their specific protein sequences and their functions as well as an inventory of clinical trials involving CAR-T and GBM., Conclusions: The aim of this review is to introduce the reader to the field of T-cell engineering using CAR-Ts to treat GBM and describe the obstacles that may need to be addressed in order to significantly delay the relentless growth of GBM., (© 2021. The Author(s).)

Background/purpose: Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials., Methods: This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825., Results: Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males., Conclusions: A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here- https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/ ., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Opinion Statement: Intracranial stereotactic radiosurgery (SRS) is an effective and convenient treatment for many brain conditions. Data regarding safety come mostly from retrospective single institutional studies and a small number of prospective studies. Variations in target delineation, treatment delivery, imaging follow-up protocols and dose prescription limit the interpretation of this data. There has been much clinical focus on radiation necrosis (RN) in particular, as it is being increasingly recognized on follow-up imaging. Symptomatic RN may be treated with medical therapy (such as corticosteroids and bevacizumab) with surgical resection being reserved for refractory patients. Nevertheless, RN remains a challenging condition to manage, and therefore upfront patient selection for SRS remains critical to provide complication-free control. Mitigation strategies need to be considered in situations where the baseline risk of RN is expected to be high-such as large target volume or re-irradiation. These may involve reduction in the prescribed dose or hypofractionated stereotactic radiation therapy (HSRT). Recently published guidelines and international meta-analysis report the benefit of HSRT in larger lesions, without compromising control rates. However, careful attention to planning parameters and SRS techniques still need to be adhered, even with HSRT. In cases where the risk is deemed to be high despite mitigation, a combination approach of surgery with or without post-operative radiation should be considered.

Purpose: This is a radiomics study investigating the ability of texture analysis of MRF maps to improve differentiation between intra-axial adult brain tumors and to predict survival in the glioblastoma cohort., Methods: Magnetic resonance fingerprinting (MRF) acquisition was performed on 31 patients across 3 groups: 17 glioblastomas, 6 low-grade gliomas, and 8 metastases. Using regions of interest for the solid tumor and peritumoral white matter on T1 and T2 maps, second-order texture features were calculated from gray-level co-occurrence matrices and gray-level run length matrices. Selected features were compared across the three tumor groups using Wilcoxon rank-sum test. Receiver operating characteristic curve analysis was performed for each feature. Kaplan-Meier method was used for survival analysis with log rank tests., Results: Low-grade gliomas and glioblastomas had significantly higher run percentage, run entropy, and information measure of correlation 1 on T1 than metastases (p < 0.017). The best separation of all three tumor types was seen utilizing inverse difference normalized and homogeneity values for peritumoral white matter in both T1 and T2 maps (p < 0.017). In solid tumor T2 maps, lower values in entropy and higher values of maximum probability and high-gray run emphasis were associated with longer survival in glioblastoma patients (p < 0.05). Several texture features were associated with longer survival in glioblastoma patients on peritumoral white matter T1 maps (p < 0.05)., Conclusion: Texture analysis of MRF-derived maps can improve our ability to differentiate common adult brain tumors by characterizing tumor heterogeneity, and may have a role in predicting outcomes in patients with glioblastoma.

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.

Background: Cancer stem-like cells are a major cause of resistance to therapy in patients with glioblastoma (GBM) as well as other cancers. Tumor cells are maintained in a stem-like proliferative state in large part through the Notch signaling pathway. The function of this pathway in turn depends on gamma secretase activity. Inhibition of this enzyme therefore inhibits the Notch pathway and tumor growth as measured by a reduction in the formation of brain tumor neurospheres in murine models. RO4929097 is an oral gamma secretase inhibitor., Objective: To estimate the 6-mo progression-free survival rate (PFS6) in patients with progressive GBM and to inhibit by 50% the generation of neurospheres in fresh tissue resected from patients treated with RO4929097., Methods: In this phase II and pharmacodynamic study, patients with recurrent GBM received RO4929097 in a study of 2 groups. Group A patients had unresectable disease and received drug in a standard phase II design. Group B patients had resectable disease and received drug before and after surgical resection. Endpoints included PFS6 and the inhibition of neurosphere formation in the resected tumor samples., Results: A total of 47 patients received treatment, 7 of whom had tumor resection. The PFS6 was 4%, and the inhibition of neurosphere formation occurred in 1 of 7 patient samples., Conclusion: RO4929097 was inactive in recurrent GBM patients and demonstrated minimal inhibition of neurosphere formation in fresh tissue samples., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: The tumorigenic potential of glioma stem cells (GSCs) is associated with multiple reversible molecular alternations, but the role of posttranslational protein sumoylation in GSCs has not been elucidated. The development of GSC-targeting drugs relies on the discovery of GSC-preferential molecular modifications and the relevant signaling pathways. In this work, we investigated the protein sumoylation status, the major sumoylated substrate, and the key regulatory enzyme in GSCs to explore the therapeutic potential of disrupting protein sumoylation for glioblastoma (GBM) treatment., Methods: Patient-derived GSCs, primary GBM sections, and intracranial GBM xenografts were used to determine protein sumoylation and the related molecular mechanisms by immunoblot, quantitative PCR, immunoprecipitation, immunofluorescence, and immunohistochemistry. Orthotopic GBM xenograft models were applied to investigate the inhibition of tumor growth by disrupting protein sumoylation with short hairpin (sh)RNAs or molecular inhibitors., Results: We show that high levels of small ubiquitin-related modifier 1 (SUMO1)-but not SUMO2/3-modified sumoylation are preferentially present in GSCs. The promyelocytic leukemia (PML) protein is a major SUMO1-sumoylated substrate in GSCs, whose sumoylation facilitates its interaction with c-Myc to stabilize c-Myc proteins. The prolyl-isomerase Pin1 is preferentially expressed in GSCs and functions as the key enzyme to promote SUMO1 sumoylation. Disruption of SUMO1 sumoylation by Pin1 silencing with shRNAs or inhibition with its inhibitor Juglone markedly abrogated GSC maintenance and mitigated GSC-driven tumor growth., Conclusions: Our findings indicate that high SUMO1-modified protein sumoylation as a feature of GSCs is critical for GSC maintenance, suggesting that targeting SUMO1 sumoylation may effectively improve GBM treatment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Brain metastases (BM) are the most common type of brain tumor malignancy in the US. They are also the most common indication for stereotactic radiosurgery (SRS). However, the incidence of both local recurrence and radiation necrosis (RN) is increasing as treatments improve. MRI imagery often fails to differentiate BM from RN; thus, patients must often undergo surgical biopsy or resection to obtain a definitive diagnosis., Objective: To hypothesize that a marker of immunosuppression might serve as a surrogate marker to differentiate patients with active vs inactive cancer-including RN., Methods: We thus purified and quantified Monocytic Myeloid-Derived Suppressor Cells (Mo-MDSC) by flow cytometry in patients proven by biopsy to represent BM or RN., Results: We report the utility of the previously reported HLA-Dr-Vnn2 Index or DVI to discriminate recurrent BM from RN using peripheral blood. The presence of CD14+ HLA-DRneg/low Mo-MDSC is significantly increased in the peripheral blood of patients with brain metastasis recurrence compared to RN (Average 61.5% vs 7%, n = 10 and n = 12, respectively, P < .0001). In contrast, expression of VNN2 on circulating CD14+ monocytes is decreased in BM patients compared to patients with RN (5.5% vs 26.5%, n = 10 and n = 12, respectively, P = .0008). In patients with biopsy confirmed recurrence of brain metastasis, the average DVI was 11.65, whereas the average DVI for RN patients was consistently <1 (Avg. of 0.17)., Conclusion: These results suggest that DVI could be a useful diagnostic tool to differentiate recurrent BM from RN using a minimally invasive blood sample., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Glioblastoma multiforme (GBM) is the most malignant primary brain cancer affecting adults. Therapeutic options for GBM have remained the same for over a decade with no significant improvement. Many therapies that are successful in culture have failed in patients, likely due to the complex microenvironment in the brain, which has yet to be reproduced in any culture model. Furthermore, the high passage number of cultured cells and clonal selection fail to recapitulate the molecular and genomic signatures of GBM. We have established orthotopic patient-derived xenografts (PDX) from 37 GBM patients with human GBM. Of the 69 patient samples analyzed, we were successful in passaging 37 lines three or more generations (53.6%). After phenotypic characterization of the xenografted tumor tissue, two different growth patterns emerged highly invasive or localized. The phenotype was dependent on malignancy and previous treatment of the patient from which the xenograft was derived. Physiologically, mice exhibited symptoms more quickly with each subsequent passage, particularly in the localized tumors. Study of these physiologically relevant human xenografts in mice will enable therapeutic screenings in a microenvironment that more closely resembles GBM and may allow development of individualized patient models which may eventually be used for simulating treatment.

The interplay between glioma stem cells (GSCs) and the tumor microenvironment plays crucial roles in promoting malignant growth of glioblastoma (GBM), the most lethal brain tumor. However, the molecular mechanisms underlying this crosstalk are incompletely understood. Here, we show that GSCs secrete the Wnt-induced signaling protein 1 (WISP1) to facilitate a pro-tumor microenvironment by promoting the survival of both GSCs and tumor-associated macrophages (TAMs). WISP1 is preferentially expressed and secreted by GSCs. Silencing WISP1 markedly disrupts GSC maintenance, reduces tumor-supportive TAMs (M2), and potently inhibits GBM growth. WISP1 signals through Integrin α6β1-Akt to maintain GSCs by an autocrine mechanism and M2 TAMs through a paracrine manner. Importantly, inhibition of Wnt/β-catenin-WISP1 signaling by carnosic acid (CA) suppresses GBM tumor growth. Collectively, these data demonstrate that WISP1 plays critical roles in maintaining GSCs and tumor-supportive TAMs in GBM, indicating that targeting Wnt/β-catenin-WISP1 signaling may effectively improve GBM treatment and the patient survival.

Background: Gliomas are the most common primary malignant brain tumor. Diffuse low-grade and intermediate-grade gliomas, which together compose the lower-grade gliomas (LGGs; World Health Organization [WHO] grades II and III), present a therapeutic challenge to physicians due to the heterogeneity of their clinical behavior. Nomograms are useful tools for individualized estimation of survival. This study aimed to develop and independently validate a survival nomogram for patients with newly diagnosed LGG., Methods: Data were obtained for newly diagnosed LGG patients from The Cancer Genome Atlas (TCGA) and the Ohio Brain Tumor Study (OBTS) with the following variables: tumor grade (II or III), age at diagnosis, sex, Karnofsky performance status (KPS), and molecular subtype (IDH mutant with 1p/19q codeletion [IDHmut-codel], IDH mutant without 1p/19q codeletion, and IDH wild-type). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using TCGA data and independently validated using the OBTS data. Models were internally validated using 10-fold cross-validation and externally validated with calibration curves., Results: A final nomogram was validated for newly diagnosed LGG. Factors that increased the probability of survival included grade II tumor, younger age at diagnosis, having a high KPS, and the IDHmut-codel molecular subtype., Conclusions: A nomogram that calculates individualized survival probabilities for patients with newly diagnosed LGG could be useful to health care providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free online software for implementing this nomogram is provided: https://hgittleman.shinyapps.io/LGG&#95;Nomogram&#95;H&#95;Gittleman/., Key Points: 1. A survival nomogram for lower-grade glioma patients has been developed and externally validated.2. Free online software for implementing this nomogram is provided allowing for ease of use by practicing health care providers., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To construct a multi-institutional radiomic model that supports upfront prediction of progression-free survival (PFS) and recurrence pattern (RP) in patients diagnosed with glioblastoma multiforme (GBM) at the time of initial diagnosis., Patients and Methods: We retrospectively identified data for patients with newly diagnosed GBM from two institutions (institution 1, n = 65; institution 2, n = 15) who underwent gross total resection followed by standard adjuvant chemoradiation therapy, with pathologically confirmed recurrence, sufficient follow-up magnetic resonance imaging (MRI) scans to reliably determine PFS, and available presurgical multiparametric MRI (MP-MRI). The advanced software suite Cancer Imaging Phenomics Toolkit (CaPTk) was leveraged to analyze standard clinical brain MP-MRI scans. A rich set of imaging features was extracted from the MP-MRI scans acquired before the initial resection and was integrated into two distinct imaging signatures for predicting mean shorter or longer PFS and near or distant RP. The predictive signatures for PFS and RP were evaluated on the basis of different classification schemes: single-institutional analysis, multi-institutional analysis with random partitioning of the data into discovery and replication cohorts, and multi-institutional assessment with data from institution 1 as the discovery cohort and data from institution 2 as the replication cohort., Results: These predictors achieved cross-validated classification performance (ie, area under the receiver operating characteristic curve) of 0.88 (single-institution analysis) and 0.82 to 0.83 (multi-institution analysis) for prediction of PFS and 0.88 (single-institution analysis) and 0.56 to 0.71 (multi-institution analysis) for prediction of RP., Conclusion: Imaging signatures of presurgical MP-MRI scans reveal relatively high predictability of time and location of GBM recurrence, subject to the patients receiving standard first-line chemoradiation therapy. Through its graphical user interface, CaPTk offers easy accessibility to advanced computational algorithms for deriving imaging signatures predictive of clinical outcome and could similarly be used for a variety of radiomic and radiogenomic analyses.

Stereotactic radiosurgery (SRS) is a costly procedure used to irradiate disease tissue while sparing healthy tissue, ideally limiting the side effects of treatment. SRS is frequently used in the setting of lung cancer, which is associated with greater rates of BM, though its cost may lead to potentially inequitable use across patient populations. This study investigates potential disparities in the use of SRS to treat Medicare patients. Surveillance, Epidemiology, and End-Results cancer registry data for patients diagnosed between the years 2010 and 2012 were examined to identify lung cancer patients diagnosed with BM at the same time as their primary cancer (SBM). Medicare claims for SRS were identified; the odds of having SRS claims and hazards of mortality associated with those odds were examined with respect to various clinical and demographic characteristics. Of 74,142 Medicare-enrolled patients diagnosed with lung cancer, 9192 were diagnosed with SBM and 3259 of those patients received SRS. Adjusting for clinical and demographic characteristics, males with SBM had 0.85 times the odds of SRS compared to females with SBM. Black patients and those of other race had significantly lower odds of evidence of SRS compared to WNH patients. SRS may not be delivered equitably among Medicare patients. Males and minority patients may have decreased odds of SRS and worse survival compared to female and WNH patients, respectively.

Bevacizumab is FDA-approved in the treatment of primary brain tumors, but its efficacy in patients with brain metastases could be better-studied. This study examines a population of non-small cell lung cancer (NSCLC) patients with synchronous brain metastases to identify predictors of the decision to use bevacizumab and survival following bevacizumab treatment. Primary cancer registry data were used to determine which NSCLC patients diagnosed in the years 2010 through 2012 had synchronous brain metastases at the time of diagnosis, and Medicare claims used to identify a population of patients treated with bevacizumab. Record of bevacizumab treatment was found for 81 and 666 patients with and without brain metastases, respectively. After adjusting for clinical and demographic characteristics, bevacizumab was associated with 0.88 times the hazard of mortality in the elderly NSCLC population (95% CI: 0.81-0.96, p: 0.003) and a corresponding hazard ratio of 0.75 in the population of elderly NSCLC patients with synchronous brain metastases (95% CI: 0.59-0.96, p: 0.020). Bevacizumab may benefit NSCLC patients with synchronous brain metastases more than it does patients without intracranial disease, possibly as a result of its multiple potential mechanisms of action simultaneously inhibiting angiogenesis and minimizing vasogenic edema.

Glioblastoma ranks among the most aggressive and lethal of all human cancers. Functionally defined glioma stem cells (GSC) contribute to this poor prognosis by driving therapeutic resistance and maintaining cellular heterogeneity. To understand the molecular processes essential for GSC maintenance and tumorigenicity, we interrogated the superenhancer landscapes of primary glioblastoma specimens and in vitro GSCs. GSCs epigenetically upregulated ELOVL2, a key polyunsaturated fatty-acid synthesis enzyme. Targeting ELOVL2 inhibited glioblastoma cell growth and tumor initiation. ELOVL2 depletion altered cellular membrane phospholipid composition, disrupted membrane structural properties, and diminished EGFR signaling through control of fatty-acid elongation. In support of the translational potential of these findings, dual targeting of polyunsaturated fatty-acid synthesis and EGFR signaling had a combinatorial cytotoxic effect on GSCs. SIGNIFICANCE: Glioblastoma remains a devastating disease despite extensive characterization. We profiled epigenomic landscapes of glioblastoma to pinpoint cell state-specific dependencies and therapeutic vulnerabilities. GSCs utilize polyunsaturated fatty-acid synthesis to support membrane architecture, inhibition of which impairs EGFR signaling and GSC proliferation. Combinatorial targeting of these networks represents a promising therapeutic strategy. See related commentary by Affronti and Wellen, p. 1161 . This article is highlighted in the In This Issue feature, p. 1143 ., (©2019 American Association for Cancer Research.)

An integrated approach has been adopted by the World Health Organization (WHO) for diagnosing brain tumors. This approach relies on the molecular characterization of biopsied tissue in conjunction with standard histology. Diffuse gliomas (grade II to grade IV malignant brain tumors) have a wide range in overall survival, from months for the worst cases of glioblastoma (GBM) to years for lower grade astrocytic and oligodendroglial tumors. We previously identified a change in the cell adhesion molecule PTPmu in brain tumors that results in the generation of proteolytic fragments. We developed agents to detect this cell surface-associated biomarker of the tumor microenvironment. In the current study, we evaluated the PTPmu biomarker in tissue microarrays and individual tumor samples of adolescent and young adult ( n = 25) and adult ( n = 69) glioma populations using a fluorescent histochemical reagent, SBK4-TR, that recognizes the PTPmu biomarker. We correlated staining with clinical data and found that high levels of the PTPmu biomarker correlate with increased survival of glioma patients, including those with GBM. Patients with high PTPmu live for 48 months on average, whereas PTPmu low patients live only 22 months. PTPmu high staining indicates a doubling of patient survival. Use of the agent to detect the PTPmu biomarker would allow differentiation of glioma patients with distinct survival outcomes and would complement current molecular approaches used in glioma prognosis.

Glioblastoma is an incurable brain cancer characterized by high genetic and pathological heterogeneity. Here, we mapped active chromatin landscapes with gene expression, whole exomes, copy number profiles, and DNA methylomes across 44 patient-derived glioblastoma stem cells (GSCs), 50 primary tumors, and 10 neural stem cells (NSCs) to identify essential super-enhancer (SE)-associated genes and the core transcription factors that establish SEs and maintain GSC identity. GSCs segregate into two groups dominated by distinct enhancer profiles and unique developmental core transcription factor regulatory programs. Group-specific transcription factors enforce GSC identity; they exhibit higher activity in glioblastomas versus NSCs, are associated with poor clinical outcomes, and are required for glioblastoma growth in vivo. Although transcription factors are commonly considered undruggable, group-specific enhancer regulation of the MAPK/ERK pathway predicts sensitivity to MEK inhibition. These data demonstrate that transcriptional identity can be leveraged to identify novel dependencies and therapeutic approaches., (© 2019 Mack et al.)

Background: The Surveillance, Epidemiology, and End Results (SEER) Program recently released data on brain metastases (BM) diagnosed during primary cancer staging workup ("synchronous" BM, or SBM); this study examines the incidence of SBM compared with that of lifetime BM (LBM) identified using Medicare claims for patients diagnosed with lung cancer, breast cancer, or melanoma., Methods: Incidence proportions (IP) and age-adjusted rates for each of SEER SBM and Medicare LBM are presented along with measures of concordance between the two sources of data, where Medicare LBM were defined by several combinations of diagnosis and putative diagnostic imaging procedure codes., Results: The SBM IP in lung, breast, and melanoma cancers were 9.6%, 0.3%, and 1.1%, respectively; the corresponding LBM IP were 13.5%, 1.8%, and 3.6%. The greatest SBM IP among patients with lung cancer was 13.4% for non-small cell lung cancer, and among patients with breast cancer was 0.7% for triple-negative breast cancer. The greatest LBM IP among lung cancers was 23.1% in small-cell lung cancer, and among breast cancers was 4.2% for cases of the triple negative subtype., Conclusions: Using a large dataset that is representative of the elderly population in the United States, these analyses estimate synchronous and lifetime incidence of BM in lung cancers, breast cancers, and melanomas., Impact: These and other population-based estimates may be used to guide development of BM screening policy and evaluation of real-world data sources., (©2019 American Association for Cancer Research.)

Object: Magnetic resonance fingerprinting (MRF) allows rapid, simultaneous mapping of T1 and T2 relaxation times and may be an important diagnostic tool to measure tissue characteristics in pediatric brain tumors. We examined children and young adults with primary brain tumors to determine whether MRF can discriminate tumor from normal-appearing white matter and distinguish tumor grade., Methods: MRF was performed in 23 patients (14 children and 9 young adults) with brain tumors (19 low-grade glioma, 4 high-grade tumors). T1 and T2 values were recorded in regions of solid tumor (ST), peritumoral white matter (PWM), and contralateral white matter (CWM). Nonparametric tests were used for comparison between groups and regions., Results: Median scan time for MRF and a sequence for tumor localization was 11 min. MRF-derived T1 and T2 values distinguished ST from CWM (T1: 1,444 ± 254 ms vs. 938 ± 96 ms, p = 0.0002; T2: 61 ± 22 ms vs. 38 ± 9 ms, p = 0.0003) and separated high-grade tumors from low-grade tumors (T1: 1,863 ± 70 ms vs. 1,355 ± 187 ms, p = 0.007; T2: 90 ± 13 ms vs. 56 ± 19 ms, p = 0.013). PWM was distinct from CWM (T1: 1,261 ± 359 ms vs. 933 ± 104 ms, p = 0.0008; T2: 65 ± 51 ms vs. 38 ± 8 ms, p = 0.008), as well as from tumor (T1: 1,261 ± 371 ms vs. 1,462 ± 248 ms, p = 0.047)., Conclusions: MRF is a fast sequence that can rapidly distinguish important tissue components in pediatric brain tumor patients. MRF-derived T1 and T2 distinguished tumor from normal-appearing white matter, differentiated tumor grade, and found abnormalities in peritumoral regions. MRF may be useful for rapid quantitative measurement of tissue characteristics and distinguish tumor grade in children and young adults with brain tumors., (© 2019 S. Karger AG, Basel.)

Genetic drivers of cancer can be dysregulated through epigenetic modifications of DNA. Although the critical role of DNA 5-methylcytosine (5mC) in the regulation of transcription is recognized, the functions of other non-canonical DNA modifications remain obscure. Here, we report the identification of novel N 6 -methyladenine (N 6 -mA) DNA modifications in human tissues and implicate this epigenetic mark in human disease, specifically the highly malignant brain cancer glioblastoma. Glioblastoma markedly upregulated N 6 -mA levels, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N 6 -mA levels were dynamically regulated by the DNA demethylase ALKBH1, depletion of which led to transcriptional silencing of oncogenic pathways through decreasing chromatin accessibility. Targeting the N 6 -mA regulator ALKBH1 in patient-derived human glioblastoma models inhibited tumor cell proliferation and extended the survival of tumor-bearing mice, supporting this novel DNA modification as a potential therapeutic target for glioblastoma. Collectively, our results uncover a novel epigenetic node in cancer through the DNA modification N 6 -mA., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: HSRT directed to large surgical beds in patients with resected brain metastases improves local control while sparing patients the toxicity associated with whole brain radiation. We review our institutional series to determine factors predictive of local failure., Methods: In a total of 39 consecutive patients with brain metastases treated from August 2011 to August 2016, 43 surgical beds were treated with HSRT in three or five fractions. All treatments were completed on a robotic radiosurgery platform using the 6D Skull tracking system. Volumetric MRIs from before and after surgery were used for radiation planning. A 2-mm PTV margin was used around the contoured surgical bed and resection margins; these were reviewed by the radiation oncologist and neurosurgeon. Lower total doses were prescribed based on proximity to critical structures or if prior radiation treatments were given. Local control in this study is defined as no volumetric MRI evidence of recurrence of tumor within the high dose radiation volume. Statistics were calculated using JMP Pro v13., Results: Of the 43 surgical beds analyzed, 23 were from NSCLC, 5 were from breast, 4 from melanoma, 5 from esophagus, and 1 each from SCLC, sarcoma, colon, renal, rectal, and unknown primary. Ten were treated with three fractions with median dose 24 Gy and 33 were treated with five fractions with median dose 27.5 Gy using an every other day fractionation. There were no reported grade 3 or higher toxicities. Median follow up was 212 days after completion of radiation. 10 (23%) surgical beds developed local failure with a median time to failure of 148 days. All but three patients developed new brain metastases outside of the treated field and were treated with stereotactic radiosurgery, whole brain radiation and/or chemotherapy. Five patients (13%) developed leptomeningeal disease. With a median follow up of 226 days, 30 Gy/5 fx was associated with the best local control (93%) with only 1 local failure. A lower total dose in five fractions (ie 27.5 or 25 Gy) had a local control rate of 70%. For three fraction SBRT, local control was 100% using a dose of 27 Gy in three fractions (follow up was > 600 days) and 71% if 24 Gy in three fractions was used. A higher total biologically equivalent dose (BED 10 ) was statistically significant for improved local control (p = 0.04) with a threshold BED 10  ≥ 48 associated with better local control., Conclusions: HSRT after surgical resection for brain metastasis is well tolerated and has improved local control with BED 10  ≥ 48 (30 Gy/5 fx and 27 Gy/3 fx). Additional study is warranted.

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax ® -L) to standard therapy for newly diagnosed glioblastoma., Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS)., Results: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone., Conclusions: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Laser-induced interstitial thermotherapy (LITT) is a modern minimally invasive treatment modality applied for management of a variety of diseases. Recent developments of techniques for precise targeting of the lesion, accurate delivery of the prescribed therapeutically effective thermal doses, and real-time visualization of the induced tissue damage during the procedure by means of intraoperative MR thermometry have stimulated a number of clinical studies testing LITT in cases of different brain pathologies, including gliomas. This modality is particularly attractive in patients with recurrent, deep-seated, and/or critically located neoplasms refractory to other treatments, where it can effectively demonstrate improvement of prognosis providing high quality of life and eliminating the risks of open tumor resection. Low morbidity rates associated with LITT and short hospital stay result in decreased cost of hospitalization. The effectiveness of thermal therapies, particularly after long-term follow-up, still needs evaluation in carefully planned randomized clinical trials, whereas elucidating the effects of laser treatment at the molecular, cellular, and organic levels will continue to expand the boundaries of its clinical applicability in neuro-oncology., (© 2018 S. Karger AG, Basel.)

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.

Glioblastoma (GBM) is the most aggressive and lethal type of brain cancer with a median survival of less than two years even following aggressive treatment (Stupp et al., N Engl J Med 352:987-996, 2005). Among the many challenges in treating patients with this devastating disease is the ability to differentiate Magnetic Resonance Imaging (MRI) images that appear following radiation therapy, often termed "radiation necrosis" from true GBM recurrence. Radiation necrosis (RN) and GBM are very difficult to distinguish and currently only a brain biopsy can conclusively differentiate these pathologies. In the present study, we introduce a differential diagnostic approach using a newly identified Myeloid-Derived Suppressor Cell (MDSC) biomarker, vascular non-inflammatory molecule 2 (VNN2 + ), in combination with expression of traditional HLA-DR on peripheral blood CD14 + monocytes isolated from GBM and/or RN patients. We performed proof-of-principle experiments confirming the sensitivity and specificity of this approach based upon the combined expression levels of HLA-DR and VNN2 among CD14 + Mo-MDSC, which we called the DR-Vanin Index or DVI. The DVI was able to distinguish GBM from RN patients with a high degree of certainty (n = 18 and n = 6 respectively; p = 0.0004). This novel, quick and inexpensive blood-based liquid biopsy could potentially replace invasive brain biopsies in differentiating GBM from RN patients using a minimally-invasive technique.

The authors present the case of a primary gliosarcoma with an isocitrate dehydrogenase-1 (IDH1) mutation. A 75-year-old man presented with a 3-day history of multiple focal seizures and was found on MRI to have a 2.2-cm left parietal enhancing mass lesion. Brain MRI for tremor performed 8 years prior to this presentation was normal. En bloc resection revealed a high-grade glioma with sarcomatous components that was immunoreactive for the R132H variant of IDH1 by antibody. Gliosarcoma is a rare variant of glioblastoma that arises most frequently as a primary tumor, and has equal or worse survival and an increased propensity for extracranial metastases compared with other Grade 4 gliomas. In contrast, isocitrate dehydrogenase-1 and -2 mutations are associated with low-grade gliomas with increased survival and less commonly with glioblastoma. To the authors' knowledge, there has been only 1 other published report of a primary gliosarcoma carrying an isocitrate dehydrogenase mutation. This rare genetic-histological combination highlights potential differences between glioblastoma and gliosarcoma and may warrant additional study.

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., (© 2017 Fang et al.)

OBJECTIVE Laser interstitial thermal therapy (LITT), sometimes referred to as "stereotactic laser ablation," has demonstrated utility in a subset of high-risk surgical patients with difficult to access (DTA) intracranial neoplasms. However, the treatment of tumors larger than 10 cm 3 is associated with suboptimal outcomes and morbidity. This may limit the utility of LITT in dealing with precisely those large or deep tumors that are most difficult to treat with conventional approaches. Recently, several groups have reported on minimally invasive transsulcal approaches utilizing tubular retracting systems. However, these approaches have been primarily used for intraventricular or paraventricular lesions, and subtotal resections have been reported for intraparenchymal lesions. Here, the authors describe a combined approach of LITT followed by minimally invasive transsulcal resection for large and DTA tumors. METHODS The authors retrospectively reviewed the results of LITT immediately followed by minimally invasive, transsulcal, transportal resection in 10 consecutive patients with unilateral, DTA malignant tumors > 10 cm 3 . The patients, 5 males and 5 females, had a median age of 65 years. Eight patients had glioblastoma multiforme (GBM), 1 had a previously treated GBM with radiation necrosis, and 1 had a melanoma brain metastasis. The median tumor volume treated was 38.0 cm 3 . RESULTS The median tumor volume treated to the yellow thermal dose threshold (TDT) line was 83% (range 76%-92%), the median tumor volume treated to the blue TDT line was 73% (range 60%-87%), and the median extent of resection was 93% (range 84%-100%). Two patients suffered mild postoperative neurological deficits, one transiently. Four patients have died since this analysis and 6 remain alive. Median progression-free survival was 280 days, and median overall survival was 482 days. CONCLUSIONS Laser interstitial thermal therapy followed by minimally invasive transsulcal resection, reported here for the first time, is a novel option for patients with large, DTA, malignant brain neoplasms. There were no unexpected neurological complications in this series, and operative characteristics improved as surgeon experience increased. Further studies are needed to elucidate any differences in survival or quality of life metrics.

OBJECTIVE Therapeutic options for brain metastases (BMs) that recur after stereotactic radiosurgery (SRS) remain limited. METHODS The authors provide the collective experience of 4 institutions where treatment of BMs that recurred after SRS was performed with stereotactic laser ablation (SLA). RESULTS Twenty-six BMs (in 23 patients) that recurred after SRS were treated with SLA (2 patients each underwent 2 SLAs for separate lesions, and a third underwent 2 serial SLAs for discrete BMs). Histological findings in the BMs treated included the following: breast (n = 6); lung (n = 6); melanoma (n = 5); colon (n = 2); ovarian (n = 1); bladder (n = 1); esophageal (n = 1); and sarcoma (n = 1). With a median follow-up duration of 141 days (range 64-794 days), 9 of the SLA-treated BMs progressed despite treatment (35%). All cases of progression occurred in BMs in which < 80% ablation was achieved, whereas no disease progression was observed in BMs in which ≥ 80% ablation was achieved. Five BMs were treated with SLA, followed 1 month later by adjuvant SRS (5 Gy daily × 5 days). No disease progression was observed in these patients despite ablation efficiency of < 80%, suggesting that adjuvant hypofractionated SRS enhances the efficacy of SLA. Of the 23 SLA-treated patients, 3 suffered transient hemiparesis (13%), 1 developed hydrocephalus requiring temporary ventricular drainage (4%), and 1 patient who underwent SLA of a 28.9-cm 3 lesion suffered a neurological deficit requiring an emergency hemicraniectomy (4%). Although there is significant heterogeneity in corticosteroid treatment post-SLA, most patients underwent a 2-week taper. CONCLUSIONS Stereotactic laser ablation is an effective treatment option for BMs in which SRS fails. Ablation of ≥ 80% of BMs is associated with decreased risk of disease progression. The efficacy of SLA in this setting may be augmented by adjuvant hypofractionated SRS.

Detailed Monte Carlo (MC) modeling of the Leksell Gamma Knife (GK) Perfexion (PFX) collimator system is the only accurate ab initio approach appearing in the literature. As a different approach, in this work, we present a MC model based on film measurement. By adjusting the model parameters and fine-tuning the derived fluence map for each individual source to match the manufacturer's ring output factors, we created a reasonable virtual source model for MC simulations to verify treatment planning dose for the GK PFX radiosurgery system. The MC simulation model was commissioned by simple single shots. Dose profiles and both ring and collimator output factors were compared with the treatment planning system (TPS). Good agreement was achieved for dose profiles especially for the region of plateau (< 2%), while larger difference (< 5%) came from the penumbra region. The maximum difference of the calculated output factor was within 0.7%. The model was further validated by a clinical test case. Good agreement was obtained. The DVHs for brainstem and the skull were almost identical and, for the target, the volume covered by the prescription (12.5 Gy to 50% isodose line) was 95.6% from MC calculation versus 100% from the TPS., (© 2016 The Authors)

The median life expectancy after a diagnosis of glioblastoma is 15 months. Although chemotherapeutics may someday cure glioblastoma by killing the highly dispersive malignant cells, the most important contribution that clinicians can currently offer to improve survival is by maximizing the extent of resection and providing concurrent chemo-radiation, which has become standard. Strides have been made in this area with the advent and implementation of methods of improved intraoperative tumor visualization. One of these techniques, optical fluorescent imaging with targeted molecular imaging agents, allows the surgeon to view fluorescently labeled tumor tissue during surgery with the use of special microscopy, thereby highlighting where to resect and indicating when tumor-free margins have been obtained. This advantage is especially important at the difficult-to-observe margins where tumor cells infiltrate normal tissue. Targeted fluorescent agents also may be valuable for identifying tumor versus nontumor tissue. In this review, we briefly summarize nontargeted fluorescent tumor imaging agents before discussing several novel targeted fluorescent agents being developed for glioma imaging in the context of fluorescent-guided surgery or live molecular navigation. Many of these agents are currently undergoing preclinical testing. As the agents become available, however, it is necessary to understand the strengths and weaknesses of each., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The nearly universal recurrence of glioblastoma (GBM) is driven in part by a treatment-resistant subpopulation of GBM stem cells (GSC). To identify improved therapeutic possibilities, we combined the EGFR/HER2 inhibitor lapatinib with a novel small molecule, CBL0137, which inhibits FACT (facilitates chromatin transcription), a histone chaperone complex predominantly expressed in undifferentiated cells. Lapatinib and CBL0137 synergistically inhibited the proliferation of patient-derived GBM cells. Compared with non-stem tumor cells (NSTC) enriched from the same specimens, the GSCs were extremely sensitive to CBL0137 monotherapy or FACT knockdown. FACT expression was elevated in GSCs compared with matched NSTCs and decreased in GSCs upon differentiation. Acute exposure of GSCs to CBL0137 increased asymmetric cell division, decreased GSC marker expression, and decreased the capacity of GSCs to form tumor spheres in vitro and to initiate tumors in vivo Oral administration of CBL0137 to mice bearing orthotopic GBM prolonged their survival. Knockdown of FACT reduced the expression of genes encoding several core stem cell transcription factors (SOX2, OCT4, NANOG, and OLIG2), and FACT occupied the promoters of these genes. FACT expression was elevated in GBM tumors compared with non-neoplastic brain tissues, portended a worse prognosis, and positively correlated with GSC markers and stem cell gene expression signatures. Preferential targeting of GSCs by CBL0137 and synergy with EGFR inhibitors support the development of clinical trials combining these two agents in GBM. Cancer Res; 76(8); 2432-42. ©2016 AACR., (©2016 American Association for Cancer Research.)

Many cancers feature cellular hierarchies that are driven by tumor-initiating cancer stem cells (CSC) and rely on complex interactions with the tumor microenvironment. Standard cell culture conditions fail to recapitulate the original tumor architecture or microenvironmental gradients and are not designed to retain the cellular heterogeneity of parental tumors. Here, we describe a three-dimensional culture system that supports the long-term growth and expansion of tumor organoids derived directly from glioblastoma specimens, including patient-derived primary cultures, xenografts, genetically engineered glioma models, or patient samples. Organoids derived from multiple regions of patient tumors retain selective tumorigenic potential. Furthermore, organoids could be established directly from brain metastases not typically amenable to in vitro culture. Once formed, tumor organoids grew for months and displayed regional heterogeneity with a rapidly dividing outer region of SOX2(+), OLIG2(+), and TLX(+) cells surrounding a hypoxic core of primarily non-stem senescent cells and diffuse, quiescent CSCs. Notably, non-stem cells within organoids were sensitive to radiotherapy, whereas adjacent CSCs were radioresistant. Orthotopic transplantation of patient-derived organoids resulted in tumors displaying histologic features, including single-cell invasiveness, that were more representative of the parental tumor compared with those formed from patient-derived sphere cultures. In conclusion, we present a new ex vivo model in which phenotypically diverse stem and non-stem glioblastoma cell populations can be simultaneously cultured to explore new facets of microenvironmental influences and CSC biology. Cancer Res; 76(8); 2465-77. ©2016 AACR., (©2016 American Association for Cancer Research.)

Question: What is the role of immunotherapy/tumor vaccines in the treatment of low grade gliomas?, Target Population: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma., Recommendations: There is no evidence to support a recommendation in regards to the efficacy of immunotherapy or tumor vaccines for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess immunotherapies and tumor vaccines for low grade gliomas., Question: What is the role of nutrition in the treatment of low grade gliomas?, Target Population: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma., Recommendations: There was no evidence to support a recommendation in regard to the efficacy of nutritional therapy for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess the efficacy of nutrition for this target population., Question: Is there a role for alternative or targeted therapies in the treatment of low grade gliomas?, Target Population: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma., Recommendation: There was no evidence to support a recommendation in regard to the efficacy of targeted or alternative agents for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess alternative and targeted therapies for this target population.

Target Population: Adult patients (age ≥18 years) who have suspected low-grade diffuse glioma., Question: What are the optimal neuropathological techniques to diagnose low-grade diffuse glioma in the adult?, Recommendation: LEVEL I: Histopathological analysis of a representative surgical sample of the lesion should be used to provide the diagnosis of low-grade diffuse glioma., Level Iii: Both frozen section and cytopathologic/smear evaluation should be used to aid the intra-operative assessment of low-grade diffuse glioma diagnosis. A resection specimen is preferred over a biopsy specimen, to minimize the potential for sampling error issues., Target Population: Patients with histologically-proven WHO grade II diffuse glioma., Question: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is testing for IDH1 mutation (R132H and/or others) warranted? If so, is there a preferred method?, Level Ii: IDH gene mutation assessment, via IDH1 R132H antibody and/or IDH1/2 mutation hotspot sequencing, is highly-specific for low-grade diffuse glioma, and is recommended as an additional test for classification and prognosis., Target Population: Patients with histologically-proven WHO grade II diffuse glioma., Question: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is testing for 1p/19q loss warranted? If so, is there a preferred method?, Level Iii: 1p/19q loss-of-heterozygosity testing, by FISH, array-CGH or PCR, is recommended as an additional test in oligodendroglial cases for prognosis and potential treatment planning., Target Population: Patients with histologically-proven WHO grade II diffuse glioma., Question: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is MGMT promoter methylation testing warranted? If so, is there a preferred method?, Recommendation: There is insufficient evidence to recommend methyl-guanine methyl-transferase (MGMT) promoter methylation testing as a routine for low-grade diffuse gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess the value of this and related markers for this target population., Target Population: Patients with histologically-proven WHO grade II diffuse glioma., Question: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is Ki-67/MIB1 immunohistochemistry warranted? If so, is there a preferred method to quantitate results?, Level Iii: Ki67/MIB1 immunohistochemistry is recommended as an option for prognostic assessment.

Question: Should patients with imaging suggestive of low grade glioma (LGG) undergo observation versus treatment involving a surgical procedure?, Target Population: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma)., Recommendations: Surgical resection is recommended over observation to improve overall survival for patients with diffuse low-grade glioma (Level III) although observation has no negative impact on cognitive performance and quality of life (Level II)., Question: What is the impact of extent of resection on progression free survival (PFS) or overall survival (OS) in LGG patients?, Target Population: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma)., Recommendations: IMPACT OF EXTENT OF RESECTION ON PFS:, Level Ii: It is recommended that GTR or STR be accomplished instead of biopsy alone when safe and feasible so as to decrease the frequency of tumor progression recognizing that the rate of progression after GTR is fairly high., Level Iii: Greater extent of resection can improve OS in LGG patients., Question: What tools are available to increase extent of resection in LGG patients?, Target Population: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma)., Recommendations: INTRAOPERATIVE MRI DURING SURGERY:, Level Iii: The use of intraoperative MRI should be considered as a method of increasing the extent of resection of LGGs., Question: What is the impact of surgical resection on seizure control and accuracy of pathology in low grade glioma patients?, Target Population: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma)., Recommendations: SURGICAL RESECTION AND SEIZURE CONTROL:, Level Iii: After taking into account the patient's clinical status and tumor location, gross total resection is recommended for patients with diffuse LGG as a way to achieve more favorable seizure control., Level Iii: Taking into account the patient's clinical status and tumor location, surgical resection should be carried out to maximize the chance of accurate diagnosis., Question: What tools can improve the safety of surgery for LGGs in eloquent locations?, Target Population: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma)., Recommendations: PREOPERATIVE IMAGING:, Level Iii: It is recommended that preoperative functional MRI and diffusion tensor imaging be utilized in the appropriate clinical setting to improve functional outcome after surgery for LGG., Level Iii: Intraoperative mapping is recommended for patients with diffuse LGGs in eloquent locations compared to patients with non-eloquently located diffuse LGGs as a way of preserving function.

Aims: To determine the efficacy of methylguanine methyltransferase (MGMT) depletion + BCNU [1,3-bis(2-chloroethyl)-1- nitrosourea: carmustine] therapy and the impact of methylation status in adults with glioblastoma multiforme (GBM) and gliosarcoma., Methods: Methylation analysis was performed on GBM patients with adequate tissue samples. Patients with newly diagnosed GBM or gliosarcoma were eligible for this Phase III open-label clinical trial. At registration, patients were randomized to Arm 1, which consisted of therapy with O(6)-benzylguanine (O(6)-BG) + BCNU 40 mg/m(2) (reduced dose) + radiation therapy (RT) (O6BG + BCNU arm), or Arm 2, which consisted of therapy with BCNU 200 mg/m(2) + RT (BCNU arm)., Results: A total of 183 patients with newly diagnosed GBM or gliosarcoma from 42 U.S. institutions were enrolled in this study. Of these, 90 eligible patients received O(6)-BG + BCNU + RT and 89 received BCNU + RT. The trial was halted at the first interim analysis in accordance with the guidelines for stopping the study due to futility (<40 % improvement among patients on the O6BG + BCNU arm). Following adjustment for stratification factors, there was no significant difference in overall survival (OS) or progression-free survival (PFS) between the two groups (one sided p = 0.94 and p = 0.88, respectively). Median OS was 11 [95 % confidence interval (CI) 8-13] months for patients in the O6BG + BCNU arm and 10 (95 % CI 8-12) months for those in the BCNU arm. PFS was 4 months for patients in each arm. Adverse events were reported in both arms, with significantly more grade 4 and 5 events in the experimental arm., Conclusions: The addition of O(6)-BG to the standard regimen of radiation and BCNU for the treatment patients with newly diagnosed GBM and gliosarcoma did not provide added benefit and in fact caused additional toxicity.

Background: High grade gliomas are the most common type of malignant brain tumor, and despite their rarity, cause significant morbidity and mortality. This study aimed to compare the treatment patterns of high grade glioma to examine survival patterns in patients who receive specific treatments between cohorts in Ohio and Taiwan., Method: Patients aged 18 years and older at age of diagnosis with World Health Organization (WHO) grade III or IV astrocytoma from 2007-2012 were selected from the Ohio Brain Tumor Study and the Taiwan Cancer Registry. The treatment information was derived from medical chart reviews in Ohio and National Health Insurance Research Data in Taiwan. Treatment examined included surgical procedure (brain biopsy and/or resection), radiotherapy (radiation and/or radiosurgery), and alkylating chemotherapy. Kaplan-Meier and parametric survival models were used to examine the effect of treatment on survival, adjusted for age, sex, and comorbidities., Results: 294 patients in Ohio and 1,097 patients in Taiwan met the inclusion criteria. 70.3% patients in Ohio and 51.4% in Taiwan received surgical resection, followed by concurrent chemoradiation. Patients who received this treatment had the highest survival rate, with a 1-year survival rate of 72.8% in Ohio and 73.4% in Taiwan. Patients who did not receive surgical resection, followed by concurrent chemoradiation had an increased risk of death (hazard ratio of 5.03 [95% confidence interval (CI): 3.61-7.02] in Ohio and 1.49 [95% CI: 1.31-1.71] in Taiwan) after adjustment for age, sex, and comorbidities., Conclusion: Surgical resection followed by concurrent chemoradiation was associated with higher survival rate of patients with high grade glioma in both Ohio and Taiwan; however, one-third of patients in Ohio and half in Taiwan did not receive this treatment.

Extra-CNS metastasis from glioblastoma (ECMGBM) is an emerging but little known clinical entity. We review pre-clinical and translational publications assessing the ability of GBM to spread locally and outside the CNS. Reported cases demonstrating ECMGBM are reviewed providing a summary of presentations for the entity. Special attention is placed on transmission of GBM through organ transplantation. Finally, predictions are made as to the future significance of ECMGBM, especially in the context of better outcomes in CNS GBM.

Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence ∼ 7 mo after diagnosis. Understanding the molecular architecture of this residual population is critical for the development of successful therapies. We used whole-genome sequencing and whole-exome sequencing of multiple sectors from primary and paired recurrent GBM tumors to reconstruct the genomic profile of residual, therapy resistant tumor initiating cells. We found that genetic alteration of the p53 pathway is a primary molecular event predictive of a high number of subclonal mutations in glioblastoma. The genomic road leading to recurrence is highly idiosyncratic but can be broadly classified into linear recurrences that share extensive genetic similarity with the primary tumor and can be directly traced to one of its specific sectors, and divergent recurrences that share few genetic alterations with the primary tumor and originate from cells that branched off early during tumorigenesis. Our study provides mechanistic insights into how genetic alterations in primary tumors impact the ensuing evolution of tumor cells and the emergence of subclonal heterogeneity., (© 2015 Kim et al.; Published by Cold Spring Harbor Laboratory Press.)