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Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.

Patients with recurrent glioblastoma (rGBM) are often started on anti-angiogenic therapy such as bevacizumab. However, determining treatment failure using conventional MRI methods remains challenging. We prospectively collected longitudinal MR spectroscopy data in 33 patients with rGBM and quantified various metabolites including N-acetylaspartate (NAA), Choline (Cho), and Lactate (Lac). After stratifying patients by 9 month survival, we found that longer-term survivors had decreased Lac/NAA and increased NAA/Cho compared to shorter-term survivors. ROC analyses illustrated that intratumoral changes in NAA/Cho were predictive of survival at 1 day (AUC 0.92), 2 weeks (AUC 0.75), 8 weeks (AUC 0.71) and 16 weeks (AUC 0.85) but not 4 weeks (AUC 0.60). Intratumoral changes in Lac/NAA were predictive of survival at all time points tested (AUCs > 0.76 for all time points). At 8 weeks, 90% of patients with increased Lac/NAA from baseline and 88% of patients with decreased NAA/Cho did not survive 9 months. Changes in NAA/Cho and Lac/NAA may serve as early biomarkers of anti-angiogenic treatment failure.

BACKGROUND Recurrent glioblastoma (rGBM) patients are often treated with anti-angiogenic agents such as bevacizumab (BEV). Despite therapeutic promise, conventional MR methods fail to determine which patients may not benefit. PURPOSE: The purpose of this study was to utilize magnetic resonance spectroscopic imaging (MRSI) with intermediate and short echo time to generate corrected Myo-inositol normalized by contralateral creatine (mI/c-Cr) in patients with rGBM treated with BEV and investigate whether it can predict survivorship prior to BEV initiation (baseline) and at 1-day, 4-weeks, and 8-weeks thereafter. METHODS We conducted a prospective, longitudinal study and evaluated spectroscopic data of myo-inositol (mI), a glial marker and osmoregulator within the brain, normalized to contralateral-creatine (mI/c-Cr) in the intratumoral, contralateral normal appearing white matter, and peritumoral volumes of rGBM patients. Area under the ROC curve (AUC) was calculated for all volumes at baseline, 1-day, 4-weeks, and 8-weeks after treatment to determine mI/c-Cr’s ability to predict survivorship. RESULTS 21 participants (62 ± 12 years, 15 men) were evaluated. Lower mI/c-Cr in the tumor prior to and during BEV treatment predicted poor survivorship, with ROC analyses illustrating an AUC of 0.75 at baseline, 0.87 at 1-day, and 1 at 8 weeks. Lower levels of mI/c-Cr were also observed in the contralateral and the peritumoral volumes for shorter-term survivors. In the contralateral volume, lower mI/Cr was predictive of shorter-term survival at baseline and all other timepoints. Within the peritumoral volume, lower mI/c-Cr was predictive of shorter-term survival at baseline (AUC=0.80), 1-day (AUC=0.93), and 4-weeks (AUC=0.68). CONCLUSIONS Lower levels of mI/c-Cr within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and anti-angiogenic treatment failure as early as one month before BEV treatment. Acquiring MRSI alongside conventional MR imaging modalities can convey critical information regarding tumor microenvironment that informs management of patients with rGBM.

BACKGROUND Comprehensive next generation sequencing (NGS) is available through many academic institutions and commercial entities, and is incorporated in practice guidelines for glioblastoma (GBM). We retrospective evaluated the practice patterns and utility of incorporating NGS data into routine care of GBM patients at a clinical trials-focused academic center. METHODS We identified 1,011 consecutive adult patients with histologically confirmed GBM with OncoPanel testing, a targeted exome NGS platform of 447 cancer-associated genes at Dana Farber Cancer Institute (DFCI), from 2013-2019. We selected and retrospectively reviewed clinical records of all IDH-wildtype GBM patients treated at DFCI. RESULTS We identified 557 GBM IDH-wildtype patients, of which 227 were male (40.7%). OncoPanel testing revealed 833 single nucleotide variants and indels in 44 therapeutically relevant genes (Tier 1 or 2 mutations) including PIK3CA (n=51), BRAF (n=9), FGFR1 (n=8), MSH2 (n=4), MSH6 (n=2) and MLH1 (n=1). Copy number analysis revealed 509 alterations in 18 therapeutically relevant genes including EGFR amplification (n= 186), PDGFRA amplification (N=39) and CDKN2A/2B homozygous loss (N=223). Median overall survival was 17.5 months for the whole cohort. Seventy-four therapeutic clinical trials accrued 144 patients in the upfront setting (25.9%) and 203 patients (36.4%) at recurrence. Altogether, NGS data for 107 patients (19.2%) were utilized for clinical trial enrollment or targeted therapy indications. High mutational burden (>17mutations/Mb) was identified in 11/464 samples (2.4%); of whom 3/11 received immune checkpoint blockade. Four patients received compassionate use therapy targeting EGFRvIII (rindopepimut, n=2), CKD4/6 (abemaciclib, n=1) and BRAFV600E (dabrafenib/trametinib, n=1). CONCLUSION While NGS has greatly improved diagnosis and molecular classification, we highlight that NGS remains underutilized in selecting therapy in GBM, even in a setting where clinical trials and off-label therapies are relatively accessible. Continued efforts to develop better targeted therapies and efficient clinical trial design are required to maximize the potential benefits of genomically-stratified data.

BACKGROUND The cyclin D-CDK4/6-Rb pathway is activated in most glioblastomas. Abemaciclib is a potent CDK4/6 inhibitor with good brain penetration approved for ER/PR/HER2- breast cancer. In order to efficiently evaluate the potential impact of abemaciclib on overall survival (OS) in newly diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, abemaciclib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. Initial randomization was equal between abemaciclib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). Ineffective arms were discontinued and new arms added by protocol amendment. We report preliminary results for the abemaciclib arm which has completed accrual. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide at standard doses or standard radiochemotherapy followed by adjuvant abemaciclib (150–200 mg orally BID) without temozolomide. Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between abemaciclib efficacy and cyclin D-CDK4/6-Rb pathway genomic alterations was also investigated. RESULTS There were 123 patients (50 control; 73 treated with abemaciclib). Abemaciclib was generally well-tolerated with no new toxicity signals identified. PFS was significantly longer (p=0.03, logrank test) with abemaciclib (median 6.31 months 95% CI [5.29, 8.18]) compared to the control arm (5.16 months 95% CI [4.37, 6.28]). 28/50 control and 36/73 abemaciclib patients remain alive. CONCLUSION Preliminary analysis suggests that abemaciclib increases PFS compared to control. Updated toxicity, PFS and survival data and potential genomic biomarker associations will be presented.

BACKGROUND CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents. METHODS Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used. RESULTS Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade > 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to < 10% at time of the trial arm closure. CONCLUSION Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

Metabolic imaging can map spatially abnormal molecular pathways with higher specificity for cancer compared to anatomical imaging. However, acquiring high resolution metabolic maps similar to anatomical MRI is challenging due to low metabolite concentrations, and alternative approaches that increase resolution by post-acquisition image processing can mitigate this limitation. We developed deep learning super-resolution MR spectroscopic imaging (MRSI) to map tumor metabolism in patients with mutant IDH glioma. We used a generative adversarial network (GAN) architecture comprised of a UNet neural network as the generator network and a discriminator network for adversarial training. For training we simulated a large data set of 9600 images with realistic quality for acquired MRSI to effectively train the deep learning model to upsample by a factor of four. Two types of training were performed: 1) using only the MRSI data, and 2) using MRSI and prior information from anatomical MRI to further enhance structural details. The performance of super-resolution methods was evaluated by peak SNR (PSNR), structure similarity index (SSIM), and feature similarity index (FSIM). After training on simulations, GAN was evaluated on measured MRSI metabolic maps acquired with resolution 5.2×5.2 mm2 and upsampled to 1.3×1.3 mm2. The GAN trained only on MRSI achieved PSNR = 27.94, SSIM = 0.88, FSIM = 0.89. Using prior anatomical MRI improved GAN performance to PSNR = 30.75, SSIM = 0.90, FSIM = 0.92. In the patient measured data, GAN super-resolution metabolic images provided clearer tumor margins and made apparent the tumor metabolic heterogeneity. Compared to conventional image interpolation such as bicubic or total variation, deep learning methods provided sharper edges and less blurring of structural details. Our results indicate that the proposed deep learning method is effective in enhancing the spatial resolution of metabolite maps which may better guide treatment in mutant IDH glioma patients.

BACKGROUND The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients with brain tumors and complement radiographic assessment in defining overall outcome. The scale has been incorporated in clinical trials. Early data is suggestive of feasibility and that NANO contributes to overall outcome assessment. However, real-world use of the NANO scale to drive clinical-decision making and the predictive value of the NANO scale to determine overall survival remains unclear in IDH-wt GBM. METHODS We report on an ongoing study using the NANO scale to evaluate neurologic function in patients with IDH-wt GBM, seen at Dana-Farber Cancer Institute (DFCI). Patient demographics, tumor histology and molecular status, treatment history and progression dates are being captured. NANO score, as collected by a built-in scale in our institutional electronic medical record (EMR), functional status (Karnofsky performance status) and corticosteroid dose are collected at prespecified time points (prior to start of therapy, and during each subsequent MRI visit). Changes in the NANO score will be correlated to overall survival. Statistical analyses including descriptive data analysis and generalized linear models will be performed using R (version 3.4.3). RESULTS Since June 2020, 50 patients have been enrolled in this study, including 42 (84%) with ≥2 follow up visits. Study accrual was initially impacted by the COVID-19 pandemic, but adaptation to a virtual platform for NANO allowed for improved recruitment and follow up of patients. Study results will be available for discussion at the 2021 SNO conference. CONCLUSIONS Evaluation of neurologic function by NANO is feasible in a virtual framework in a prospective study in patients with GBM, aided by integration of the scale in our institutional EMR. NANO is able to objectively track neurologic function throughout disease course in IDH-wt GBM.

BACKGROUND Like most proliferating tumors, GBM relies heavily on accurate DNA repair for maintenance of genome stability. Dysfunction in repair of both single and double strand DNA breaks by PARP inhibition and impairment of homologous recombination, respectively, would be synthetically lethal. In this study we combined the PARP inhibitor olaparib with cediranib, a pan VEGF receptor inhibitor. Cediranib may mediate disruption in the homologous recombination pathway through its antiangiogenic properties. METHODS Through the Experimental Therapeutics Clinical Trials Network, we performed an open-label randomized phase II study of bevacizumab (BEV)- naive adult patients with first or second recurrence of glioblastoma after radiation and temozolomide. Patients were randomized 1:1 to receive either olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily or BEV 10 mg/kg IV every 2 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included safety and overall survival. Exploratory objectives included blood, tissue and imaging-based biomarkers of response to treatment. RESULTS Seventy patients were enrolled. Median age was 60.5 years (range: 19–79), 39% females, median KPS was 90 (range: 60–100). Baseline characteristics were well balanced. With a data cut-off of 5/2/2019, PFS6 was 14% [95% CI 4–30%] in the cediranib/olaparib arm vs 30.9% [95% CI 12.7–51.2%] in the BEV arm. Median OS was 247 days in the cediranib/olaparib arm vs 201 days in the BEV arm, HR 0.816, 95% CI (0.431, 1.546). Related grade 3, 4 or 5 toxicity was experienced in 29% vs 12% of patients for the cediranib/olaparib vs BEV arm. CONCLUSION Treatment with cediranib/olaparib failed to increase PFS and OS in patients with recurrent GBM. Blood, tissue and imaging correlates will be presented to help understand why this treatment combination was unsuccessful.

Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases are limited. We discovered novel candidate drivers of progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 lung adenocarcinoma brain metastases to a control cohort of 503 primary lung adenocarcinomas. We identified 3 genomic regions with significantly more frequent amplifications in brain metastases compared to the control cohort: MYC (12% vs 6%), YAP1 (7% vs 0.8%) and MMP13 (10% vs 0.6%). We also identified CDKN2A/B as a region deleted at a significantly greater frequency in brain metastases compared to primary lung adenocarcinomas (27% vs 13%, respectively). We confirmed frequent amplifications of MYC and YAP1/MMP13 in an independent validation cohort of 105 lung adenocarcinoma brain metastasis samples using fluorescence in situ hybridization. We further validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model. We found a higher incidence of metastases to the brain in mice receiving intracardiac injections of tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ as a control. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. The candidate brain metastasis drivers that we identified may serve as therapeutic targets in patients with lung adenocarcinomas who develop this devastating complication.

BACKGROUND Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. MATERIAL AND METHODS Here, we intravitally study preclinical syngenetic models of glioma as well as patient-derived cells transplanted orthotopically. Moreover, we profoundly confirm our preclinical results with histological studies on patient specimens. RESULTS We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. CONCLUSION Here, we show that glioma is able to employ vessel co-option, i.e. the movement of tumor cells towards and along the pre-existing vasculature. Glioma oligodendrocyte-like (OPCL) cells express Wnt7 that is necessary for vessel co-option and Wnt inhibitors significantly improve survival with temozolomide. Moreover, we demonstrated that anti-VEGF-treatment of glioma selects for Olig2/Wnt7+ cells

ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus has the highest extra-striatal expression of DRD2, we performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019, PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group. For non-recurrent patients, with median follow up of 21.9 months (8.6–26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1 CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for non-recurrent patients (4 on-trial patients experienced regressions that are yet unconfirmed responses). Median duration of response for recurrent patients is 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. In summary, single agent ONC201 administered at recurrence, or adjuvantly following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental DRD2 expression explains the early exceptional responses in thalamic H3 K27M-mutant glioma.

BACKGROUND: ONC201 selectively antagonizes DRD2, crosses the blood-brain barrier and induces apoptosis in high grade gliomas and other advanced cancers. ONC201 efficacy is pronounced in glioma cells that harbor low DRD5 expression and is associated with induction of the ATF4/CHOP/DR5-mediated integrated stress response pathway. DRD2 antagonism also induces activation of NK and other immune cells. We previously reported the single agent activity of ONC201 in 17 adult patients with recurrent glioblastoma that demonstrated the safety, systemic pharmacodynamics, and a durable objective response when administered orally once every 3 weeks. Here, we evaluated the intratumoral drug concentrations and pharmacodynamic activity of ONC201 in adult recurrent glioblastoma patients that were treated on a weekly schedule. METHODS: Six patients >18 years old with first recurrence of glioblastoma who were eligible for salvage surgical resection were enrolled. ONC201 was administered orally as 625 mg once a week. Salvage surgery was performed approximately 24 hours after the second dose of ONC201 and patients continued on ONC201 until radiographic and/or clinical progression. Tumor tissue was flash-frozen and formalin-fixed for assessment of intratumoral drug concentrations by LC-MS and pharmacodynamics by IHC, respectively. RESULTS: Of the 6 enrolled patients, 5 had sufficient tissue for evaluation. Intratumoral drug concentrations exceeded therapeutic thresholds: median 1.5 µM (range 600 nM 9.3 µM). Investigation of biomarkers related to downstream signaling induced by ONC201 revealed heterogeneous intratumoral induction of ATF4/CHOP/DR5 expression and tumor cell apoptosis (TUNEL). Stronger induction of the pharmacodynamic signaling was associated with stronger induction of apoptosis and inversely associated with DRD5 expression, but not with drug concentration. No drug-related adverse events were reported in this cohort. Evaluation of immune cytokines and effectors molecules in serum and immune infiltration into the tumor is ongoing. CONCLUSIONS: ONC201 is biologically active and well tolerated in recurrent glioblastoma tumors when administered to adults.

The compression of brain tissue by a tumor mass is believed to be a major cause of the clinical symptoms seen in patients. However, the biological consequences of these physical stresses on the brain tissue are unknown. Using clinical imaging and preclinical studies, we discovered that a subgroup of primary and metastatic brain tumors, classified as nodular based on the growth pattern, exert compressive solid stress on the surrounding brain tissue, leading to a decrease in local vascular perfusion, as well as neuronal death and impaired function. We demonstrated a causal link between solid stress and neurological dysfunction, by applying and removing cerebral compression, mimicking the mechanics of tumor growth and surgical resection respectively. Finally, we showed that treatment with lithium reduced solid stress-induced neuronal death and improved motor coordination in mice. Our results indicate that brain tumor-generated solid stress impairs neurological function in patients and show lithium as a potential therapeutic intervention to counter these effects.

The imipridone ONC201 is the first selective antagonist of the G protein-coupled receptor DRD2 for clinical oncology. ONC201 induces p53-independent apoptosis in newly diagnosed and recurrent glioblastoma in vitro, ex vivo, and in vivo. We performed a Phase II clinical trial that enrolled an initial cohort of 17 patients with recurrent, bevacizumab-naïve, IDH1/2 WT glioblastoma who received 625mg ONC201 every three weeks. One patient continues to have a durable objective response that has deepened over time, exhibiting an 92% regression by 92% after 15 months of therapy. Another patient remains disease-free 14 months after enrolling on this trial following a re-resection. Median OS was 41.6 weeks with an OS12 of 35%. No drug-related SAEs or treatment discontinuation due to toxicity occurred. Plasma PK at 2 hours post-dose was 2.6 ug/mL and serum prolactin induction was observed as a surrogate marker of target engagement. In addition to cytotoxic effects in tumor cells, DRD2 antagonism can induce the activation of NK and other immune cells. We found that immune effector levels in the serum correlated with the kinetics of the objective response. Preclinical studies have identified a DRD2+DRD5- tumor biomarker signature that is predictive of innate sensitivity to ONC201. Among the 15 available archival tumor tissue specimens, all had expression of DRD2 and 8/17 patients had low expression of DRD5. Patients with PFS>5 month had no detectable expression of DRD5 unlike those with PFS57 weeks and 0/7 DRD2+DRD5+ patients remain alive. In summary, ONC201 is a well tolerated novel therapy with potential anti-glioblastoma activity that may be associated with a predictive biomarker signature and immune activation. The pharmacodynamic activity and clinical efficacy of ONC201 continues to be explored in additional cohorts of glioblastoma patients at first recurrence (NCT02525692).

Background Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor. Standard-of-care treatment involves maximal surgical resection of the tumor followed by radiation and chemotherapy (temozolomide [TMZ]). The 5-year survival rate of patients with GBM is Methods A drug screening aimed at evaluating the potential recycling and repurposing of known drugs was conducted in TMZ-resistant GBM cell lines and primary cultures of newly diagnosed GBM with different MGMT promoter methylation status, phenotypic/genotypic background and subtype, and validated with sphere formation, cell migration assays, and quantitative invasive orthotopic in vivo models. Results We identified hydroxyurea (HU) to synergize with TMZ in GBM cells in culture and in vivo, irrespective of MGMT promoter methylation status, subtype, and/or stemness. HU acts specifically on the S-phase of the cell cycle by inhibiting the M2 unit of enzyme ribonucleotide reductase. Knockdown of this enzyme using RNA interference and other known chemical inhibitors exerted a similar effect to HU in combination with TMZ both in culture and in vivo. Conclusions We demonstrate preclinical efficacy of repurposing hydroxyurea in combination with TMZ for adjuvant GBM therapy. This combination benefit is of direct clinical interest given the extensive use of TMZ and the associated problems with TMZ-related resistance and treatment failure.

The Oxford Textbook of Neuro-Oncology examines the epidemiology, pathogenesis, clinical features, and management of adult and childhood central nervous system (CNS) tumours. The book is organized according to the World Health Organization (WHO) classification of CNS tumours and includes an introductory chapter discussing the new, revised WHO classification that will be used in future editions of this textbook. The book reviews primary CNS tumours, metastatic CNS tumours, and familial tumour syndromes. Each chapter is organized according to a uniform framework, addressing epidemiology, aetiology, pathogenesis, clinical presentation, imaging, and treatment, with a focus on different treatment modalities and specific consideration of paediatric aspects, where applicable. Each chapter is authored by a multidisciplinary, international group of senior specialists representing the United States, Canada, Europe, and the Asia/Pacific region. It is written for generalists and specialists managing these various conditions. It provides an outlook on how current developments in molecular diagnostics, which have in part been integrated into the new WHO classification, may shape clinical decision-making in the future.

‘Tumours of the haematopoietic system’ examines the epidemiology, the pathogenesis, and the clinical features of adult and childhood primary central nervous system lymphomas (PCNSLs), extranodal forms of non-Hodgkin lymphoma, as well as the histiocytoses included in the World Health Organization (WHO) classification of central nervous system (CNS) tumours. It reviews these features in the most common PCNSL, primary central nervous system diffuse large B-cell lymphoma, as well as the other rare histopathological PCNSL variants including lymphomatoid granulomatosis, T-cell lymphoma, anaplastic large T-cell lymphoma, natural killer/T-cell lymphoma, low-grade lymphoma, mucosa-associated lymphoid tissue (MALT) of the dura, and Hodgkin lymphoma. The chapter also discusses clinical and anatomical PCNSL variants including vitreoretinal lymphoma, leptomeningeal lymphoma, intramedullary spinal cord lymphoma, intravascular lymphoma, and PCNSL in the immunocompromised host. It also reviews the CNS presentations of Langerhans cell histiocytosis and the following non-Langerhans cell histiocytoses: Erdheim–Chester disease, Rosai–Dorfman disease, juvenile xanthogranuloma, and histiocytic sarcoma. It is written for specialists and non-specialists managing these various conditions.

Background Treatment of aggressive pituitary adenomas typically involves a multimodality approach based on histopathological features and may include pharmacotherapy, surgery, and occasionally radiation therapy. In cases of treatment-refractory tumor progression, chemotherapy may be considered; however, no standard chemotherapeutic regimen has been established. Literature review suggests that temozolomide may have a beneficial role in a subset of cases. To understand the efficacy of temozolomide in progressive pituitary tumors, we reviewed the outcomes of cases at our center. Methods We performed a retrospective chart review to report the outcome and unique features of 7 patients with aggressive functioning pituitary adenomas or carcinomas treated with temozolomide. Tumor pathology included somatotroph (n = 1), corticotroph (n = 3), and lactotroph (n = 3) tumors. Results Four of the 7 patients had at least 2 prior resections, and all had prior radiation and surgery before treatment with temozolomide. Notably, all patients showed response to therapy, defined as either stable disease (43%) or partial response (57%). Median progression-free survival was 1.66 years, and median overall survival was 4 years. Conclusion Our data suggest that temozolomide has an important role in the management of aggressive functioning pituitary tumors that are resistant to standard therapies, and that optimization of therapy with temozolomide may involve individualized regimens. Future prospective clinical trials should be considered.

Glioneuronal tumors constitute a histologically diverse group of primary CNS neoplasms, with no effective systemic therapy after surgery has failed. To further characterize this group of tumors, we collected a cohort of 26 glioneuronal tumors and performed in-depth genomic analysis. We identified mutations in BRAF (34%) and oncogenic fusions (30%). In addition, we discovered novel oncogenic fusions involving members of the NTRK gene family in a subset of our cohort. One patient with BCAN exon 13 fused to NTRK1 exon 11 initially underwent a subtotal resection for a 4th ventricular glioneuronal tumor but ultimately required additional therapy due to progressive, symptomatic disease. Given the patient’s targetable fusion, the patient was enrolled on a clinical trial with entrectinib, a pan-Trk, ROS1 and ALK inhibitor. The patient was treated for 11 months and during this time volumetric analysis of the lesion demonstrated a maximum reduction of 60% in the contrast-enhancing tumor compared to his pre-treatment MRI. The radiologic response was associated with resolution of his clinical symptoms and was maintained for eleven months on treatment. This represents the first report of BCAN-NTRK1 fusion in glioneuronal tumors and highlights its clinical importance as a novel, targetable alteration.

Background Molecular profile of glioblastoma multiforme (GBM) revealed 4 subtypes, 2 of which, proneural and mesenchymal, have been predominantly observed, with the latter displaying a more aggressive phenotype and increased therapeutic resistance. Single-cell RNA sequencing revealed that multiple subtypes actually reside within the same tumor, suggesting cellular heterogeneity in GBM. Further, plasticity between these 2 subtypes is observed during tumor recurrence and in response to radiation therapy. Methods Patient-derived GBM stemlike cells were cultured as neurospheres. These cells were differentiated in serum by attaching to the culture dishes. The "floating" cells that were not attached/differentiated were harvested from the conditioned medium. The characteristics of these cells were studied with limiting dilution assays and immunofluorescence staining. Cell growth and nuclear factor-kappaB (NFkB) activation were monitored using bioluminescent assays as well as quantitative polymerase chain reaction and western blotting. In vivo tumorigenesis was evaluated in orthotopic xenograft models using bioluminescence imaging. Results Patient-derived GBM stemlike cells undergo differentiation by attaching to the culture dish in serum-containing medium. We observed that a small subset of these cells escape this adhesion/differentiation and grow as floating cells. These cells displayed enhanced cancer stem cell properties with a molecular and phenotypic mesenchymal signature, including resistance to radiation and targeted therapies, a more aggressive tumor formation, and NFkB activation. Conclusion Our results endorse inherent intratumor molecular subtype heterogeneity in glioblastoma and provide a valuable approach to study phenotypic plasticity, which could be applied to find novel therapeutic strategies to eradicate this aggressive tumor and can be extended to other cancer types.

Background Gliomas with mutant isocitrate dehydrogenase (IDH) produce high levels of 2-hydroxyglutarate (2HG) that can be quantitatively measured by 3D magnetic resonance spectroscopic imaging (MRSI). Current glioma MRI primarily relies upon fluid-attenuated inversion recovery (FLAIR) hyperintensity for treatment planning, although this lacks specificity for tumor cells. Here, we investigated the relationship between 2HG and FLAIR in mutant IDH glioma patients to determine whether 2HG mapping is valuable for radiotherapy planning. Methods Seventeen patients with mutant IDH1 gliomas were imaged by 3 T MRI. A 3D MRSI sequence was employed to specifically image 2HG. FLAIR imaging was performed using standard clinical protocol. Regions of interest (ROIs) were determined for FLAIR and optimally thresholded 2HG hyperintensities. The overlap, displacement, and volumes of 2HG and FLAIR ROIs were calculated. Results In 8 of 17 (47%) patients, the 2HG volume was larger than FLAIR volume. Across the entire cohort, the mean volume of 2HG was 35.3 cc (range, 5.3-92.7 cc), while the mean volume of FLAIR was 35.8 cc (range, 6.3-140.8 cc). FLAIR and 2HG ROIs had mean overlap of 0.28 (Dice coefficients range, 0.03-0.57) and mean displacement of 12.2 mm (range, 3.2-23.5 mm) between their centers of mass. Conclusions Our results indicate that for a substantial number of patients, the 2HG volumetric assessment of tumor burden is more extensive than FLAIR volume. In addition, there is only partial overlap and asymmetric displacement between the centers of FLAIR and 2HG ROIs. These results may have important implications for radiotherapy planning of IDH mutant glioma.

Rapid tumor growth is often accompanied by increased glycolytic metabolism and production of lactic acid creating an acidic tumor environment. Under these conditions, only tumor cells resistant to low pH are able to survive. Glioma stem cells tend to be localized to tumor niches where limited oxygen availability and low pH are predominant. Two glioma stem cells subtypes, proneural and mesenchymal, have been described with the latter displaying a more aggressive phenotype and increased therapeutic resistance. Plasticity between these two subtypes has been observed during tumor recurrence or in response to radiation therapy. Modeling glioblastoma mesenchymal plasticity could have many clinical implications. Here, we show that certain culture conditions reproducibly trigger mesenchymal transition of primary glioblastoma stem cells neurospheres. We identified a subpopulation of glioblastoma stem cells growing as floating cells even under differentiation conditions in the presence of serum. These floating cells displayed stem-like properties with a molecular and phenotypic mesenchymal signature, including resistance to radiation and targeted therapies along with a more aggressive tumor formation. Our results suggest that acidic pH in the cell culture medium promotes this mesenchymal transition. These findings provide a valuable approach to study phenotypic plasticity of glioblastoma, which could be applied to find novel therapeutic strategies to eradicate this aggressive tumor type and could be extended to other cancer types.

BACKGROUND: O6-methylguanine methyltransferase (MGMT) methylation status is prognostic in glioblastoma. It is a critical datum in optimizing care in elderly glioblastoma patients. Further, MGMT methylation status is increasingly required for clinical trial enrollment (e.g. NCT02336165, NCT02287428). As such, maximizing efficiency of molecular tumor testing is critical in order to provide the best care for glioblastoma patients. METHODS: Using the longitudinal electronic medical record and pathology sample tracking systems, we determined the turn around time (TAT) from tumor resection to MGMT methylation status reporting, along with various intermediate steps along the way. We performed interdepartmental process mapping to identify opportunities for process change, followed by 2 process interventions with follow-up tracking of TAT with statistical process control testing. RESULTS: The baseline average interval from craniotomy to MGMT methylation result was 25.1 days for the 30 weeks prior to intervention, which included ∼5 days from craniotomy to pathological diagnosis, and ∼18 days from pathological diagnosis to MGMT result. Two tests of change were implemented, including a switch from batched to daily DNA extraction and MGMT methylation testing, and implementation of a new procedure for pathology sample inventory within the molecular pathology laboratory. The median time from craniotomy to MGMT methylation status reporting was reduced to from 25.1 days to 17 days after the first intervention, and to 15 days after the second intervention, with significant TAT reduction. CONCLUSIONS: Through clinical process improvement strategies and interdepartmental collaboration, we significantly reduced the TAT from craniotomy to MGMT methylation status reporting by an average of 10 days (40%). This allows for improved patient care by accelerating the delivery of potentially treatment-altering information as well as supplying earlier eligibility information for clinical trial enrollment. We continue to study additional opportunities for intervention, as this work highlights the possibility for neuro-oncology care improvement through process improvement strategies.

Background Despite being a highly vascularized tumor, glioblastoma response to anti-vascular endothelial growth factor (VEGF) therapy is transient, possibly because of tumor co-option of preexisting blood vessels and infiltration into surrounding brain. Integrins, which are upregulated after VEGF inhibition, may play a critical role in this resistance mechanism. We designed a study of cediranib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, combined with cilengitide, an integrin inhibitor. Methods This phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent glioblastoma. Once the maximum tolerated dose was determined, 40 patients enrolled in a dose expansion cohort with 20 being exposed to anti-VEGF therapy and 20 being naive. The primary endpoint was safety. Secondary endpoints included overall survival, proportion of participants alive and progression free at 6 months, radiographic response, and exploratory analyses of physiological imaging and blood biomarkers. Results Forty-five patients enrolled, and no dose toxicities were observed at a dose of cediranib 30 mg daily and cilengitide 2000 mg twice weekly. Complete response was seen in 2 participants, partial response in 2, stable disease in 13, and progression in 21; 7 participants were not evaluable. Median overall survival was 6.5 months, median progression-free survival was 1.9 months, and progression-free survival at 6 months was 4.4%. Plasma-soluble VEGFR2 decreased with treatment and placental growth factor, carbonic anhydrase IX, and SDF1α, and cerebral blood flow increased. Conclusions The combination of cediranib with cilengitide was well tolerated and associated with changes in pharmacodynamic blood and imaging biomarkers. However, the survival and response rates do not warrant further development of this combination.

High-grade gliomas, which include glioblastomas (GBMs) and anaplastic gliomas (AGs), are the most common malignant primary brain tumors in adults1 and are associated with poor survival despite maximal surgery, radiation, and chemotherapy.2–4 Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is frequently used to treat recurrent high-grade glioma (HGG). Bevacizumab monotherapy received accelerated approval for recurrent GBM by the United States Food and Drug Administration in 2009 on the basis of phase II clinical trials demonstrating response rates of 20%–26%, 6-month progression-free survival (PFS6) rates of 29%–42.6%, and median overall survival (OS) of 7.1–9.2 months.5,6 Phase II studies in recurrent AG suggest that bevacizumab plus irinotecan also has activity in this patient population with response rates of 55%–66% and PFS6 rates of 56%–61%.7,8 However, responses to bevacizumab are not durable, and some patients fail to benefit.9 Panobinostat is a potent, small-molecule inhibitor of classes I, II, and IV histone deacetylases (HDACs) with greater potency than vorinostat.10 HDAC inhibitors, including panobinostat, may inhibit angiogenesis by reducing VEGF secretion and modulating the expression of other VEGF family members via inhibition of HIF-1α.11–14 In addition, the SDF-1α/CXCR4 pathway has been implicated in bevacizumab resistance,15–17 and panobinostat depletes CXCR4 levels and signaling.18 A phase I study of panobinostat in combination with bevacizumab for recurrent HGG suggested that oral panobinostat 30 mg 3 times per week, every other week, can be safely combined with bevacizumab 10 mg/kg every other week.19 We conducted a multicenter, phase II trial of panobinostat in combination with bevacizumab in patients with recurrent GBM. We also examined the same combination of agents in patients with recurrent AG as an exploratory arm.

Although anti-angiogenic therapy for high-grade glioma is promising, responses are not durable. The SDF-1/CXCR4 axis may help mediate resistance to VEGFR inhibition. Plerixafor is a reversible CXCR4 inhibitor that has demonstrated growth inhibition in glioblastoma xenografts. We conducted a Phase I study to determine the safety and tolerability of plerixafor in combination with bevacizumab in patients with recurrent HGG. A 3 x 3 dose escalation design to a maximum planned dose level of plerixafor 320 µg/kg on Days 1-21 and bevacizumab 10 mg/kg on Days 1 and 15 of each 28 day cycle was used. DLTs were determined during the initial 4 weeks of therapy and included drug-related Grade ≥ 3 non-hematologic toxicities and Grade ≥ 4 hematologic toxicities. Part 1 of the study has been completed with a total of 23 patients enrolled with the following characteristics: median age 58 (23-72), median KPS 90 (70-100), 11 women (47.8%). One DLT (grade 3 rectal fistula) was seen at a dose level of plerixafor 240 µg/kg + bevacizumab and the cohort was expanded. Because no further DLTs were seen at the 240 µg/kg dose level, the maximum planned dose level of plerixafor 320 µg/kg + bevacizumb opened and a total of 12 patients were treated with no DLTs. Treatment was well tolerated with one grade 3 hypophosphatemia and one grade 3 rectal fistula. Preliminary pharmacokinetic data on plerixafor from the first two cohorts compares well with historical PK data. Combination treatment with bevacizumab and plerixafor was well tolerated in the studied HGG patients. No DLTs were encountered at the maximum planned dose level. The study will now expand to a surgical cohort to examine tumor tissue penetration as well as a separate non-surgical cohort with patients treated with continuous daily dosing of plerixafor 320 µg/kg and bevacizumab. Updated results will be presented.

Bevacizumab is frequently used to treat recurrent high-grade gliomas, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in glioma models and may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat in combination with bevacizumab. Two cohorts were enrolled: one with recurrent glioblastoma (GBM) as the primary study and one with recurrent anaplastic glioma (AG) as the exploratory study. Patients received oral panobinostat 30 mg 3 x per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was PFS6 in the GBM cohort and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). At planned interim analysis, 13 of the first 21 patients accrued to the GBM cohort had progressed within 6 months of initiating study treatment. The GBM cohort did not meet criteria for continued accrual and was closed early. In the GBM cohort, PFS6 rate was 30.4%, median PFS 5 months, median OS 9 months. Accrual in the AG cohort continued to completion and a total of 15 patients were enrolled. In the AG cohort, PFS6 rate was 46.7%, median PFS 7 months, median OS 17 months. The most common grade 3 or 4 toxicities in the GBM arm were hypophosphatemia (12.5%), thrombocytopenia (12.5%), lymphopenia (8.3%), neutropenia (8.3%), and ALT elevation (8.3%). In the AG arm, the most common toxicities were thrombocytopenia (20.0%) and hypophosphatemia (13.3%). Although reasonably well-tolerated, this phase II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the GBM cohort of the study was closed. In the recurrent AG cohort, the PFS6 rate was similar to historical controls. Updated data will be presented.

BACKGROUND: Bevacizumab, a monoclonal antibody against VEGF-A, is approved for recurrent glioblastoma (GBM) but must be administered as an intravenous infusion twice a month. We designed a Phase II study of oral tivozanib, a VEGFR tyrosine kinase inhibitor, to determine if an oral substitute could be found. METHODS: A two-stage, Phase II study of tivozanib monotherapy was conducted in patients with recurrent GBM. Standard eligibility criteria were included and all patients had at least 1 cm of residual disease to assess radiographic tumor response. The primary endpoint was the proportion of patients progression-free at 6 months (PFS6). Secondary endpoints included median PFS, OS, toxicity, radiographic response (RR), and exploratory analyses of perfusion, permeability, diffusion MRI as well as blood biomarkers of angiogenesis. RESULTS: Ten patients were enrolled in stage 1 with a median age of 62 (51-73). Best MacDonald criteria responses were: CR (1), PR (1), SD (4), PD (4). By volume measurements, 8 patients exhibited a >20% decrease in tumor size. Median duration of response was 3.6 mo (1.7-3.8mo). One patient was taken off study for skin toxicity/fatigue and 8 patients were taken off study for PD. There were no patients progression-free at 6 months although 1 patient remains on treatment at 5 months. Since it was not possible to achieve the pre-specified PFS6 the study was terminated after stage 1. One patient experienced grade 3 hypertension probably related to tivozanib. Two of 4 patients who were on steroids at the start of treatment were able to decrease or discontinue steroids. CONCLUSION: Tivozanib was well tolerated but the PFS6 did not meet the pre-specified efficacy threshold for further analysis. Ongoing analysis of the correlative imaging (perfusion, diffusion, permeability) and blood biomarkers may shed light on why this oral VEGFR inhibitor was ineffective in this patient population.

BACKGROUND: This is a prospective study to evaluate potential treatment toxicity and progression free survival (PFS) of low grade glioma patients treated with proton radiation therapy. METHODS: Twenty WHO grade II glioma patients indicated for radiation therapy (8 new high risk diagnoses; 12 recurrent/progressive disease) were enrolled on a prospective single arm trial of proton therapy receiving 54 Gy(RBE) in 30 fractions. Comprehensive baseline and regular post treatment evaluations of neurocognitive function, neuroendocrine function, and quality of life (QOL) were performed. RESULTS: All 20 patients (median age 37.5 years) tolerated treatment without difficulty. Median follow up after proton therapy was 5.1 years. Baseline level of intellectual functioning on a standardized IQ measure was within the normal range for the group and remained stable over time. Performances in the cognitive domains of visuospatial ability, language function, attention/working memory, and processing speed were also in the normal range at baseline and did not decline over time. New endocrine dysfunction was detected in six patients and all but one had direct irradiation of the hypothalamic-pituitary axis. QOL assessment showed no change over time with the extended follow up. PFS at 3 years was 85% and at 5 years was 40%. CONCLUSIONS: Low grade glioma patients tolerate proton therapy well and a subset develops neuroendocrine deficiencies. There was no evidence for decline in cognitive function or QOL which may be partially attributable to reduced radiation dose to the normal brain by use of proton therapy. PFS was similar to that of photon based therapy.

Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O(6)-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance.This was a multicenter, phase 2, single-arm study of temozolomide (75-100 mg/m(2)/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6).Fifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25-79 years) and a median Karnofsky performance score of 90 (range, 60-100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2).Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.

The objectives of this study were to determine the safety and efficacy of polyinosinic-polycytidylic acid stabilized with poly-l-lysine and carboxymethylcellulose (poly-ICLC) when added to radiation and temozolomide (TMZ) in adults with newly diagnosed glioblastoma (GB). Patients received external beam radiation with concurrent TMZ (75 mg/m(2)/day) followed by adjuvant TMZ (150-200 mg/m(2)/day for 5 consecutive days once every 9 weeks) and intramuscular poly-ICLC (20 mg/kg/dose given 3× per week for weeks 2-8). An adjuvant cycle was operationally defined as 9 weeks and patients continued adjuvant therapy until toxicity or disease progression. Ninety-seven patients were enrolled (60 men) with a median age of 56 years (range 21-85) and Karnofsky performance status of 90% (range 60%-100%). Fourteen patients did not start adjuvant treatment. Common treatment-related Grade 3-4 toxicities included neutropenia (20.6%), leukopenia (16.5%), thrombocytopenia (9%), and rash (1%). The entire cohort had a median survival of 17.2 months (95% CI: 15.5-19.3 months) with survival at 12, 18, and 24 months of 73.2%, 47.4%, and 29.9%. For subjects 18-70 years old, median overall survival was 18.3 months (95% CI: 15.9-19.8 months), as compared with 14.6 (95% CI: 13.2-16.8) reported by the EORTC 26981/22981 trial. These results demonstrate that poly-ICLC can be added to standard radiation and TMZ in patients with newly diagnosed GB without additional significant toxicities. Survival data at 12 and 18 months suggest that this may improve the efficacy of chemoradiation and adjuvant TMZ in this patient population.