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Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship withEligible patients whose tumors screened positively forOf 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients withGSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Background Magnetic resonance spectroscopic imaging (MRSI) can be used in glioma patients to map the metabolic alterations associated with IDH1,2 mutations that are central criteria for glioma diagnosis. The aim of this study was to achieve super-resolution (SR) MRSI using deep learning to image tumor metabolism in patients with mutant IDH glioma. Methods We developed a deep learning method based on generative adversarial network (GAN) using Unet as generator network to upsample MRSI by a factor of 4. Neural networks were trained on simulated metabolic images from 75 glioma patients. The performance of deep neuronal networks was evaluated on MRSI data measured in 20 glioma patients and 10 healthy controls at 3T with a whole-brain 3D MRSI protocol optimized for detection of d-2-hydroxyglutarate (2HG). To further enhance structural details of metabolic maps we used prior information from high-resolution anatomical MR imaging. SR MRSI was compared to ground truth by Mann–Whitney U-test of peak signal-to-noise ratio (PSNR), structure similarity index measure (SSIM), feature-based similarity index measure (FSIM), and mean opinion score (MOS). Results Deep learning SR improved PSNR by 17%, SSIM by 5%, FSIM by 7%, and MOS by 30% compared to conventional interpolation methods. In mutant IDH glioma patients proposed method provided the highest resolution for 2HG maps to clearly delineate tumor margins and tumor heterogeneity. Conclusions Our results indicate that proposed deep learning methods are effective in enhancing spatial resolution of metabolite maps. Patient results suggest that this may have great clinical potential for image guided precision oncology therapy.

Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. Establishment of glioma-specific methylation patterns by mIDH1 reprogramming drives oncogenic features of cancer metabolism, stemness and therapeutic resistance. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1. Treatment of glioma cells with mIDH1 specific inhibitor AGI-5198, upregulated gene networks involved in replication stress. Specifically, we found that the expression of ZMYND8, a regulator of DNA damage response was decreased in three patient-derived glioma cell cultures (GCC) after treatment with AGI-5198. ZMYND8 functions as a chromatin reader to modulate enhancer activity and recruit DNA repair machinery. Knockdown of ZMYND8 expression sensitized mIDH1 GCCs to radiotherapy marked by decreased cellular viability. Following IR, mIDH1 glioma cells with ZMYND8 knockout (KO) exhibit significant phosphorylation of ATM and sustained γH2AX activation. ZMYND8 KO mIDH1 GCCs were further responsive to IR when treated with either BRD4 or HDAC inhibitors. The accumulation of DNA damage in ZMYND8 KO mIDH1 GCCs promoted the phosphorylation of cell cycle checkpoint proteins Chk1 and Chk2. In addition, the recruitment of ZMYND8 to sites of DNA damage has been shown to be PARP- dependent. PARP inhibition further enhanced the efficacy of radiotherapy in ZMYND8 KO mIDH1 glioma cells. These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma.Translational Relevance:Our understanding of radioresistance mechanisms in patient-derived glioma cell cultures (GCC) that endogenously express mIDH1-R132H are limited. We have uncovered a novel gene target Zinc Finger MYND-Type Containing 8 (ZMYND8) that is downregulated following treatment of human mIDH1 GCCs with mIDH1 specific inhibitors. We demonstrate that suppression of ZMYND8 expression by shRNA knockdown or genetic knockout reduces the cellular viability of mIDH1 GCCs to ionizing radiation (IR). Our findings reveal an epigenetic vulnerability of mIDH1 GCCs to ZMYND8 knockout (KO) which results in impaired resolution of IR-induced DNA damage and induction of cell cycle arrest. Additionally, ZMYND8 KO mIDH1 GCCs display increased radiosensitivity to inhibition of epigenetic regulators BRD4, HDAC, and PARP which could be mediated by enhanced replicative stress.

Adamantinomatous craniopharyngiomas (ACP) are characterized by alterations in the CTNNB1 gene while almost all papillary craniopharyngiomas (PCP) harbor a canonical V600E mutation in the BRAF gene. Although other recurrent driver genes have not been described to date in craniopharyngiomas, the heterogeneous clinical course of these tumors might be associated with the acquisition of further genomic alterations. It is well known that telomerase reverse transcriptase (TERT) promoter (TERTp) alterations, including mutations or methylation, upregulate the expression of TERT and increase telomerase activity, promoting tumorigenesis. We investigated whether TERTp mutations or methylation are associated with tumor relapse in a subset of craniopharyngiomas. Samples from 42 patients with histologically confirmed craniopharyngioma were retrieved. We determined TERTp, BRAF, and CTNNB1 hotspot mutations in all samples using targeted sequencing and the TERTp methylation status by methylation-specific polymerase chain reaction (PCR) in 30 samples. While BRAF V600E mutations and CTNNB1 mutations were detected in 12 (28.6%) and 21 patients (50%) in the initial tumors and subsequent recurrences, respectively, none of the patients in our cohort, including those with multiple relapses, harbored a TERTp mutation. Furthermore, TERTp methylation was detected in 14 out of 24 cases (58.3%) with available primary samples; however, no correlation between TERTp methylation with the pathological subtype, genotype, or tumor aggressiveness was detected. These data suggest that elevated telomerase activity via acquisition of TERTp mutations is an infrequent pathway in the tumorigenesis of craniopharyngiomas, regardless of their clinical course.

Surgical resection represents the standard of care in diffuse glioma, and more extensive tumour resection appears to be associated with favourable outcome. Up to now, terminology to describe extent of resection has been inconsistently applied across clinical trials which hampers comparative analysis of cohorts between different studies. Based on a comprehensive literature review, we developed evidence-based expert recommendations on categories for extent of resection. Recommendations are formulated for the categories ‘biopsy’, ‘partial resection’, ‘subtotal resection’, ‘near total resection’, ‘complete resection’ and ‘supramaximal resection’. Definitions rest on reduction of contrast- and non–contrast-enhancing tumour in glioblastoma, and on reduction of T2/FLAIR-hyperintense tumour in gliomas WHO grade 2 or 3. Both relative reduction of tumour volume (in percentage) as a measurement of surgical efficacy and absolute residual tumour volume (in cm3) as a measurement of remaining tumour burden are incorporated into the categories for extent of resection. Class of evidence for the proposed categories ranges from class IIB to IV. Limitations of the suggested categories are discussed. The proposed categories on extent of resection offer a framework to standardize nomenclature based on previous studies, and will need to be evaluated in prospective, molecularly well-defined cohorts. Our categories may eventually help as a stratification factor for future clinical trials.

Recent studies suggest that the cyclin-dependent kinase (CDK) pathway may be a therapeutic target for brain metastases (BM). Here, we present interim analysis of a basket trial evaluating the intracranial efficacy of the CDK inhibitor palbociclib in patients with progressive BM and CDK alterations. Our study met its primary endpoint and provides evidence for performing molecular testing of archival BM tissue, if available, to inform the choice of CNS-penetrant targeted therapy. Brastianos and colleagues report interim trial results on the intracranial clinical benefit of palbociclib for patients with progressive metastatic brain cancer carrying cyclin-dependent kinase pathway alterations.

Most clinical trials in neurooncology are led by investigators primarily trained in neurology or medical oncology. While neurosurgeons are trained to be problem-solvers and innovators, research training has historically been focused on laboratory-based discovery approaches and formalized training in prospective clinical trials research is not part of routine graduate training. We reviewed literature that demonstrates that innovation and problem-solving are integral to the practice of neurosurgery cite multiple examples of advances in technique and technology that may have had an empirical origin but that led to prospective clinical trials resulting in change in practice. Neurosurgeons have developed and led both traditional (clinical outcome-oriented) and translational prospective clinical trials that have evaluated the best use of currently available therapeutics or tested the ability of novel therapeutics to alter the biology and/or course of disease. In this review, we focus on a number of the recently developed technologies and therapeutics that were evaluated in clinical trials led or co-led by neurosurgeons. We also highlight some of the barriers that need to be addressed in order to foster neurosurgical participation and leadership in the prospective development of novel therapeutics.

The work of modern neurosurgical glioma practice combines securing accurate diagnoses, under the 2016 revised World Health Organization (WHO) Classification of Tumors of the Central Nervous System, with an aggressive and safe surgical pursuit of tumor removal. The evidence base that drives clinical decision-making has undergone a critical reevaluation with the incorporation of molecular classifiers into the updated WHO diagnoses including the 3 most common diffuse gliomas in adults: glioblastoma IDH wild-type, astrocytoma IDH mutant, and oligodendroglioma IDH mutant 1p/19q codeleted. The studies that form the foundation of modern practice, and the areas for future inquiry are reviewed.

Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein–Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease. Significance: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform.

Isocitrate Dehydrogenase 1/2 (IDH1/2) mutations are diagnostic for Astrocytoma or Oligodendroglioma, IDH-mutant. In these IDH-mutant gliomas, retinoic acid-related gene expression is commonly silenced by DNA hypermethylation. DNA demethylating agents can epigenetically reprogram IDH-mutant cells and reduce proliferation, likely by re-expression of silenced tumor suppressor pathways. We hypothesized that DNA demethylation might restore the retinoic acid pathway and slow tumor growth. This was the rationale for a preclinical evaluation combining the DNA demethylating agent, 5-Azacytidine (5-Aza), and retinoic acid pathway activation with all-trans retinoic acid (atRA) in IDH-mutant glioma.In this study, we evaluated the effect of 5-Aza and atRA combination on cell proliferation, apoptosis, and gene expression in human glioma cells. In addition, the efficacy of this combination was tested in patient-derived xenograft (PDX) bearing the IDH1R132H mutation, utilizing subcutaneous and orthotopic models.5-Aza reduced the DNA methylation profile and increased the gene expression of retinoic acid-related genes. Combination of 5-Aza and atRA reduced cell growth, increased differentiation marker expression, and apoptosis in IDH1R132H glioma cells. Mechanistically, 5-Aza sensitized IDHIR132H glioma cells to atRA via upregulation of the retinoic acid pathway. Importantly, the drug combination reduced significantly the growth rate of subcutaneous tumors, but in an orthotopic mouse model, the combination did not improve survival and 5-Aza alone provided the best survival benefit.Use of DNA demethylating agent in combination with retinoids shows promise, but further optimization and preclinical studies are required for treatment of intracranial IDH-mutant gliomas.

The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT). However, the potential impact of NAD+ depletion on the brain tumor microenvironment has not been elaborated. In addition, systemic toxicity of NAMPT inhibition remains a significant concern. Here we show that microparticle-mediated intratumoral delivery of NAMPT inhibitor GMX1778 induces specific immunologic changes in the tumor microenvironment of murine GBM, characterized by upregulation of immune checkpoint PD-L1, recruitment of CD3+, CD4+, and CD8+ T cells, and reduction of M2-polarized immunosuppressive macrophages. NAD+ depletion and autophagy induced by NAMPT inhibitors mediated the upregulation of PD-L1 transcripts and cell surface protein levels in GBM cells. NAMPT inhibitor modulation of the tumor immune microenvironment was therefore combined with PD-1 checkpoint blockade in vivo, significantly increasing the survival of GBM-bearing animals. Thus, the therapeutic impacts of NAMPT inhibition extended beyond neoplastic cells, shaping surrounding immune effectors. Microparticle delivery and release of NAMPT inhibitor at the tumor site offers a safe and robust means to alter an immune tumor microenvironment that could potentiate checkpoint immunotherapy for glioblastoma. Significance: Microparticle-mediated local inhibition of NAMPT modulates the tumor immune microenvironment and acts cooperatively with anti-PD-1 checkpoint blockade, offering a combination immunotherapy strategy for the treatment of GBM.

OBJECTIVEIntraoperative MRI (iMRI) is used in the surgical treatment of glioblastoma, with uncertain effects on outcomes. The authors evaluated the impact of iMRI on extent of resection (EOR) and overall survival (OS) while controlling for other known and suspected predictors.METHODSA multicenter retrospective cohort of 640 adult patients with newly diagnosed supratentorial glioblastoma who underwent resection was evaluated. iMRI was performed in 332/640 cases (51.9%). Reviews of MRI features and tumor volumetric analysis were performed on a subsample of cases (n = 286; 110 non-iMRI, 176 iMRI) from a single institution.RESULTSThe median age was 60.0 years (mean 58.5 years, range 20.5–86.3 years). The median OS was 17.0 months (95% CI 15.6–18.4 months). Gross-total resection (GTR) was achieved in 403/640 cases (63.0%). Kaplan-Meier analysis of 286 cases with volumetric analysis for EOR (grouped into 100%, 95%–99%, 80%–94%, and 50%–79%) showed longer OS for 100% EOR compared to all other groups (p < 0.01). Additional resection after iMRI was performed in 104/122 cases (85.2%) with initial subtotal resection (STR), leading to a 6.3% mean increase in EOR and a 2.2-cm3 mean decrease in tumor volume. For iMRI cases with volumetric analysis, the GTR rate increased from 54/176 (30.7%) on iMRI to 126/176 (71.5%) postoperatively. The EOR was significantly higher in the iMRI group for intended GTR and STR groups (p = 0.02 and p < 0.01, respectively). Predictors of GTR on multivariate logistic regression included iMRI use and intended GTR. Predictors of shorter OS on multivariate Cox regression included older age, STR, isocitrate dehydrogenase 1 (IDH1) wild type, no O6-methylguanine DNA methyltransferase (MGMT) methylation, and no Stupp therapy. iMRI was a significant predictor of OS on univariate (HR 0.82, 95% CI 0.69–0.98; p = 0.03) but not multivariate analyses. Use of iMRI was not associated with an increased rate of new permanent neurological deficits.CONCLUSIONSGTR increased OS for patients with newly diagnosed glioblastoma after adjusting for other prognostic factors. iMRI increased EOR and GTR rate and was a significant predictor of GTR on multivariate analysis; however, iMRI was not an independent predictor of OS. Additional supporting evidence is needed to determine the clinical benefit of iMRI in the management of glioblastoma.

Background Decitabine (DAC) is an FDA-approved DNA methyltransferase (DNMT) inhibitor that is used in the treatment of patients with myelodysplastic syndromes. Previously, we showed that DAC marks antitumor activity against gliomas with isocitrate dehydrogenase 1 (IDH1) mutations. Based on promising preclinical results, a clinical trial has been launched to determine the effect of DAC in IDH-mutant gliomas. The next step is to comprehensively assess the efficacy and potential determinants of response to DAC in malignant gliomas. Methods The expression and activity of telomerase reverse transcriptase (TERT) and DNMT1 were manipulated in patient-derived IDH1-mutant and -wildtype glioma lines, followed by assessment of cell proliferation with DAC treatment alone or in combination with telomerase inhibitors. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and correlation analysis were performed. Results IDH1-mutant glioma tumorspheres with hemizygous codeletion of chromosome arms 1p/19q were particularly sensitive to DAC and showed significant inhibition of DNA replication genes. Our transcriptome analysis revealed that DAC induced expression of cyclin-dependent kinase inhibitor 1A/p21 (CDKN1A), along with downregulation of TERT. These molecular changes were also observed following doxorubicin treatment, supporting the importance of DAC-induced DNA damage in contributing to this effect. We demonstrated that knockdown of p21 led to TERT upregulation. Strikingly, TERT overexpression increased DNMT1 levels and DAC sensitivity via a telomerase-independent mechanism. Furthermore, RNA inhibition (RNAi) targeting of DNMT1 abrogated DAC response in TERT-proficient glioma cells. Conclusions DAC downregulates TERT through p21 induction. Our data point to TERT and DNMT1 levels as potential determinants of response to DAC treatment.

Metabolic imaging of the human brain by in-vivo magnetic resonance spectroscopic imaging (MRSI) can non-invasively probe neurochemistry in healthy and disease conditions. MRSI at ultra-high field (≥ 7 T) provides increased sensitivity for fast high-resolution metabolic imaging, but comes with technical challenges due to non-uniform B0 field. Here, we show that an integrated RF-receive/B0-shim (AC/DC) array coil can be used to mitigate 7 T B0 inhomogeneity, which improves spectral quality and metabolite quantification over a whole-brain slab. Our results from simulations, phantoms, healthy and brain tumor human subjects indicate improvements of global B0 homogeneity by 55%, narrower spectral linewidth by 29%, higher signal-to-noise ratio by 31%, more precise metabolite quantification by 22%, and an increase by 21% of the brain volume that can be reliably analyzed. AC/DC shimming provide the highest correlation (R2 = 0.98, P = 0.001) with ground-truth values for metabolite concentration. Clinical translation of AC/DC and MRSI is demonstrated in a patient with mutant-IDH1 glioma where it enables imaging of D-2-hydroxyglutarate oncometabolite with a 2.8-fold increase in contrast-to-noise ratio at higher resolution and more brain coverage compared to previous 7 T studies. Hence, AC/DC technology may help ultra-high field MRSI become more feasible to take advantage of higher signal/contrast-to-noise in clinical applications.

BACKGROUND Few studies use large, multi-institutional patient cohorts to examine the role of intraoperative magnetic resonance imaging (iMRI) in the resection of grade II gliomas. OBJECTIVE To assess the impact of iMRI and other factors on overall survival (OS) and progression-free survival (PFS) for newly diagnosed grade II astrocytomas and oligodendrogliomas. METHODS Retrospective analyses of a multicenter database assessed the impact of patient-, treatment-, and tumor-related factors on OS and PFS. RESULTS A total of 232 resections (112 astrocytomas and 120 oligodendrogliomas) were analyzed. Oligodendrogliomas had longer OS (P

Background Isocitrate dehydrogenase (IDH)–mutant tumors exhibit an altered metabolic state and are critically dependent upon nicotinamide adenine dinucleotide (NAD+) for cellular survival. NAD+ steady-state levels can be influenced by both biosynthetic and consumptive processes. Here, we investigated activation of sirtuin (SIRT) enzymes, which consume NAD+ as a coenzyme, as a potential mechanism to reduce cellular NAD+ levels in these tumors. Methods The effect of inhibition or activation of sirtuin activity, using (i) small molecules, (ii) clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 gene editing, and (iii) inducible overexpression, was investigated in IDH-mutant tumor lines, including patient-derived IDH-mutant glioma lines. Results We found that Sirt1 activation led to marked augmentation of NAD+ depletion and accentuation of cytotoxicity when combined with inhibition of nicotinamide phosphoribosyltransferase (NAMPT), consistent with the enzymatic activity of SIRT1 as a primary cellular NAD+ consumer in IDH-mutant cells. Activation of Sirt1 through either genetic overexpression or pharmacologic Sirt1-activating compounds (STACs), an existing class of well-tolerated drugs, led to inhibition of IDH1-mutant tumor cell growth. Conclusions Activation of Sirt1 can selectively target IDH-mutant tumors. These findings indicate that relatively nontoxic STACs, administered either alone or in combination with NAMPT inhibition, could alter the growth trajectory of IDH-mutant gliomas while minimizing toxicity associated with cytotoxic chemotherapeutic regimens.

Treatment of recurrent gliomas is especially challenging, as many of these patients have previously been treated with extensive surgery, radiation, or systemic therapy. Due to this, the optimum therapy for patients with recurrent glioma is controversial, with widely variable practice patterns. In this opinion piece, a multidisciplinary panel of experts provides rationale for their treatment approach in a patient with recurrent glioma following subtotal resection with adjuvant chemoradiation for an anaplastic astrocytoma. In summary, the consensus of the panel was to recommend re-resection if possible with hypofractionated radiotherapy schedules, with re-irradiation and systemic therapy as directed by a multidisciplinary team through repeat analysis of the tumor specimen for an updated mutational burden.

An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1–3. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients—17 with breast cancer, two with lung cancer and one with ovarian cancer—were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2–12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39–0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab. In a phase 2 clinical trial cohort of patients with leptomeningeal disease, anti-PD-1 monotherapy was safe and associated with a 3-month overall survival of 60%.

Purpose: Emergence of mismatch repair (MMR) deficiency is a frequent mechanism of acquired resistance to the alkylating chemotherapeutic temozolomide (TMZ) in gliomas. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been shown to potentiate TMZ cytotoxicity in several cancer types, including gliomas. We tested whether PARP inhibition could re-sensitize MSH6-null MMR-deficient gliomas to TMZ, and assessed the role of the base excision repair (BER) DNA damage repair pathway in PARPi-mediated effects. Experimental Design: Isogenic pairs of MSH6 wild-type and MSH6-inactivated human glioblastoma (GBM) cells (including both IDH1/2 wild-type and IDH1 mutant), as well as MSH6-null cells derived from a patient with recurrent GBM were treated with TMZ, the PARPi veliparib or olaparib, and combination thereof. Efficacy of PARPi combined with TMZ was assessed in vivo. We used genetic and pharmacological approaches to dissect the contribution of BER. Results: While having no detectable effect in MSH6 wild-type GBMs, PARPi selectively restored TMZ sensitivity in MSH6-deficient GBM cells. This genotype-specific restoration of activity translated in vivo, where combination treatment of veliparib and TMZ showed potent suppression of tumor growth of MSH6-inactivated orthotopic xenografts, compared with TMZ monotherapy. Unlike PARPi, genetic and pharmacological blockage of BER pathway did not re-sensitize MSH6-inactivated GBM cells to TMZ. Similarly, CRISPR PARP1 knockout did not re-sensitize MSH6-inactivated GBM cells to TMZ. Conclusions: PARPi restoration of TMZ chemosensitivity in MSH6-inactivated glioma represents a promising strategy to overcome acquired chemoresistance caused by MMR deficiency. Mechanistically, this PARPi-mediated synthetic phenotype was independent of BER blockage and was not recapitulated by loss of PARP1.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

BackgroundTERT gene alterations (TERT-alt) have been linked to increased risk of recurrence in meningiomas, whereas the association to mortality largely remain incompletely investigated. As incongruence between clinical course and WHO grade exists, reliable biomarkers have been sought.MethodsWe applied the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data Statement. We compiled data from eight studies and allocated patients to TERT-alt (n=59) or TERT promoter wild-type (TERTp-wt; n=618). We compared the two groups stratified for WHO grades as: incidence rates, survival probabilities and cumulative recurrences. We estimated the effects of WHO grade, age at diagnosis and sex as HRs.ResultsTERT-alt occurred in 4.7%, 7.9% and 15.4% of WHO-I/WHO-II/WHO-III meningiomas, respectively. The median recurrence-free survival was 14 months for all TERT-alt patients versus 101 months for all TERTp-wt patients. The HR for TERT-alt was 3.74 in reference to TERTp-wt. For all TERT-alt patients versus all TERTp-wt patients, the median overall survival was 58 months and 160 months, respectively. The HR for TERT-alt was 2.77 compared with TERTp-wt. TERT-alt affected prognosis independent of WHO grades. Particularly, the recurrence rate was 4.8 times higher in WHO-I/-II TERT-alt patients compared with WHO-III TERTp-wt patients. The mortality rate was 2.7 times higher in the WHO-I and WHO-II TERT-alt patients compared with WHO-III TERTp-wt patients.ConclusionsTERT-alt is an important biomarker for significantly higher risk of recurrence and death in meningiomas. TERT-alt should be managed and surveilled aggressively. We propose that TERT-alt analysis should be implemented as a routine diagnostic test in meningioma and integrated into the WHO classification.Trial registration numberPROSPERO: CRD42018110566.

BACKGROUND: Absolute quantification of metabolites in MR spectroscopic imaging (MRSI) requires a stable reference signal of known concentration. The Electronic REference To access In vivo Concentrations (ERETIC) has shown great promise but has not been applied in patients and 3D MRSI. ERETIC hardware has not been integrated with receive arrays due to technical challenges, such as coil combination and unwanted coupling between multiple ERETIC and receive channels, for which we developed mitigation strategies. PURPOSE: To develop absolute quantification for whole-brain MRSI in glioma patients. STUDY TYPE: Prospective. POPULATION: Five healthy volunteers and three patients with isocitrate dehydrogenase mutant glioma (27% female). Calibration and coil loading phantoms. FIELD STRENGTH/SEQUENCE: A 3T; Adiabatic spin-echo spiral 3D MRSI with real-time motion correction, Fluid Attenuated Inversion Recovery (FLAIR), Gradient Recalled Echo (GRE), Multi-echo Magnetization Prepared Rapid Acquisition of Gradient Echo (MEMPRAGE). ASSESSMENT: Absolute quantification was performed for five brain metabolites (total N-acetyl-aspartate [NAA]/creatine/choline, glutamine + glutamate, myoinositol) and the oncometabolite 2-hydroxyglutarate using a custom-built 4x-ERETIC/8x-receive array coil. Metabolite quantification was performed with both EREIC and internal water reference methods. ERETIC signal was transmitted via optical link and used to correct coil loading. Inductive and radiative coupling between ERETIC and receive channels were measured. STATISTICAL TESTS: ERETIC and internal water methods for metabolite quantification were compared using Bland–Altman (BA) analysis and the nonparametric Mann–Whitney test. P < 0.05 was considered statistically significant. RESULTS: ERETIC could be integrated in receive arrays and inductive coupling dominated (5–886 times) radiative coupling. Phantoms show proportional scaling of the ERETIC signal with coil loading. The BA analysis demonstrated very good agreement (3.3% ± 1.6%) in healthy volunteers, while there was a large difference (36.1% ± 3.8%) in glioma tumors between metabolite concentrations by ERETIC and internal water quantification. CONCLUSION: Our results indicate that ERETIC integrated with receive arrays and whole-brain MRSI is feasible for brain metabolites quantification. Further validation is required to probe that ERETIC provides more accurate metabolite concentration in glioma patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1

SUMMARYMutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they appear less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1 mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH mutant gliomas. Mechanistically, this vulnerability selectively applies to de novo pyrimidine, but not purine, synthesis because glioma cells engage disparate programs to produce these nucleotide species and because IDH oncogenes increase DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.

SummaryRecent data showed promising signs of objective tumor responses in subsets of patients with low grade glioma treated with inhibitors of mutant IDH (IDHi) (1). However, the molecular and cellular underpinnings of such responses are not known. Here, we profiled 6,039 transcriptomes by single-cell or single-nucleus RNA-sequencing isolated from three IDH-mutant oligodendroglioma patients with clinical response to IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation and our dataset includes a matched pre- and on-treatment sample pair. We integrate our findings with analysis of 8,241 transcriptomes from seven untreated samples, 134 bulk samples from the TCGA and experimental models.(2,3) We find that IDHi treatment induces a robust differentiation towards glial lineages, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Our study provides the first evidence in patients of the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas.

INTRODUCTION High-grade meningiomas are associated with significant neuro-cognitive morbidity and a poor prognosis. Systemic therapies, to date, have demonstrated minimal efficacy. We recently found that high-grade meningiomas harbor an immunosuppressive tumor microenvironment and that programmed cell death-ligand 1 (PD-L1) expression may contribute to the aggressive phenotype of these tumors. Therefore, we conducted a single-arm, open-label phase II trial evaluating efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 24 patients with recurrent and progressive grade II and III meningiomas. METHODS The primary endpoint was the rate of progression-free survival at 6 months. The trial distinguished between 6-month PFS (PFS-6) rates of 26% vs. 52%. If at least 10 patients demonstrated a 6-month PFS, among the 24 patients, the agent would be considered worthy of further study. This design has at least 88% power using an exact binomial test with a one-sided significance level of 0.1. RESULTS Between November 2017 to December 2019, twenty-four patients were enrolled. The majority of the patients in our cohort were heavily pre-treated; prior to enrolling to the study, twenty patients underwent more than one surgical resection and twelve patients had received more than one round of radiotherapy. Our study met its primary endpoint and achieved a 6-month progression-free survival rate of 0.50 (90% exact CI: 0.32-0.68) and a median PFS of 8.3 months (90% CI: 4.1-12.9 months). For the twelve patients who achieved the PFS-6 primary endpoint, median PFS from the start of treatment was 17.3 months (90% CI: 9.7 – 24.3 months). Four patients had grade-3 or higher adverse events that were at least possibly treatment-related, including colitis, skin infection, encephalopathy and transaminitis. CONCLUSION Our study achieved its primary endpoint. These results suggest that pembrolizumab exerts promising activity on these tumors and results in prolonged PFS compared to historical controls.

Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressively and lead to untimely death. Recurrent IDH mutant tumors are less responsive to conventional treatments, highlighting the need for improved therapeutic strategies at this stage of the disease. At least 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, which results in aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors, which are approved for use in a variety of other cancer types. We examined the relationship between CDK4/6 inhibitor sensitivity and CDKN2A loss using patient-derived models of IDH mutant glioma with endogenous CDKN2A homozygous deletion as well as with CRIPSR-mediated gene deletion. We observed enhanced cytotoxicity in glioma models with CDKN2A loss in vitro. Studies to examine the efficacy of CDK4/6 inhibitor treatment on slowing tumor growth in patient-derived xenograft models are ongoing. These preclinical results provide foundational data for design of a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.

Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.

Leptomeningeal metastasis (LMD) is a late complication of cancer with poor prognosis and median survival of approximately 4-6 weeks without treatment. Whole brain radiation remains the mainstay of treatment, however it can cause significant neurocognitive sequelae and has not been shown to prolong overall survival. Thus, new treatment strategies are urgently needed to improve outcomes in patients with LMD. Results from recent Phase 2 studies of immune checkpoint inhibitors in LMD shows promising improvement in overall survival. Combining anti-VEGF therapy and immunotherapy may control symptoms due to inflammation and tumor-induced irritation, minimize steroid use, and promote improved efficacy of immunotherapy through modulation of the tumor immune microenvironment. We designed a multi-institutional, single-arm Phase 2 study of pembrolizumab in combination with lenvatinib in patients with LMD from any solid tumor. The primary objective is to estimate the overall survival rate at 6 months (OS6). A Simon two-stage design with a total sample size of 19 evaluable patients will be used to compare a null hypothesis of OS6 of 25% against an alternative hypothesis of 55%. Secondary objectives include assessing safety of pembrolizumab and lenvatinib in this patient population, systemic response rate, intracranial/intraspinal response rate, and progression-free survival. We will also explore clinician-reported neurologic outcomes and patient-reported quality of life and symptom burden. Blood, cerebrospinal fluid, and tissue biomarkers will be analyzed to determine predictors of response. Patients must be on minimal doses of steroids prior to study enrollment and cannot have received prior immune checkpoint inhibitor or anti-VEGF therapy. Response to treatment will be determined using RANO-BM for intracranial disease and RECIST 1.1 for systemic disease. Study accrual is anticipated over 12-24 months with anticipated total study duration of 30 months.

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results., Leptomeningeal metastases from solid tumors are a rare complication with a very poor prognosis. Here the authors report the efficacy and safety of combined ipilimumab and nivolumab in patients with leptomeningeal carcinomatosis.

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research., Leptomeningeal disease (LMD) is a serious complication of metastatic solid tumors with a poor prognosis. Here, by using single-cell RNA sequencing of cerebrospinal fluid, the authors report genomic and immune correlates of response to immunotherapy in two cohorts of patients with LMD treated with immune checkpoint inhibitors.

MR spectroscopic imaging (MRSI) noninvasively maps the metabolism of human brains. In particular, the imaging of D-2-hydroxyglutarate (2HG) produced by glioma isocitrate dehydrogenase (IDH) mutations has become a key application in neuro-oncology. However, the performance of full field-of-view MRSI is limited by B0 spatial nonuniformity and lipid artifacts from tissues surrounding the brain. Array coils that multiplex RF-receive and B0 -shim electrical currents (AC/DC mixing) over the same conductive loops provide many degrees of freedom to improve B0 uniformity and reduce lipid artifacts. AC/DC coils are highly efficient due to compact design, requiring low shim currents (

TERT promoter mutations have been associated with increased risk of recurrence in meningioma cohorts, thus a potential biomarker for aggressive phenotypes. A main purpose of refining tumour classification is better predictions on the patient level. We compiled data from previous published cohorts to investigate patient-level predictions of recurrence based on TERTp-mut status. Implementation of TERTp-mut into the WHO grading led to better patient prognostication by improved prediction of recurrence. Our results support implementation of TERTp-mut into diagnostics and classification of meningiomas.

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need due to central nervous system (CNS) progression as a frequent, end-stage site of disease. Immune checkpoint inhibition (ICI) represents a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique MBM-TME elements and correlates of MBM-ICI response, we collected 32 fresh MBM and performed single cell RNA sequencing of the MBM-TME and T cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity, most notably multiple distinct neutrophil states including an IL-8 expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. Additionally, we observe significant relationships between intracranial T cell phenotypes and the distribution of T cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data demonstrate unique features of the MBM-TME, which may represent potential targets to improve clinical outcomes for patients with MBM.

MR spectroscopic imaging (MRSI) noninvasively maps the metabolism of human brains. In particular, the imaging of D-2-hydroxyglutarate (2HG) produced by glioma isocitrate dehydrogenase (IDH) mutations has become a key application in neuro-oncology. However, the performance of full field-of-view MRSI is limited by B(0) spatial nonuniformity and lipid artifacts from tissues surrounding the brain. Array coils that multiplex RF-receive and B(0)-shim electrical currents (AC/DC mixing) over the same conductive loops provide many degrees of freedom to improve B(0) uniformity and reduce lipid artifacts. AC/DC coils are highly efficient due to compact design, requiring low shim currents (

High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31–0.66) and a median PFS of 7.6 months (90% CI: 3.4–12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.

Key Points Question Can cell-free DNA analysis of cerebrospinal fluid provide additional diagnostic utility beyond cytologic assessment? Findings In this diagnostic study of 43 cerebrospinal fluid samples from 22 patients with leptomeningeal disease confirmed by cytologic assessment who did not have parenchymal tumors abutting their cerebrospinal fluid, tumor-derived cell-free DNA was detected in the cerebrospinal fluid of 40 (93%) samples, whereas 31 (72%) of the samples were positive for malignant neoplasm as determined by cytologic analysis, a significant difference. Meaning These findings suggest that cerebrospinal fluid cell-free DNA analysis may be more sensitive than cytologic analysis for diagnosing leptomeningeal disease., Importance Leptomeningeal disease (LMD) is a devastating complication of cancer that is frequently underdiagnosed owing to the low sensitivity of cerebrospinal fluid (CSF) cytologic assessment, the current benchmark diagnostic method. Improving diagnostic sensitivity may lead to improved treatment decisions. Objective To assess whether cell-free DNA (cfDNA) analysis of CSF may be used to diagnose LMD more accurately than cytologic analysis. Design, Setting, and Participants This diagnostic study conducted in a neuro-oncology clinic at 2 large, tertiary medical centers assessed the use of genomic sequencing of CSF samples obtained from 30 patients with suspected or confirmed LMD from 2015 through 2018 to identify tumor-derived cfDNA. From the same CSF samples, cytologic analyses were conducted, and the results of the 2 tests were compared. This study consisted of 2 patient populations: 22 patients with cytologically confirmed LMD without parenchymal tumors abutting their CSF and 8 patients with parenchymal brain metastases with no evidence of LMD. Patients were considered positive for the presence of LMD if previous CSF cytologic analysis was positive for malignant cells. The analysis was conducted from 2015 to 2018. Main Outcomes and Measures The primary outcome was the diagnostic accuracy of cfDNA analysis, defined as the number of tests that resulted in correct diagnoses out of the total number of tests assayed. Hypotheses were formed before data collection. Results In total, 30 patients (23 women [77%]; median age, 51 years [range, 28-81 years]), primarily presenting with metastatic solid malignant neoplasms, participated in this study. For 48 follow-up samples from patients previously diagnosed via cytologic analysis as having LMD with no parenchymal tumor abutting CSF, cfDNA findings were accurate in the assessment of LMD in 45 samples (94%; 95% CI, 83%-99%), whereas cytologic analysis was accurate in 36 samples (75%; 95% CI, 60%-86%), a significant difference (P = .02). Of 43 LMD-positive samples, CSF cfDNA analysis was sensitive to LMD in 40 samples (93%; 95% CI, 81%-99%), and cytologic analysis was sensitive to LMD in 31 samples (72%; 95% CI, 56%-85%), a significant difference (P = .02). For 3 patients with parenchymal brain metastases abutting the CSF and no suspicion of LMD, cytologic findings were negative for LMD in all 3 patients, whereas cfDNA findings were positive in all 3 patients. Conclusions and Relevance This diagnostic study found improved sensitivity and accuracy of cfDNA CSF testing vs cytologic assessment for diagnosing LMD with the exception of parenchymal tumors abutting CSF, suggesting improved ability to diagnosis LMD. Consideration of incorporating CSF cfDNA analysis into clinical care is warranted., This diagnostic study compares the sensitivity and accuracy for detecting leptomeningeal disease via genomic sequencing of cell-free DNA with that of cytologic assessment of cerebrospinal fluid obtained from patients with suspected or cytologically confirmed leptomeningeal disease.

No systemic treatment has been established for meningioma progressing after local therapies.This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses.Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS.Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.

Chimeric antigen receptor (CAR)-T-cell therapy for solid tumors is limited due to heterogeneous target antigen expression and outgrowth of tumors lacking the antigen targeted by CAR-T cells directed against single antigens. Here, we developed a bicistronic construct to drive expression of a CAR specific for EGFRvIII, a glioblastoma-specific tumor antigen, and a bispecific T-cell engager (BiTE) against EGFR, an antigen frequently overexpressed in glioblastoma but also expressed in normal tissues. CART.BiTE cells secreted EGFR-specific BiTEs that redirect CAR-T cells and recruit untransduced bystander T cells against wild-type EGFR. EGFRvIII-specific CAR-T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive glioblastoma. However, CART.BiTE cells eliminated heterogenous tumors in mouse models of glioblastoma. BiTE-EGFR was locally effective but was not detected systemically after intracranial delivery of CART.BiTE cells. Unlike EGFR-specific CAR-T cells, CART.BiTE cells did not result in toxicity against human skin grafts in vivo.

Papillary craniopharyngiomas (PCPs) are characterized by the presence of BRAF V600E mutations, which are emerging as a useful guide for diagnosis and treatment decision making. The ongoing multicenter phase 2 Alliance A071601 trial is evaluating the efficacy of BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors for patients with PCPs. With continued successful responses, it is proposed that BRAF (and MEK) inhibitors be evaluated for the neoadjuvant treatment of patients with PCPs.

Purpose: Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression. Experimental Design: Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo. Results: A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1R132H and 1p/19q codeletion) and PIK3CAE542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo—evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma. Conclusions: Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.

High-grade meningiomas (HGMs; World Health Organization [WHO] classification grade II and III) have high relapse rates and poor clinical outcomes despite surgery and radiation treatments. No effective medical therapy currently exists for HGMs, and developing novel therapeutic strategies depends on the identification of molecular drivers. In cancer, β1 integrin enhances malignant characteristics, including proliferation, invasion, and drug resistance. We conducted this study to investigate whether β1 integrin could be a therapeutic target in HGMs. Expression of β1 integrin was examined in gene array datasets, with proteomics of clinical meningioma specimens, and in patient-derived HGM xenografts. Anti-tumor activity of OS2966, a first-in-class humanized antagonizing monoclonal antibody against β1 integrin, was tested in vitro and in vivo using an orthotopic mouse model of patient-derived malignant meningioma. β1 integrin was expressed in meningiomas of all WHO grades and two xenografts tested. In vitro, OS2966 suppressed the viability of NF2-deficient MN3 sphere cells and NF2-wild-type IOMM-Lee malignant meningioma cells only when plated on laminin-coated plastic. While OS2966 decreased phosphorylation of ERK1/2 in both MN3 cells and laminin-grown IOMM-Lee cells, OS2966 only affected the phosphorylation of FAK (Tyr397) in MN3, and of Akt (Ser473) in IOMM-Lee cells, respectively, indicating differential pathway inhibition. Systemic administration of OS2966 in mice bearing orthotopic MN3 HGMs inhibited HGM cell proliferation and significantly extended overall survival of the treated mice. β1 Integrin may be a therapeutic target in HGMs, and further preclinical and clinical development of OS2966 for HGM therapy is warranted.

Following the identification of key molecular alterations that provided superior prognostication and led to the updated 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification, the understanding of glioma behavior has rapidly evolved. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are present in the majority of adult grade 2 and 3 gliomas, and when used in conjunction with 1p/19q codeletion for classification, the prognostic distinction between grade 2 versus grade 3 is diminished. As such, the previously often used term of “low-grade glioma,” which referred to grade 2 gliomas, has now been replaced by the phrase “lower-grade glioma” to encompass both grade 2 and 3 tumors. Additional molecular characterization is ongoing to even further classify this heterogeneous group of tumors. With such a colossal shift in the understanding of lower-grade gliomas, management of disease is being redefined in the setting of emerging molecular-genetic biomarkers. In this article, we review recent progress and future directions regarding the surgical, radiotherapeutic, chemotherapeutic, and long-term management of adult lower-grade gliomas.