AbstractPrognosis of patients diagnosed with IDHwt glioblastoma is influenced by known clinical and demographic factors, and likely by physiological characteristics. Our goal is to determine tumor-intrinsic gene expression signatures associated with aggressive tumor growth in patient-derived xenografts (PDXs). Cancer stem cell (CSC) lines established from 10 IDHwt glioblastoma tumors were implanted orthotopically in cohorts of 10 to 15 nude mice (3x10E5 viable cells/mouse), for development of PDX...
Mon Nov 11, 2019 02:00
AbstractPURPOSECombined surgical strategy with both trans-cranial surgery and trans-sphenoid surgery is necessary for selected giant pituitary adenoma with both intra-cranial and intra-sphenoidal invasion. Cases of staged surgery were reviewed retrospectively to deeply investigate this treatment strategy. METHODSAdult cases received staged surgery were reviewed. Data regarding clinical presentation, laboratory tests, image examination, surgery details, and outcome were analyzed. The size and invasion...
Mon Nov 11, 2019 02:00
AbstractGlioblastoma (GBM) is the most common and malignant adult brain tumor. Despite years of research, few advancements have been made in its management. One promising avenue of research has been treatment with BRD4 inhibitors, which decrease oncogene expression in GBM cells. However, resistance to these inhibitors is rapidly acquired. Kinome reprogramming is thought to underlie this resistance, suggesting a need for combination therapy with kinase inhibitors. The goal of this study is to determine...
Mon Nov 11, 2019 02:00
AbstractGlioblastoma (GBM), the deadliest and most common adult brain malignancy, is molecularly and clinically heterogeneous. The most common subtype (both primary and recurrent), mesenchymal (MES)-GBM, has the worst prognosis and highest treatment resistance. MES-GBM exhibits hyperactive transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in GBMs predicts short survival. Yet, how Hippo-TAZ dysregulation might drive GBM MES transition...
Mon Nov 11, 2019 02:00
AbstractLow-grade gliomas (LGGs), which include grade II astrocytoma and grade II oligodendroglioma, inevitably recur despite aggressive treatment with surgery, and sometimes, with radiation and the chemotherapeutic agent temozolomide (TMZ). The clinical benefit of TMZ in LGG is unclear, and a subset of TMZ-treated LGGs recur with hypermutation in association with malignant progression to high-grade tumors. It is currently unknown why some TMZ-treated LGGs recur with hypermutation while others do...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONImmunotherapy with engineered CAR T cells is a promising new therapy for glioblastoma, for which predictive and prognostic biomarkers are needed to inform effective intervention. Recently, our group analyzed standard-of-care (SOC) MRI images of long-term and short-term glioblastoma survivors and identified six intratumoral “habitats” of which “Habitat 6” was correlated with survival at diagnosis in high-grade glioma. Based on the MRI characteristics of “Habitat 6”, viz. high enhancement...
Mon Nov 11, 2019 02:00
AbstractGlioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of only 15 months with standard of care treatment. Lacunarity, a quantitative morphological measure of how shapes fill space, and fractal dimension, another morphological measure of the complexity of pixel arrangement, of segmented necrotic regions on gadolinium-enhanced T1 weighted (T1gd) MRI have previously been shown to distinguish both overall survival (OS) and progression free survival (PFS) in GBM (n...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDCerebral radiation necrosis (RN) is a critical complication of radiotherapy for brain tumors. Treatment with corticosteroids provides suboptimal symptom relief, and may have considerable side effects. Small-scale studies support the use of bevacizumab, but systematic data from clinical practice on its efficacy and toxicity remain scarce. METHODSIn this retrospective cohort study, we included consecutive patients with symptomatic RN that underwent treatment with bevacizumab in our...
Mon Nov 11, 2019 02:00
AbstractAnywhere from 30–70% of osseous metastatic disease occurs in the spine across many different tumor types. These metastases lead to debilitating pain and neurologic dysfunction significantly reducing patients’ quality of life. Unfortunately, the cause of preferential metastatic growth to the spine is not understood. The purpose of this study was to identify the role of NCOR1 and NCOR2/SMRT, genes included in Cancer Gene Census (https://cancer.sanger.ac.uk/cosmic), in the promotion of metastatic...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDGlioblastoma (GBM) patient survival and therapy response is greatly hindered by the presence of invasive glioma stem cells (GSC) and the blood-brain barrier (BBB) which limits effective drug delivery. WNT/beta-catenin signaling is important in the development and maintenance of the BBB by mediating transcription of growth factors, multidrug resistance proteins, and junctional proteins. In WNT-subtype medulloblastoma, activating mutations of beta-catenin lead to reciprocal secretion...
Mon Nov 11, 2019 02:00
AbstractAtypical teratoid/rhabdoid tumors (AT/RTs) are rare pediatric brain tumors affecting mainly infants and young children. However, AT/RTs encompass almost 10% of death caused by pediatric brain tumors, and the 2-year overall survival for these children remains below 20%. For this reason, AT/RT ranks among the deadliest pediatric brain tumors. Therefore, it is clear we need to find out new therapeutic options for these children. Delta-24-RGD oncolytic adenovirus has already demonstrated its...
Mon Nov 11, 2019 02:00
AbstractWhile diffuse gliomas are notorious for their histopathological, genetic and transcriptional spatial heterogeneity, little is known about their epigenetic spatial heterogeneity. The result of spatial (epi)genetic analysis is strongly influenced by the proportion of cancer cells in a sample, so called tumor purity. However, a gold standard for assessment of tumor purity is lacking. We set out to analyze tumor purity using different measurement modalities and explore tumor purity-corrected...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDWomen ages 35–44 have three-fold higher risk of meningioma compared to men. Epidemiologic studies have implicated exogenous hormone use, but endogenous hormonal factors are inconsistently associated. Elevated body mass index (BMI) is consistently associated with meningioma risk in both men and women, and personal history of breast cancer has also been associated with meningioma risk. Recent genome-wide association studies (GWAS) have identified a meningioma risk locus on chromosome...
Mon Nov 11, 2019 02:00
AbstractBACKGROUND & SIGNIFICANCECancer is a disease in 3-dimensions and there is a desperate need for infrastructure and models to study immuno-oncology treatment strategies in 3D. A new culture system for long-duration maturation of patient derived microtumors has been developed. This system enables in situconfocal imaging and movies of T-cells and tumor model interactions, including measurements of T-cell migration, infiltration, and killing. HYPOTHESIS: Biofabrication of 3D microtumors using...
Mon Nov 11, 2019 02:00
AbstractEmbryonal tumors with multi-layered rosettes (ETMR) are aggressive brain cancers with characteristic C19MC oncomiR amplification and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a potent C19MC-LIN28A-MYCN circuitry driven by multiple regulatory loops and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. C19MC and LIN28A targets respectively converge on critical cell cycle tumor suppressors and...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONWhile immunotherapy through anti-PD1 checkpoint inhibition has demonstrated impressive clinical efficacy against a number of tumor types, its application has been ineffective against glioblastomas. METHODSWe wished to determine whether high intensity focused ultrasound (HIFU) augment the efficacy of anti-PD1 checkpoint inhibition against glioblastomas. HIFU can be surgically administered through low-duty cycle to induce subcellular fragmentation without causing temperature elevation...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONThe new understanding of molecular pathways in cancer is paving the way towards personalized cancer medicine, especially in refractory disease. High-grade gliomas (HGG) are common pediatric brain tumors that tend to recur, with no available standard therapy upon recurrence. HGG are challenging tumors with illusive biology and poor outcome. We report here the molecular testing of 27 pediatric HGG patients. MATERIALS AND METHODSAn analysis of pediatric patients with HGG treated...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDHigh grade glioma patients are prone to lapses in treatment due to the complexities related to coordination of care, the timing of adjuvant treatment, and insurance barriers. The purpose of this study was to determine the impact of an institutional multidisciplinary protocol on transitions of care after surgery for high grade gliomas between 2015 and 2018. METHODSA retrospective cohort study was conducted using CPT codes for enrolled glioma patients between 2015–2018 with unplanned...
Mon Nov 11, 2019 02:00
AbstractOBJECTIVENeuronavigation systems with magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging (methionine [MET], fluorothymidine [FLT], and fluoromisonidazole [FMISO]) are routinely used in glioblastoma surgery. Residual tumor identified using intraoperative MRI (IoMRI) or 5-aminolevulinic acid (5-ALA) fluorescence is removed. Neoadjuvant bevacizumab therapy is offered to patients with low Karnovsky performance status (KPS) or with tumors in eloquent regions. We evaluated...
Mon Nov 11, 2019 02:00
AbstractGlioblastoma treatment options remain limited due to its aggressive and invasive nature. It is increasingly appreciated that molecular heterogeneity between tumors and within tumors likely contributes to the lack of therapeutic advances. To maintain the inherent heterogeneity of glioblastoma, we employed a novel method to rapidly culture glioblastoma organoids (GBOs) directly from neurosurgical resection. GBOs are routinely generated around two weeks following initial resection. Comprehensive...
Mon Nov 11, 2019 02:00
AbstractDiffusely infiltrating gliomas feature loss-of-function mutations in the chromatin remodeler gene ATRX as defining molecular alterations delineating major adult and pediatric disease subtypes. We recently reported that Atrx deficiency drives glioma-relevant phenotypes, such as increased motility and astrocytic differentiation profiles, by directly modulating epigenomic landscapes and the corresponding transcriptional profiles in glioma cells of origin. In particular, Atrx deficiency was associated...
Mon Nov 11, 2019 02:00
AbstractBACKGROUND & SIGNIFICANCEThe immune response is a coordinated effort directed by cytokine gradients and concentrations. High sensitivity and spatial resolution are necessary to resolve cytokine gradients in 3-dimensions. This system uses in situ confocal fluorescent microscopy with printed bead-based immunoassays. The combination of 3D printing of the beads and biofabrication of patient derived tumors allows for direct imaging, quantification, and movies of tumor cytokine secretion in...
Mon Nov 11, 2019 02:00
AbstractThere have been increasing efforts to standardize MRI scanning protocols for both routine and clinical trial imaging of glioma. The recent BTIP guidelines propose acquisition of T2-weighted images after gadiolinium (Gd) based contrast injection and before post-contrast 3D T1-weighted (T1W) images to control timing of images after contrast administration. While Gd-contrast shortens T1W signal and appears hyperintense on magnetic resonance imaging (MRI), Gd-contrast also shortens T2W signal,...
Mon Nov 11, 2019 02:00
AbstractAdvanced multimodality treatments that have led to longer survival rates for patients with low-grade gliomas (LGGs) have also resulted in significant changes in cognition and quality of life (QoL). These changes remain poorly understood, largely due to the lack of multifactorial and in-depth studies on cognitive impairment in patients with LGG. Resting-state functional MRI (rs-fMRI) has been widely used as a reliable imaging biomarker to evaluate the treatment outcome by characterizing the...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDMeningiomas are the most common primary brain tumor in adults. While the majority of meningiomas are low-grade and effectively treated by resection alone, there is a subset of tumors that have a high incidence of recurrence, metastatic potential, and morbidity. Radiation has been employed with variable success for high-grade meningiomas. No chemotherapeutic approaches have proven effective against these tumors to date. There is a need for a better understanding of this tumor type...
Mon Nov 11, 2019 02:00
AbstractNearly all patients diagnosed with Glioblastoma (GBM) will experience a fatal recurrence of the tumor. Thought to be in part driven by immense tumor heterogeneity it is important to explore the small subpopulations of tumor cells with in depth single cell sequencing pre and post therapy in order to understand recurrence. To this end, we created an experimental in vivo pipeline that allows us profile not only gene expression changes during therapy, but also epigenetic shifts due to methylation...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONIn patients with newly diagnosed intracerebral lesions, gliomas are often suspected. However, other conditions such as multiple sclerosis, abscess or lymphoma are possible, as well. Furthermore, biopsy can be challenging due to eloquent and/or deep location within the brain. In this prospective, blinded study, analysis of plasma isolated cell-free DNA and exosome mRNA and miRNA from newly diagnosed glioma patients and from cancer-free volunteers was used to predict disease. METHODSPlasma...
Mon Nov 11, 2019 02:00
AbstractOBJECTIVEBrain metastases are the most common malignant tumors of the central nervous system. In patients with brain metastases with surgical indications, total surgical resection is the most effective treatment for prolonging patient survival and relieving neurological symptoms. In this study, the clinical data of 147 patients in a single group underwent microsurgery of brain metastases were retrospectively analyzed to investigate the therapeutic value of microsurgery in patients with brain...
Mon Nov 11, 2019 02:00
AbstractPURPOSEOmmaya reservoirs are frequently inserted in patients requiring regular delivery of intrathecal medications. The incidence of intracranial hemorrhage following insertion ranges from 1–3% and is typically associated with thrombocytopenia. However, the exact platelet count at which it is considered safe to insert an Ommaya reservoir has not been previously reported. The purpose of this study is to investigate the nature of the relationship between thrombocytopenia and post-operative...
Mon Nov 11, 2019 02:00
AbstractGlioblastomas (GBMs) are known to be complex tumors comprising multiple subpopulations of genetically-distinct cancer cells; it is thought that this genetic variation is a major factor in the lack of observed survival benefit of treatment regimes that target one of these subpopulations. The field of radiogenomics seeks to study correlations between MRI patterns and genetic features of GBM tumors. Spatial radiogenomic maps produced using machine-learning (ML) methods that are trained against...
Mon Nov 11, 2019 02:00
AbstractPediatric and adult high-grade gliomas are characterized by extensive intra-tumoral transcriptional heterogeneity. When measured by single cell RNA sequencing, gliomas reveal themselves as continuums of stemness and differentiation programs with important implications for therapy, but to date this transcriptional information has not been directly linked to physiological behaviors of cells. Recent work from our group establishes the electrical integration of glioma cells into neural circuitry....
Mon Nov 11, 2019 02:00
AbstractUnderstanding cancer cell immortality in primary glioblastoma (GBM) is essential for the development of more informed treatments. Multiple cancer types, including >80% of GBMs, undergo immortalization by reactivating Telomerase Reverse Transcriptase (TERT) through acquired mutations in the TERT promoter. TERT, the catalytically active and rate-limiting subunit of telomerase, functions to maintain telomeres, which cap and protect the ends of chromosomes. Our past work has demonstrated that...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONLarge scale clinical trials have failed to determine efficacy of adjuvant PD-1 blockade in recurrent glioblastoma (GBM). However, recent phase 2 clinical trial results demonstrating the potential of neo-adjuvant anti-PD-1 treatment have renewed enthusiasm for the use of immune checkpoint inhibitors (ICIs) in GBM. Additional benefit of ICIs in GBM will likely derive from development of novel therapies directed against immunosuppressive resistance mechanisms. Chemokine receptor...
Mon Nov 11, 2019 02:00
AbstractGlioblastoma (GBM) is the most common and aggressive form of primary brain tumor in adults. We recently investigated the hypothesis that treating GBM patients with psychosocial modifiers would be associated with improved overall survival (OS). Our study retrospectively analyzed 497 patients with GBM treated at Northwestern Medicine with or without selective serotonin reuptake inhibitors (SSRI) between the years 2000 and 2018. Information from the Northwestern Medicine Enterprise Data Warehouse...
Mon Nov 11, 2019 02:00
AbstractOBJECTIVEPersonalized treatment strategies in Glioblastoma multiforme (GBM) has been hampered by intra-tumoral heterogeneity. The goals of this study were to (1) determine the impact of intra-tumoral heterogeneity on established predictive and prognostic transcriptional signatures in human GBM, and (2) develop methods to mitigate the impact of tissue heterogeneity on transcriptomic-based patient stratification. METHODSWe analyzed transcriptional profiles of GBM histological structures from...
Mon Nov 11, 2019 02:00
AbstractWhile most children develop cancer without a clear etiology, some pediatric cancers arise in the context of tumor predisposition syndromes, typically caused by germline mutations in genes that regulate cell growth. The most common of these syndromes, Neurofibromatosis type 1 (NF1), affects ~1:3,000 individuals worldwide, 15% of whom will develop low-grade tumors of the optic pathway (optic pathway gliomas; OPGs). However, it is currently unclear which children with NF1 will develop an OPG,...
Mon Nov 11, 2019 02:00
AbstractGliomas are a leading cause of cancer mortality in children and adults and new targeted therapies are desperately needed. ATRX is a chromatin remodeling protein that is recurrently mutated in H3F3A-mutant pediatric GBM and IDH-mutant grade 2/3 adult glioma. We previously showed that loss of ATRX in glioma results in tumor growth and additional tumor mutations. However, the mechanism driving these phenotypes has not been fully established. We found that in ChIP-Seq datasets of mouse neuronal...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONAlthough diffuse gliomas of oligodendrocytic lineage demonstrate chemosensitivity, the survival outcomes associated with single- (i.e. temozolomide; TMZ) or multi-agent (i.e. PCV) chemotherapy regimens remain uncertain for anaplastic oligodendrogliomas (AO). METHODSPatients presenting between 2010–2016 with 1p/19q-codeleted WHO grade III AO were identified by ICD-O3 and site-specific factors from the National Cancer Database, which comprises >70% of cancers newly-diagnosed...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDThe purpose of this study was (i) to assess the reproducibility of the previously described T2-FLAIR mismatch sign as a highly specific MR imaging marker in non-enhancing IDH-mutant, 1p/19q non-codeleted lower-grade gliomas (LGG) of the WHO grades II or III, and (ii) its association with the uptake of the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) in PET to further metabolically characterize that sign, which is currently poorly understood. METHODSConsecutive...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONVestibular schwannomas (VS) are known to be slow-growing lesions that can present significant issues for patients. Here, we sought to better understand their outcomes and risks for recurrence. METHODSWe retrospectively reviewed clinical outcomes data for patients who had VS tumor that underwent whole-exome sequencing after surgical resection between 2015 and 2018. The association between any two categorical variables was investigated using Fisher’s exact test. The mean of a continuous...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDIntracranial meningiomas have been associated with a heterogenous set of genetic and molecular alterations. Despite these genetic associations, targeted therapies have been unable to increase survival in recurrent or residual meningiomas. There is a need for identification of therapeutic targets in meningioma. MATERIALS & METHODSNormal brain tissue from routine autopsy and tumor specimens from patients undergoing primary surgical resection of meningioma were analyzed. Pathologic...
Mon Nov 11, 2019 02:00
AbstractGlioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite aggressive treatment, the median survival for patients with GBM remains approximately 1 year. Recent evidence demonstrates GBM is a sexually dimorphic disease, and that females have greater overall survival. We previously showed expression levels of HFE, an iron-regulating gene, significantly impacts survival in GBM. Moreover, this effect is sex-specific: females with low HFE expressing tumors have significantly...
Mon Nov 11, 2019 02:00
AbstractPURPOSEDiffusion tensor-based tractography (DTT) is a method to estimate the direction of white matter fibers, but it is difficult to verify the relationship with brain function spatially with high accuracy. We developed a registration method to fuse the real space (brain surface photograph) and preoperative fused 3D image (virtual space) using the landmark method and thin plate spline method. In our previous study, this method was able to achieve highly accurate alignment registration error...
Mon Nov 11, 2019 02:00
AbstractPrimary brain tumors are serious and life-threatening; thus, accurate histopathologic diagnosis is critical for determining the proper clinical treatment regimen. Grade II/III gliomas (lower grade gliomas, or LGGs), including astrocytomas and oligodendrogliomas, are heterogeneous and potentially contain low- and high-grade areas within the same tumor. Therefore, it is critical to target biopsies to the most aggressive portion of the tumor to avoid tumor under-grading and under-treatment....
Mon Nov 11, 2019 02:00
AbstractThe newer modalities of GBM treatment on the horizon are targeted therapy utilizing precision medicine, immunotherapy, Laser interstitial thermal therapy (LITT), ChemoID, CAR-T cell therapy, etc. There is always dilemma about referring a patient to the clinical trials which restrict the patient to one therapeutic agent Vs using a multi-disciplinary approach to improve patient’s survival. We present a single- institution retrospective data of the multidisciplinary management of our high grade...
Mon Nov 11, 2019 02:00
AbstractGenetic and epigenetic alterations contribute to the observed intratumoral heterogeneity in adult glioma. Current glioma classification, based on genotype (e.g., IDH1 mutations) and DNA methylation profiles (e.g., glioma CpG Island Methylator Phenotype), can provide clinically relevant tumor subgroups. However, traditional bulk sampling fails to adequately capture the full complement of epigenomic heterogeneity, and may mask deadly features present in less abundant glioma cells. To more precisely...
Mon Nov 11, 2019 02:00
AbstractPediatric high grade gliomas (pHGGs) have a median survival (MS) of 9–15 months and are the most common malignant brain tumors in children. No significant improvement in the MS of these patients has been registered in decades. Thus, a representative in vivo model to study these tumors is critical. Recurrent mutations in genes encoding histones H3.3 and H3.1 have been described, which are distinctive of pHGGs. To stablish a mouse model for pHGG harboring the mutation H3.3-G34R, which co-occurs...
Mon Nov 11, 2019 02:00
AbstractThe characterization of the immune landscape of glioblastoma multiforme (GBM) is rapidly emerging. Current immunotherapeutic efforts for GBM would benefit from a comprehensive and mechanistic understanding of the relationship between distinct driver gene mutations and the composition and function of the immune tumor microenvironment. The majority of GBM tumors overexpress EGFR and EGFRvIII and ~40% are mutated for PTEN. Using genetically engineered and accurate preclinical mouse models of...
Mon Nov 11, 2019 02:00
AbstractPURPOSEPosterior fossa ependymoma is classified as PFA and PFB based on underlying genetic/mutational characteristics, and PFA is reported to have poor prognosis compared to PFB. Recently, immunohistochemical findings of negative H3K27me3 have been reported to suggest PFA and attracted the attention as a surrogate marker. We classified our cases into PFA and PFB guided by immunohistochemical staining results of H3K27me3 and examined their clinical course. MATERIALS AND METHODSBetween 1999...
Mon Nov 11, 2019 02:00
AbstractWe provide a comprehensive analysis of the antigenic landscape of glioblastoma using a multi-omics approach including ligandome mapping of the Human Leukocyte Antigen (HLA) ligandome, next generation sequencing (NGS) as well as an in-depth characterization of tumor-infiltrating lymphocytes (TIL) using mass cytometry and ultra-deep sequencing of the T-cell receptor (TCR). Tumor-exclusive HLA class I and class II ligands (immune precipitation and LC-MS/MS) of 24 isocitrate dehydrogenase 1 wild...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDIn the molecular era, the relevance of tumor grade for prognostication of IDH-wildtype (WT) astrocytomas has been debated. It has been suggested that lower-grade gliomas with molecular features of glioblastoma, IDH-WT have a similar prognosis to glioblastoma and should be considered for the same clinical trials. METHODSWe integrated prospective clinical sequencing via the FDA-approved genomic sequencing assay MSK-IMPACT from 564 patients with IDH-WT astrocytomas (26 grade II, 71...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONWe have previously demonstrated that standard dose (SD) temozolomide results in T cell exhaustion in glioblastoma. In this study, we hypothesized that cellular immunotherapies will prevent T cell exhaustion. We tested temozolomide treatment with adoptive T cell transfer alone, dendritic cell (DC) vaccines alone and T cell transfer in combination with DC vaccines. METHODGL-261-gp100 tumor-bearing mice were treated with SD (50 mg/kg for 5 days) or metronomic dose (MD) (25 mg/kg...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDAdjuvant radiotherapy (RT) in atypical meningioma, especially for gross-totally resected tumors, remains controversial. METHODSWe retrospectively identified histologically-confirmed cases of WHO Grade II atypical meningioma at a large academic institution from 2004–2018. Clinicodemographic, surgical, radiation therapy (RT), and histopathologic data were collected, as well as imaging and clinical outcomes, with a median follow-up time of 26 months (IQR 32). Patients were stratified...
Mon Nov 11, 2019 02:00
AbstractGliomas are the most common primary central nervous system malignancy in adults, but the molecular mechanisms responsible for their development and progression are not fully understood. Recent genomic analysis of World Health Organization grade II-III gliomas identifies 3 molecular subtypes of low grade glioma: no IDH mutation; IDH mutation without 1p/19q co-deletion; and IDH mutation with 1p/19q co-deletion. The latter, categorized as oligodendroglioma, commonly expresses loss of function...
Mon Nov 11, 2019 02:00
AbstractINTRO/OBJECTIVEGlioblastoma (GBM) and MGMT have been reported to have sexual dimorphism. In multiple studies, including our own population-based cohort analysis, females had higher rates of MGMT methylation and improved methylation-associated progression-free and overall survival outcomes compared to males. MGMT methylation is assessed as a mean of five cysteine-phosphate-guanine (CpG1-5) islands (CpG methylation is highly inversely correlated with MGMT RNA expression). The primary objective...
Mon Nov 11, 2019 02:00
AbstractONC201 is the first clinical bitopic antagonist of DRD2, an oncogenic receptor in brain and neuroendocrine tumors. ONC206, a derivative of ONC201 that shares the imipridone core structure, is also a bitopic DRD2 antagonist that exhibits enhanced non-competitive effects, high specificity, nanomolar potency, and disruption of DRD2 homodimers. Broad nanomolar efficacy of ONC206 (GI50 < 78-889nM, CellTitre-Glo, 72h) was observed in >1,000 GDSC cancer cell lines. Maximal ONC206 sensitivity...
Mon Nov 11, 2019 02:00
AbstractVenous thromboembolism (VTE) impacts an estimated one in every three patients with malignant glioma (MG), resulting in increased morbidity and mortality. Despite the high prevalence and serious consequences of VTE, there is no outpatient standard of care prevention strategy. There have been three prospective clinical trials of VTE prophylaxis in patients with newly diagnosed MG, all of which used an injectable low molecular weight heparin (LMWH) product. We performed an open-label safety...
Mon Nov 11, 2019 02:00
AbstractThe tumor suppressor TP53 (p53) is the most commonly mutated gene in cancer and among the most frequently mutated genes in glioblastoma (GBM). The majority of p53 mutations in GBM are missense mutations in the DNA binding domain that lead to the production of full length mutant p53 protein. In addition to the complete loss of tumor suppressor function, these mutations have gain-of-function (GOF) properties either through attenuation of wild-type function or neomorphic functions. The variability...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONMulticentric glioblastoma (m-GBM) is a rare GBM variant (6–13% of all GBM cases). Published data is scarce and focus largely on enhancing foci. We performed a retrospective study to determine the incidence, imaging characteristics, treatment, pattern of relapse and prognosis of m-GBM. METHODSThe neuropathological database of our institution was surveyed for histological diagnosis of adult GBM diagnosed between 01/01/2015 and 31/05/2018. All pre-operative MRI were reviewed to identify...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONLaser interstitial thermal therapy (LITT) is a minimally invasive treatment method that provides surgeons with cytoreductive techniques to treat neurosurgical conditions such as primary brain neoplasms, brain metastases, radiation necrosis, and epileptogenic lesions, many of which are located in operative corridors that would be difficult to address via open surgical or are amenable via minimally invasive approaches. Although the use of lasers is not a new concept in neurosurgery,...
Mon Nov 11, 2019 02:00
AbstractGlioblastoma showing primarily extensive subarachnoid spreading has much worse prognosis than intracortical glioblastoma. Nevertheless, their genetic pathogenesis is still unknown due to its low incidence. Present report is a rare case of glioblastoma with primitive neuroectodermal tumor (PNET)-like feature, showing extensive subarachnoid spread, as well as the distinguishing result of its molecular analysis using next generation sequencing (NGS). A 37-year-old male presented with a new onset,...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONThe development of diabetes insipidus (DI) after pituitary adenoma resection is associated with worse post-surgical morbidity and longer hospital stay. Identification of clinical predictors of development of DI would allow for appropriate stratification of patients to optimize preoperative counseling and postoperative management. METHODSWe conducted a retrospective review of 349 patients who underwent pituitary adenoma resection at Johns Hopkins Hospital between 2003 and 2017....
Mon Nov 11, 2019 02:00
NIMG-28. VALIDATION OF SINGLE-DOSE DSC-MRI PROTOCOLS FOR ROBUST PERFUSION ASSESSMENT IN BRAIN TUMORS
AbstractDynamic susceptibility contrast (DSC) MRI measures of brain tumor cerebral blood volume (CBV) are able to predict grade, overall survival and response to treatment. Wide-spread acceptance of DSC-MRI has been challenged by the need to balance contrast agent dose and CBV accuracy. The goal of this study was to identify and validate single-dose, BTIP compliant, DSC-MRI protocols. Using a validated, patient-based DRO, we evaluated CBV accuracy across a range of acquisition parameters (field strength,...
Mon Nov 11, 2019 02:00
AbstractHigh levels of D-2-hydroxyglutarate (D2HG) are found in several types of cancers, most notably low grade gliomas (LGGs). The accumulation of D-2HG contributes to tumorigenesis through a variety of mechanisms including decreased utilization of oxidative phosphorylation and histone hypermethylation. The use of the budding yeast Saccharomyces cerevisiae as a model system to study cancer allows for faster, more efficient elucidation of various molecular mechanisms, including functional genomics...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDDiffuse intrinsic pontine gliomas (DIPG), known today as diffuse midline gliomas with the H3K27M mutation, are inoperable and aggressive brain tumors found predominantly in children. Despite extensive research no treatment or cure has been elucidated. Studies in 2012 showed that the majority of DIPG tumors have the H3K27M mutation, but the development of novel therapeutics has been hindered by lack of good laboratory models. Although patient derived cell lines with the H3K27M mutation...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDFailure of many brain tumor treatments has been attributed to the inability of a compound to cross the blood-brain barrier. Convection-enhanced delivery (CED) offers a method to administer drugs directly to the tumor site, thereby mitigating this limitation. CED has been used in several preclinical and clinical studies, though an approved treatment is yet to come to fruition. A medical device suitable for repeated intraparenchymal delivery is valuable for brain tumor treatment strategies,...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONTargeted next-generation sequencing (NGS) offers promising diagnostic perspectives by making it possible to detect genetic alterations with high accuracy in multiple genes as part of the daily diagnostic work-up. The importance of genetic alterations is reflected in the 2016 WHO classification of CNS tumors, where specific alterations are incorporated in the definition of certain entities. The aim of this study was to assess the diagnostic potential of a customized targeted glioma-tailored...
Mon Nov 11, 2019 02:00
AbstractSuccinate dehydrogenase (SDH) is a mitochondrial enzyme that plays an important role in both the Krebs cycle and the electron transport chain. SDH inactivation is associated with tumorigenesis in certain types of tumor. SDH consists of subunits A, B, C and D (SDHA, SDHB, SDHC, and SDHD, respectively). Immunohistochemistry for SDHB is a reliable method for detecting the inactivation of SDH by mutations in SDHA, SDHB, SDHC, SDHD and SDH complex assembly factor 2 (SDHAF2) genes with high sensitivity...
Mon Nov 11, 2019 02:00
AbstractStudying the immune microenvironment of primary CNS tumors is critical for the development of novel immunotherapies. At this time, immunotherapy is likely underused and may have a promising future in their treatment. Current limitations in studying the TME of the CNS are the small amount of tissue often available and the laborious, time consuming process of testing for individual markers. Multiplexed immunohistochemistry (mIHC) is a process of evaluating multiple tumor biomarkers on a single...
Mon Nov 11, 2019 02:00
AbstractGlioblastomas are malignant brain tumors that carry a poor prognosis. The tumor microenvironment has been identified as an important regulator of tumor growth and may represent a novel target for therapy. Transcriptional subtypes of glioma are a major source of heterogeneity of expression in gliomas. Gliomas are highly heterogeneous diseases and can be classified into different subtypes including proneural, classical and mesenchymal tumors. We hypothesized that different subtypes of glioma...
Mon Nov 11, 2019 02:00
AbstractCurrent guidelines recommend antiepileptic drug (AED) therapy for glioma patients only in patients who have experienced a seizure. There is no current recommendation in regards to performing EEG monitoring in glioma patients. Thus, typically only clinical seizures have prompted AED therapy in glioma patients. Our purpose was to investigate the rate of EEG monitoring in glioma patients entered into our glioma registry, along with seizure and AED rates. Using our glioma registry to date, of...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDAlthough the recent studies have identified “T2-FLAIR mismatch sign” specific to IDH-mutant and 1p/19q-intact gliomas, it is unclear what the mismatch sign represents. We aimed to investigate the mechanisms and validate the clinical utility. METHODSWe identified 79 lower-grade gliomas treated at Kobe University Hospital, and classified into three groups: (i) LGGIDH(m),1p19q(-) (n = 18): IDH-mutant and 1p/19q-intact, (ii) LGGIDH(m),1p19q(+) (n=26): IDH-mutant and 1p/19q co-deleted,...
Mon Nov 11, 2019 02:00
AbstractInvasive procedures for diagnosis of CNS malignancies carry inherent risks of high morbidity and mortality. Although circulating biomarkers such as cell free DNA (cfDNA) and microvesicle (MV) borne nucleic acids have been proposed as potential diagnostic aids, their stand-alone utility has inherent limitations. However, Circulating Glial Cells (CGCs) combined with cfDNA could offer a viable alternative to invasive biopsies for diagnosis of CNS malignancies; yet the technological challenge...
Mon Nov 11, 2019 02:00
AbstractGiven the modest effects current immune checkpoint-inhibitors have on patients with CNS tumors, we focused our studies on the novel CD200 immune checkpoint. The CD200 checkpoint suppresses the immune system through binding of the inhibitory CD200 protein to the inhibitory receptor (CD200R1) expressed on immune cells. In addition to CD200R1, the CD200 checkpoint includes activation receptors (CD200AR), which we are targeting with a peptide ligand (CD200AR-L) to reverse the inhibitory effects...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDThe lack of appropriate preclinical murine glioblastoma models limits comprehensive toxicity/efficacy evaluation of investigational agents. To overcome this challenge, we evaluated the safety and activity of a new immunotherapeutic technology that we have pioneered (composed of tumor mRNA complexed into a custom lipid-nanoparticle formulation) in client-owned canines (pet dogs) diagnosed with malignant gliomas. OBJECTIVE/METHODSCanine malignant gliomas were biopsied for generation...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONIdentifying both aggressive hypercellular (HCV) and hyperperfused (hCBV) regions of glioblastoma (GBM) prior to radiation (RT) using multiparametric MRI (mpMRI) predicts PFS and recurrence better than either technique alone, and is under investigation in a phase II trial as a novel target for dose-intensified RT. We hypothesized that early response in combined HCV/hCBV could be assessed using mpMRI and predict OS better than baseline assessment. METHODSForty-three patients with...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONSpecific genetic mutations are linked to clinical prognosis in gliomas. There has been increasing demand to understand the association between tissue biomarker expression and survival. Using patient-derived samples, WHO grade II-IV gliomas were evaluated by the protein-staining pattern of molecular markers of interest across tumor grade, and the association between their expression and survival was investigated. METHODSTissue microarrays (TMA) containing duplicate 1 mm cores were...
Mon Nov 11, 2019 02:00
AbstractGlioblastoma is a lethal brain tumor, heavily infiltrated by tumor-associated myeloid cells (TAMCs). As up to 30% of a glioma cellular mass may be attributed to immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). TAMCs impede natural and immunotherapy-driven anti-tumor responses, they are a high-priority and promising therapeutic target currently being evaluated in clinical trials. Multiple preclinical and clinical trials...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONRecent studies have reported that NFKBIA deletion (dNFKBIA) was potentially associated with worse prognosis in glioblastoma (GBM) patients. However, no consensus has been reached to its universal prognostic value. Here, we investigated the survival impact of dNFKBIA using two primary IDH wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). Additionally, prognostic impact of a combination of NFKBIA copy number and MGMT methylation...
Mon Nov 11, 2019 02:00
AbstractThe spine is a common site of metastatic spread of many cancers, causing debilitating pain and suffering. Treatment of spinal metastases is limited by resistance to radiation, chemotherapy, and proximity to the spinal cord. It is currently not known what causes the high incidence of spinal metastases, yet theories have been proposed, like the venous metastatic spread theory (Batson, 1940) and the “seed and soil” hypothesis (Paget, 1889), postulating that factors intrinsic to the tumor cells...
Mon Nov 11, 2019 02:00
AbstractVB-111 is a non-replicating adenovirus carrying a pro-apoptotic transgene for TNFR1/Fas under the control of a modified murine promoter to pre-proendothelin 1. The transgene is expressed only in angiogenic endothelial cells, and therefore VB-111 results in targeted apoptosis of neovascular vessels. The current study characterizes the quantitative radiographic results and impact on OS in phase 2 and 3 trials of recurrent glioblastoma (GBM) patients treated with VB-111 with or without bevacizumab...
Mon Nov 11, 2019 02:00
AbstractMalignant tumors reprogram cellular metabolism, resulting in altered concentration of some metabolites. We measured glycine (GLY) and 2-hydroxyglutarate (2HG) in 37 adult subjects with gliomas noninvasively using proton magnetic resonance spectroscopy and examined their association with immunochemical analyses of tumor biopsies and overall patient survival. MRS data were acquired using optimized point-resolved spectroscopy (PRESS TE 97ms) at 3T and the millimolar concentrations of metabolites...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONIntratumor genetic heterogeneity is commonly caused by a stochastic evolution, but can also show remarkable selectivity resulting in directional evolution. We hypothesized that directional evolution is driven by its genetic onset-stage. This process could enforce already existing traits resulting in an enhancement of linear pathways rather than the complementary/parallel evolution. METHODSWe generated a prediction model for directional evolution based on its genetic onset-stage....
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONLarge number of diverse imaging [e.g., multi-parametric MRI (mpMRI), and digital pathology images] and non-imaging (e.g., clinical) biomedical data streams are being routinely acquired as part of the standard clinical workflow for glioblastoma patients. However, under the current clinical practice, these data streams are not collectively used for diagnosis. We sought to assess the synergies between pathologic, and radiomic features by evaluating the predictive value of each group...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDPineoblastoma (PB) is a rare but aggressive pediatric brain tumour arising from the pineal gland. Overall survival rates are estimated at 50–70%, with younger patients (< 5 years old) faring much worse (15–40%) despite intensive treatment regimens. Although germline RB1 and DICER1 alterations have been reported in a small proportion of PB, the clinical significance of such alterations and the biology of sporadic cases remains unknown. METHODSWe collected tumor tissue from 93...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDDiffuse intrinsic pontine glioma (DIPG) is one of the most devastating brain neoplasms. Despite 50 years of clinical trials, no improvement of survival has been observed and most children die within 2 years of diagnosis. Only radiotherapy transiently controls disease progression. METHODS/AIMS: BIOMEDE was conceived as a randomized multi-arm multi-stage program (drop-the-loser adaptive design). It started with an open-label phase-II trial comparing three drugs (everolimus, dasatinib,...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONGlioma is a debilitating and early fatal cancer arising in the glial cells of brain. Glioblastoma, the most aggressive form of gliomas, has a 5-year survival rate of 5% with treatment options limited to surgery, radiotherapy or chemotherapy with temozolomide. OBJECTIVEWhile radiation and immunotherapies are routinely studied in the murine Gl261 glioma model, little is known about its inherent immune response. In this study we quantified the temporal and spatial localisation of...
Mon Nov 11, 2019 02:00
AbstractThere has been considerable interest in repurposing the poly ADP ribose polymerase inhibitor and purported radiosensitiser olaparib (Lynparza), with a recent dose escalation study of olaparib plus temozolomide in recurrent GBM showing good tolerance (Fulton et al 2018). Due to systemic therapy-associated caveats such as dose-limiting toxicities and blood-brain-barrier penetration, here we assess localised post-surgical delivery of olaparib from our previously developed poly(DL-lactic-co-glycolic...
Mon Nov 11, 2019 02:00
AbstractBrain tumors are the leading cause of cancer-related deaths in children. To identify novel therapeutic targets in two types of pediatric brain tumors, medulloblastoma (MB) and central nervous system primitive neuroectodermal tumors (CNS-PNETs), we performed a Sleeping Beauty transposon mutagenesis screen in mice. In doing this, we identified FOXR2 (Forkhead box R2) as a candidate oncogene in MB. FOXR2 is expressed at high levels in a subset of human MB and increased FOXR2 expression drives...
Mon Nov 11, 2019 02:00
AbstractMalignant gliomas (MG) are one of the deadliest cancers with very limited therapeutic options. Chimeric antigen receptor (CAR)-T cell therapy has emerged as a powerful strategy for B-cell malignancies and may offer new opportunities to improve outcomes for patients with MGs. Our team is clinically evaluating IL13Rα2-targeted CAR-T cells for the treatment of recurrent IL13Rα2-positive MGs [NCT02208362]. While this trial is ongoing, we have previously reported that one patient with recurrent...
Mon Nov 11, 2019 02:00
AbstractGliomas are the most frequently diagnosed human primary brain tumors. Mutations in Isocitrate Dehydrogenase (IDH) 1 occur in the vast majority of low grade gliomas and secondary high grade glioblastomas. A single amino acid missense mutation in IDH1 at arginine 132 (R132H) is an early event in tumor development. IDH1R132H leads to the production of the oncometabolite 2-R-2-hydroxyglutarate. However the exact roles played by IDH1R132H in the development and malignant transformation of the...
Mon Nov 11, 2019 02:00
AbstractINTRODUCTIONCognitive concerns and objective cognitive impairment are both common in cancer patients, although the relationship between these variables is uncertain. Brain metastases have the potential to affect both outcomes. We examined the relationships between cognitive concerns, cognitive performance, and psychological disturbance in mNSCLC patients with and without brain metastases. METHODSmNSCLC patients completed standardized neuropsychological tests (HVLT-R, TMTA/B, COWA) and questionnaires...
Mon Nov 11, 2019 02:00
AbstractBACKGROUNDAccurately identifying the boundary of invasive brain tumors is critical for planning effective treatment. Conventional imaging includes T1-weighted contrast-enhanced MRI to identify regions where tumor angiogenesis has broken down the blood-brain barrier. However, conventional MRI has limited sensitivity for identifying invading tumor cells. Amino acid PET with 18F-fluciclovine may offer improved sensitivity. We investigate whether 18F-fluciclovine PET provides a superior measure...
Mon Nov 11, 2019 02:00
AbstractRecurrent glioblastoma patients achieving response to bevacizumab combination therapy have clinical improvement and prolonged survival. High gene-expression of angiotensinogen (AGT) is associated with a poor response to bevacizumab combination therapy. Because AGT gene-expression is epigenetically regulated, we investigate if lower AGT promoter methylation in tumor tissue predicts a poor response to bevacizumab combination therapy in recurrent glioblastoma patients. Methods: Patients were...
Mon Nov 11, 2019 02:00
Nature Reviews Drug Discovery, Published online: 11 November 2019; doi:10.1038/s41573-019-0046-zGenomic screenings have enabled the discovery of synthetic lethal partners as potential drug targets in cancer. This Review discusses how the genetic concept of synthetic lethality paired with CRISPR-based functional genomic screening can be applied to identify additional synthetic lethal pairs as new and druggable cancer targets.
Mon Nov 11, 2019 02:00
Nature Reviews Drug Discovery, Published online: 11 November 2019; doi:10.1038/d41573-019-00193-7Cloud-based systems for data submitted by sponsors to drug regulatory agencies have the potential to accelerate drug development, streamline regulatory review and enhance regulatory decision-making. Here, we provide a vision for integrating cloud-enabled practices in drug regulation globally.
Mon Nov 11, 2019 02:00
Abstract Purpose of Review Graft-versus-host disease (GVHD) is an immune mediated disorder affecting 30–70% of patients after allogeneic hematopoietic stem cell transplantation (alloHSCT), and is a major cause of morbidity and non-relapse mortality (NRM) as reported by Jagasia, et al. (Blood 119:296-307, •2012). Dermatologists play a critical role in acute and chronic GVHD, as skin involvement is common and often the earliest involved...
Mon Nov 11, 2019 02:00
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