tbuckley/cabot-search huggingface dataset:
GENE-08. SCHWANNOMATOSIS SCHWANNOMAS HARBOR DISTINCT DNA METHYLATION PROFILES
Authors: Sheila Mansouri, Irene Paganini, Shirin Karimi, Suganth Suppiah, Yasin Mamatjan, Olivia Singh, Anat Stemmer-Rachamimov, Laura Papi, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2018)

Schwannomas are characteristic manifestations of NF2 and schwannomatosis syndromes. However, the majority of schwannomas are solitary and sporadic. It is unclear whether and to what extent sporadic and syndrome-associated schwannomas or their histologic subtypes represent distinct biological groups. Clinically, although schwannomatosis schwannomas are considered benign, the majority of patients experience unmanageable pain; however, the underlying mechanism of this pain is not well understood. There is increasing evidence for DNA methylation profiling being able to distinguish biologically relevant tumor subgroups, even within the same cellular lineage and histopathologically similar tumors. In this study, we used Illumina Methylation EPIC arrays for methylome-based characterization of 88 schwannomatosis schwannomas, in comparison to 90 sporadic schwannomas and 14 NF-2 schwannomas. We performed unsupervised hierarchical clustering selecting 30,000 probes that showed the highest median absolute deviation (MAD) across all beta values. Three different clustering sets were utilized to obtain the most refined differentiation. Schwannomatosis schwannomas formed 3 distinct methylome-based subgroups, which were fully distinct from sporadic schwannomas and NF-2 schwannomas. Additionally, we performed copy number analysis using the DNA methylation data to infer gross chromosomal deletions or gains among the sporadic and syndromic schwannomas, in addition to schwannomas with hybrid features. Methylation subgroups were further correlated with clinical parameters including age, gender, anatomic location, tumor size, germline mutation status (LZTR1/SMARCB1), and 22q LOH, in addition to the histopathologic features associated with each tumor. Furthermore, RNA sequencing was performed to examine gene expression profiles associated with the 3 methylome subgroups and the data was integrated with DNA methylation profiles to establish the biological relevance of hypo- and hyper-methylation of the top varying CpG sites. Cumulatively, these data will be correlated with the extent and type of pain experienced by schwannomatosis patients to elucidate the underlying mechanism of pain.
NCOG-06. PREDICTING TUMOR TREATING FIELD COMPLIANCE USING NEUROCOGNITIVE TESTING
Authors: Kaitlin Qualls, Brandon Baughman, Majari Pandey, L Michael, Jeffrey Sorenson, Matthew Ballo
Journal: Neuro-Oncology (2018)

PURPOSE: To determine if neurocognitive functional status can be used as a predictor of Tumor Treating Field (TTFields) use and compliance METHODS AND MATERIALS: Twelve patients diagnosed with primary GBM underwent a battery of neurocognitive tests to determine their neurocognitive functional status. A retrospective analysis was performed to determine if neurocognitive function is related to TTField use and compliance. Of the 12 patients, 10 were male and the median age was 64 years. ECOG performance status was 0 or 1 in all patients. Nine initiated TTFields therapy, and we followed their TTField use and compliance. We reviewed the mean score on each of the neurocognitive tests in TTField users and non-users and found no significant difference. We also analyzed the means of the TTField users and compared those who had a compliance of > 75% versus 0–75%. In this comparison, we found that patients who had a compliance of > 75% trended towards better neurocognitive function in 2 of the tests, the Trailmaking Test A (TMTA) and the Test of Premorbid Function (TOPF). The TMTA is a measure of simple visual-motor processing speed and visual attention, and the TOPF represents an estimation of the patients premorbid intellectual abilities. The mean TMTA z-scores were -3.40 in patients who had a compliance of > 75% and -0.943 those with compliance of 0–75% (p=0.080). The mean TOPF standard scores were 108 in patients with compliance > 75% compared to 88.7 in those with a compliance of 0–75% (p=0.062). CONCLUSIONS: Neurocognitive testing may be used a potential predictor of TTField compliance. In our small patient population, those with higher premorbid intelligence and faster psychomotor speed tended to have better compliance in TTField use. We expect that further investigation, in a larger dataset, may lead to a more refined neurocognitive profile of TTField compliance.
NCOG-07. NEUROCOGNITIVE EVALUATION IN ELDERLY MALIGNANT GLIOMA PATIENTS
Authors: Andrea Pace, Antonio Tanzilli, Stefano Telera, Chiara Zucchella, Irene Terrenato, Carmine Maria Carapella, Riccardo Boccaletti, Veronica Villani
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common primary brain tumor in adults, with an increasing incidence in patients aged 75 through 85. Prognosis in these patients is particularly dismal due to more aggressive tumor biology, lower functional reserve and high prevalence of comorbidities. Many studies report cognitive impairment in GBM patients, ranging from 29 to 90%. This study was aimed at evaluating neurocognitive status and comorbidities of an elderly population with high grade glioma and the correlation with clinical and demographical variables. Patients underwent an extended neuropsychological evaluation with a battery of standardized tests on 8 cognitive domains: global function (GF); verbal learning (VL); short and long-term memory (STM); executive functions (EF); abstract reasoning (AR); attention (ATT) and visuo-constructional abilities (CA). Moreover, the Cumulative Illness Rating Scale was administered to each patient for comorbidities evaluation. We assessed 69 patients with median age at diagnosis of 74 years (range 65–85). 43 patients (62%) presented multi-domain cognitive impairment, and only 8 (12%) showed no cognitive impairment. Neuropsychological deficit mainly affected executive functions (n=42), short term memory (n=28), long term memory and attention (n=22). Patients with AR deficit had a poorer PFS and OS (p<0.001%). At the follow up, 7 out of 12 patients showed cognitive improvement, 4 resulted furtherly deteriorated and 1 patient was stable. Attention was the most affected function at follow up, while verbal learning was the most improved one. CONCLUSIONS: Our results highlight the high prevalence of cognitive deficits in patients with Glioma. Moreover, this study underlines the need to include cognitive functioning and comorbidities evaluation in the assessment of elderly neuro-oncological patients.
Abstract 16472: Large Area of Complex-Fractionated Atrial Electrograms Disrupt Identification of Rotors and Focal Sources for Atrial Fibrillation After Pulmonary Vein Isolation
Authors: Yoshiyuki Hama, Yuji Matsudo, Taishi Kuwahara, Haruka Fujimaki, Noriko Eguchi, Ikuto Terabayashi, Kohei Kamishita, Bi Katsu, Shuzo Tanaka, Norimasa Tonoike, Kyokushi Hou, Tai Sekine, Yoshihide Fujimoto, Masashi Yamamoto, Toshiharu Himi
Journal: Circulation (2014)

Background: The mapping of the electrical propagation to identify the underlying mechanisms that perpetuate atrial fibrillation (AF) is difficult because of Complex-fractionated Atrial Electrograms (CFAE). We hypothesized that the organization of AF would facilitate the identification of rotors or focal sources (AF sources) after pulmonary vein isolation (PVI). Methods: We prospectively enrolled 87 patients undergoing an ablation for persistent AF. SR was restored for at least 2 weeks prior to ablation. If SR could not be maintained, pulmonary vein isolation (PVI) and linear ablation were performed. Radiofrequency ablation was performed during induced AF. If AF was sustained or induced after the PVI, activation maps to identify AF sources (Rotor map) were created by a 64-pole basket catheter, 20-pole circular mapping catheter and CS catheter with the use of the Velocity system. A rotor was defined as follow: reproducible reentrant atrial activity which was repeatedly present for more than 40% of the 3.8 s...
IMMU-21. MULTIDIMENSIONAL CHARACTERIZATION OF IMMUNE CELL POPULATIONS IN THE GLIOMA TUMOR MICROENVIRONMENT REVEALS A DOMINANT PROPORTION OF CELLS DERIVED FROM THE MYELO-MONOCYTIC LINEAGE
Authors: Alexander Lee, Aaron Mochizuki, Moe Ishihara, Alejandro Garcia, David Nathanson, Anthony Wang, Richard Everson, Linda Liau, Robert Prins
Journal: Neuro-Oncology (2018)

Immunotherapy represents an exciting new strategy to treat patients with malignant gliomas; however, we and others have previously shown that the presence of other immune cell populations in the tumor microenvironment can reduce the effectiveness of immunotherapy. To date, a comprehensive and quantitative examination of immune cell composition in the glioma microenvironment has not been performed. We purified CD45+ cells from freshly digested tumor samples of 35 malignant glioma patients undergoing surgical resection at UCLA and performed CyTOF mass cytometry. We then analyzed the lineage and functional marker expression of these populations. Next, to pursue an unbiased analysis of the multi-dimensional data, we used a computational algorithm that clusters cells into phenotypically distinct populations in an unsupervised manner. CD11b+ myelo-monocytic cells (1542.13 ± 306.82 cells/mg of tumor; 51.33 ± 6.43% of all cells) represented the dominant population and were more abundant than CD3+ T lymphocytes (233.65 ± 59.53 cell/mg of tumor; 8.41 ± 1.47% of all cells; p < 0.001). Meanwhile, our unsupervised clustering algorithm generated 12 distinct phenotypic clusters. Amongst the immune cells, 76.81% were grouped into 6 clusters that derived from populations of a monocytic lineage including a classical monocytic population, an inflammatory monocyte population, and a differentiated M2 macrophage population. 12.37% of the tumor-infiltrating immune cells grouped into 2 clusters of a NK lineage, 9.06% grouped into 2 clusters of a T cell lineage, 0.3% grouped into 1 cluster of a B cell lineage, and 1.46% cells in 1 cluster of an unable to be classified cell lineage. Cells of monocytic origin represented the dominant fraction of cells within the tumor-infiltrating immune cell population. Understanding the immune cell composition in the tumor microenvironment may help improve current and future immunotherapies against gliomas.
EXTH-57. PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF THE PROCASPASE-ACTIVATING COMPOUND, PAC-1, FOLLOWING ORAL ADMINISTRATION IN A NON-HUMAN PRIMATE MODEL
Authors: Cynthia Lester McCully, Rafael Cruz, Alexander V Lyubimov, Alexander D Zakharov, James H Fischer, Paul J Hergenrother, Katherine E Warren
Journal: Neuro-Oncology (2018)

PAC-1 is a novel compound which induces apoptosis via activation of the procaspase-3 pathway in cancer cells. Human clinical trials are ongoing with PAC-1 as a single agent (late-stage cancers) and in combination therapies (malignant glioma), in addition to studies in pet canines (glioma). This study evaluated the CSF penetration of PAC-1 via plasma and CSF pharmacokinetics in a nonhuman primate CSF Ventricular Reservoir or Lumbar Port model that allows serial CSF collection. 4 male rhesus macaques received 15 mg/kg (Human Equivalent Dose of 558 mg/m2/day) of PAC-1 in 6 studies with two formulations; liquid (n=1) or pill (n=5). 1 animal received both formulations. Paired plasma and CSF (lumbar n=2 and ventricular n=4) samples were collected for 0–72 hours. PAC-1 was quantified by LC-MC/MS. The lower limit of quantitation for plasma was 10.0 ng/ml and CSF 0.2 ng/ml. PK parameters were calculated via noncompartmental methods. 5 studies were evaluable (n=1 liquid and n=4 pill). Plasma-Quanitifible (n=5). Liquid Formulation (n=1): AUC0-∞ 5299.91 hr*ng/ml, Half-Life 4.99 hr, and Clearance 57.43 L/hr/m2. Pill Formulation PK range (n=4): AUC0-∞ 1527.7–8036.08 hr*ng/ml, Half-Life 10.2–31.5 hr, and Clearance 37.65–199.49 L/hr/m2. CSF-Quanitifible (n=3; 2 lumbar & 1 ventricular) or undectable (n=2 ventricular). Liquid Formulation (lumbar n=1): AUC0-∞ 50.90 hr*ng/ml, Half-Life 4.59 hr, and Clearance 5979.56 L/hr/m2 Pill Formulation PK range (lumbar n=1 and ventricular n=1): AUC0-∞ 7.53–31.25 hr*ng/ml, Half-Life 22.35–28.88 hr, and Clearance 9955.96–40178.44 L/hr/m2. Plasma Ratio formulation comparison: 0.96% liquid and 0.46% pill. In this animal model, the CSF penetration of PAC-1 is low and formulation-dependent, with Plasma ratio 2 fold greater with liquid verses pill formulation. The CSF clearance is rapid. FUTURE 10.08 and 12.1 mg/kg dosages (Human Equivalent Dose 375 and 450, mg/m2/day, respectively) are currently undergoing evaluation in this NHP model.
Abstract 20132: A Device for the Quantification of Oxygen Consumption and Caloric Expenditure in Neonates
Authors: Einav Nachman, Peter Clemensen, Kathryn Santos, Alexis Cole, Brian D Polizzotti, Kimberly Mills, John N Kheir
Journal: Circulation (2017)

Introduction: The accurate measurement of oxygen consumption (VO2) and resting energy expenditure (REE) is essential for the proper treatment of neonates with congenital heart disease. Matching nut...
NIMG-66. COMPARISON OF STEADY STATE AND DYNAMIC BRAIN METABOLISM BY USING 1H MRSI AND HYPERPOLARIZED [1-13C]PYRUVATE IMAGING IN PATIENTS WITH GLIOMA
Authors: Yan Li, Adam Autry, Jeremy Gordon, Jason Crane, Beck Olson, Marisa Lafontaine, Ilwoo Park, Javier Villanueva-Meyer, Daniel Vigneron, Susan Chang, Sarah Nelson
Journal: Neuro-Oncology (2018)

Proton magnetic resonance spectroscopic imaging (1H MRSI) is a powerful noninvasive method for assessing the spatial extent and properties of abnormal metabolism in patients with glioma. Hyperpolarized 13C metabolic imaging is a new molecular imaging modality that can be used to assess real-time changes in metabolism and has been shown to be safe and feasible in patients with glioma. In this study, both 3D 1H lactate-edited MRSI and hyperpolarized [1-13C]pyruvate imaging data were obtained and compared in thirteen patients with glioma to assess steady state versus dynamic brain metabolism. FLAIR images from the 1H examination were registered to the FSE images from the 13C examination for each subject. The corresponding transformation matrix was then applied to spectra and metabolite maps from the excitation volume of the 1H MRSI data. The volumes of the anatomic and metabolic lesions varied between patients, and using a multi-slice frequency specific EPI sequence allowed improved coverage of the lesion of interest compared to a 2D dynamic EPSI sequence. The choline-to-NAA index values and levels of steady state lactate peak heights from the 1H MRSI data were elevated in the lesion, while 13C bicarbonate levels were reduced and 13C lactate levels were similar or lower compared with normal appearing brain. The initial results indicated that there was a negative association between estimates of hyperpolarized 13C lactate/pyruvate and steady state normalized lactate peak heights, and a positive association between hyperpolarized 13C lactate/pyruvate and Cho/NAA in the T2 lesion. For one patient who received repeated examinations within 2 months and was assessed as having stable disease after treatment, the 13C lactate-to-pyruvate ratio in the T2 lesion was 0.65 vs. 0.35 and 0.43 vs. 0.43 in normal appearing brain. Future studies will evaluate a larger patient population to see whether these relationships hold up.
NIMG-37. ASSOCIATION BETWEEN METABOLIC PARAMETERS FROM DYNAMIC 18FMC PET, PHARMACOKINETIC DCE-MRI PARAMETERS, MRS CHOLINE TO CREATINE RATIOS AND TISSUE IMMUNOHISTOCHEMISTRY FOR CHOLINE KINASE ALPHA EXPRESSION IN HUMAN BRAIN GLIOMA
Authors: Matthew Grech-Sollars, Marianna Inglese, Katherine Ordidge, Claire Davies, Vijaykumar Vaja, Babar Vaqas, Sophie Camp, David Peterson, Lesley Honeyfield, Sameer Khan, Kevin O’Neill, Federico Roncaroli, Eric Aboagye, Tara Barwick, Adam Waldman
Journal: Neuro-Oncology (2018)

Proton MR spectroscopy and Choline-PET probe different aspects of choline metabolism, and quantitative dynamic MRI yields information on vascular permeability and perfusion. The relationship between these features in different grades of glioma is, however, unclear. METHOD: 14 patients with suspected primary supratentorial glioma were recruited to this study. The mean values over the whole tumour (T2-FLAIR hyperintense regions) of DCE-derived pharmacokinetic parameters were correlated with tumour to background ratio (TBR: ratio of SUVmax in tumour to SUVmean in contralateral white matter for the 7-17-minute static PET images). Dynamic PET macroparameters were quantified with spectral analysis (SA) in six patients for whom metabolite data were available. Choline to creatine ratios (Cho/Cr) were extracted from 2D-CSI data over 257 MRS voxels and correlated with TBR. Tissue immunohistochemistry for choline kinase alpha expression in targeted biopsies was carried out in regions of tumour with high and low uptake on PET and Cho/Cr on MRS. We observed a positive significant correlation between DCE-MRI derived parameters and parameters obtained through SA of the dynamic choline-PET data as well as TBR. We also observed a positive significant correlation between MRS Cho/Cr and TBR, although this was weak when excluding WHO Grade IV tumours. We did not observe a strong correlation between choline markers on imaging and choline kinase alpha expression. The correlation between both DCE and MRS parameters with TBR indicates that a number of biological features affect the uptake of the PET tracer. DCE-MRI provides complimentary information to blood volume and permeability that may augment interpretation of PET data; and help address questions such as the degree to which tracer uptake is dominated by blood brain barrier permeability rather than metabolic activity. Choline imaging with PET and MRS may reflect metabolic processes that are not simply related to choline kinase alpha expression.
DDIS-13. UNDERSTANDING GLIOBLASTOMA SUSCEPTIBILITY TO TOP2-TARGETING DRUGS FOR PERSONALIZED THERAPY
Authors: Chidiebere Awah, Edgar Gonzalez-Buendía, Junfei Zhao, Eric Feldstein, Li Chen, Aayushi Mahajan, Louisa Warnke, Lu Wang, Cheol Park, Jan Winter, Silvana Konermann, Ali Shilatifard, C David James, Raul Rabadan, Patrick Hsu, Mukesh Bansal, Atique Ahmed, Adam Sonabend
Journal: Neuro-Oncology (2018)

Poor outcomes in glioblastoma are partially explained by unpredictable individual responses to therapy. Topoisomerase II (TOP2) poisons Etoposide and Doxorubicin, which induce double-strand DNA breaks, are effective for some glioblastoma lines. On the other hand, the TOP2-enzymatic inhibitor MST16 is used for lymphomas, but has not been tested for glioblastoma. We investigated biomarkers for glioblastoma susceptibility to these drugs to repurpose them with a precision medicine approach. We performed a genome-scale CRISPR knockout (KO) screen on an Etoposide-susceptible cell line using this drug to select resistant clones. The screen identified 106 genes from DNA damage response, a pathway that was over-represented among genes involved in etoposide susceptibility. We overlapped genes whose loss confers Etoposide resistance from our screen with genes whose expression correlates with susceptibility to this drug across 35 glioma cell lines. This approach elucidated 6 genes, including some that regulate protein synthesis, as TOP2 poison biomarker candidates. Validation through CRISPR KO of several of these confirmed that their loss confers resistance to Etoposide and Doxorubicin, and their protein levels were predictive for TOP2 poison susceptibility across glioma cell lines. In contrast, these biomarkers were not predictive of glioma response to TOP2-inhibitor drug MST-16. Through ChIP-seq, we discovered that TOP2B binding coincides with open chromatin in promoters of PDGFRA. Moreover, TOP2 inhibition with MST-16 downregulated this gene. Baseline expression of PDGFRA across glioma cell lines was highly predictive of MST-16 susceptibility, which was confirmed in an independent dataset of patient-derived glioma xenograft lines. Using complementary unbiased approaches, we identified several novel biomarkers for personalizing TOP2-targeting therapy for this disease. Inter-individual differences in glioblastoma susceptibility to TOP2 poisons relates to protein synthesis and DNA damage, whereas susceptibility to TOP2 inhibitors relates to TOP2B-mediated transcriptional regulation of an oncogene.
EXTH-11. GLIOBLASTOMA STEM CELL GROWTH DEPENDENCE ON NUTRIENTS: MORE THAN BASAL METABOLIC ACTIVITIES
Authors: Chen Zhang, Jie Ding, Kang Jin Jeong, Soon Young Park, Shaofang Wu, Xiaolong Li, Feng Gao, W K Alfred Yung, Dimpy Koul
Journal: Neuro-Oncology (2018)

Deregulated uptake of glucose and amino acids is one of the hallmarks of cancer metabolism. Clinical trials and numerous drugs have been designed to target cancer cell metabolism, however, the effect on cell growth inhibition and how tumor cell metabolism couples with cell growth remain unclear. In this study, we report the glioblastoma stem cells (GSCs) growth dependence on nutrients (glucose, amino acid, and fatty acid) and oxygen. We show that the basal metabolic activities are unable to reflect the extent of proliferation inhibition by metabolic inhibitors. 2-DG (20mM) downregulated extracellular acidification rate (ECAR) more effectively in GSCs with higher glycolytic activity (Pearson r=0.71, p=0.08), the basal glycolytic activity, however, was not significantly correlated with glycolysis inhibitor (2-Deoxy-D-glucose, 2-DG) sensitivity (Pearson r=0.35, p=0.44), indicating basal glycolytic activity cannot predict GSC response to glycolysis inhibitor. Similarly, basal oxidative phosphorylation (OXPHOS) activity also failed to predict GSC responses to OXPHOS inhibition. Although GSCs showed the consistent susceptibility against oligomycin (complex V inhibitor) and hypoxia (Pearson r=0.61, p=0.15), there is no significant correlation between basal oxygen consumption rate (OCR) and oligomycin/hypoxia-induced proliferation inhibition. Thus, both basal glycolytic and basal OXPHOS activities were unable to explain their roles in GSC growth. Studies are underway to investigate the effect of fatty acid and amino acid on tumor growth. As drugs targeting cancer metabolic processes always show dose-limiting toxicity, our study will focus on identifying new “druggable” targets according to GSC nutrient dependences and developing specific therapeutic strategy for GBM populations with certain nutrient dependence.
PDTM-03. CREDENTIALING NOVEL PEDIATRIC GLIOMA MODELS
Authors: David Rincon Fernandez Pacheco, Gi Bum Kim, David Saxon, Amy Yang, Sara Sabet, Hannah Park, Shea Chandra, Kristyna Sendivakova, Chintda Santiskulvong, Yizhou Wang, Jie Tang, Moise Danielpour, Joshua Breunig
Journal: Neuro-Oncology (2018)

We have developed a simple and generalizable in vivo method for brain tumor modeling, mosaic analysis by dual recombinase-mediated cassette exchange (MADR). MADR allows for stable labeling of mutant cells expressing transgenic elements from a precisely-defined chromosomal locus. We have demonstrated the power and versatility of MADR by creating novel glioma models with mixed, reporter-defined zygosity, or with “personalized” H3.3-containing driver mutation signatures from pediatric glioma--each manipulation altering the spatiotemporal profile of resulting tumors. Further we have generated ependymoma models by employing patient-derived fusion driver mutations. Notably, each model displays divergent spatiotemporal tumor expansion profiles and cellular phenotypes. Now, we use single-cell RNA-seq to compare these models to their cells of mutation and to human datasets to elucidate the fundamental transcriptional programs and markers within and across these tumor types. This investigation will assess and credential these models against their clinical counterparts by scrutinizing the resulting datasets and validating their clinical relevance as pre-clinical models for therapeutic discovery and testing.