tbuckley/cabot-search huggingface dataset:
NIMG-03. RADIOMIC TEXTURE ANALYSIS TO PREDICT RESPONSE TO IMMUNOTHERAPY
Authors: Rivka Colen, Ahmed Hassan, Nabil Elshafeey, Pascal Zinn, Amy Heimberger, John de Groot
Journal: Neuro-Oncology (2018)

Radiomic texture analysis (TA) from standard MRI imaging may be able to discriminate between responders versus non-responders in glioblastoma patients treated with pembrolizumab immunotherapy. 14 patients (5 males; mean age 58 years; range: 32–72 years), with pathologically-proven recurrent GBM, enrolled in a pembrolizumab clinical trial, were retrospectively evaluated. Immunotherapy Response Assessment in Neuro-Oncology(iRANO) were performed. Patients were categorized based on: 1) best response or 2) overall response (OR) using the iRANO status at the last scan time in the trial. Patients with progressive disease (PD) were classified as non-responders, while patients with partial response (PR) or stable disease (SD) were classified as responders. T2-FLAIR (edema/invasion) and post-contrast T1WI (enhancing tumor) of baseline scans were co-registered and segmented (3D Slicer, v.4.3.1) to create a volume of interest for Radiomic TA. A total of 4880 texture features were extracted. Feature selection was performed using Lasso regularization. For classification and predictive model building, gbtree booster of XGboost with Leave-One-Out Cross-Validation (LOOCV) was used on the selected texture features to build a binary logistic regression model and classify the patients into respective groups<.strong> Using the best response classification, 10 patients were classified as non-responders and four patients classified as responders (1 SD; 3 PR). Using 13 radiomic features, these patients could be classified into their respective responding groups with a sensitivity, specificity and accuracy of 100%, p-value=0.0089. Based on OR, 12 patients were classified as non-responders and two as responders (2 SD). Seven features were able to differentiate the responding patients with a sensitivity, specificity and accuracy of 100%, p-value=0.0089. Radiomic TA was able to discriminate and predict those GBM patients that are responders versus non-responders to pembrolizumab with high robustness. Of note, given the small number of patients in this cohort, a larger cohort of patients is needed to minimize overfitting.
Global Coronary Flow Reserve Measured During Stress Cardiac Magnetic Resonance Imaging Is an Independent Predictor of Adverse Cardiovascular Events
Authors: Raksha Indorkar, Raymond Y. Kwong, Simone Romano, Brent E. White, Richard C. Chia, Michael Trybula, Kaleigh Evans, Chetan Shenoy, Afshin Farzaneh-Far
Journal: JACC. Cardiovascular imaging (2018)
QOLP-13. PSYCHOSOCIAL DISTRESS IN PATIENTS WITH RECURRENT MENINGIOMAS
Authors: Dina Randazzo, John Kirkpatrick, Frances McSherry, James Herndon, Mary Affronti, Margaret Johnson, Zachary Vaslow, Eric Lipp, Annick Desjardins, Henry Friedman, Katherine Peters
Journal: Neuro-Oncology (2018)

Meningiomas, the most common CNS neoplasm, are often deemed less threatening than their glial counterparts. Unfortunately, these tumors recur and necessitate surgery, radiation, and/or systemic treatment. We explored the psychosocial distress of patients with recurrent meningioma using The National Comprehensive Cancer Network Distress Thermometer (NCCN-DT) and Problem List. This was a retrospective analysis of patients with recurrent meningioma seen at the Preston Robert Tisch Brain Tumor Center between 12/31/2004–10/10/2018 who completed a NCCN-DT and Problem List. The first or only NCCN-DT assessment after initial recurrence was used for analysis with a score of 4 indicating moderate to severe distress. 45 patients were identified, 56% female, median age was 61 years and 58% had unifocal disease. 60% were Grade 1, 33% Grade II, 4% Grade III, and 2% indeterminate recurrent meningioma. The median NCCN-DT score was 3, and 49% had a NCCN-DT score 4 indicating moderate to severe distress. 64% of females vs 30% of males reported distress scores 4 (p=0.04). 65% of patients with unifocal disease reported 4 scores compared to 26% with multifocal disease (p=0.02). Fatigue (N=24), Worry (N=23), Nervousness (N=22), Depression (N=19) and Memory/Concentration (N=19) were the most commonly reported problems. A higher incidence of worry among females (64%) than males (35%) was the only problem showing a trend towards significance (p=0.08). Between initial recurrence and NCCN assessment, the type and number of treatments patients received included: surgery (median=1, range 0–5), radiation (median=2, range 0–5), systemic treatment (median=2, range 0–12). There was no association between distress and the number of surgeries (p=0.99), radiation treatments (p=0.49) or systemic therapies (p=0.87). CONCLUSIONS: In our study population, nearly half of recurrent meningioma patients reported moderate to severe distress. Therefore, even in this benign tumor population, the NCCN-DT and problem list should be administered at every clinic visit.
IMMU-61. INHIBITION OF MUTANT IDH1 WITH AGI-5198 ENHANCES THE EFFICACY OF RADIOTHERAPY ELICITING IMMUNOLOGICAL MEMORY AND IMPROVING OVERALL SURVIVAL
Authors: Padma Kadiyala, Felipe Nunez, Dan Li, Anna Schwendeman, Pedro Lowenstein, Maria Castro
Journal: Neuro-Oncology (2018)

Mutant IDH1 gliomas have are heterogeneous tumors with a high incidence of relapse. We are studying a glioma subtype, genetically characterized by inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) gene, TP53 and gain of function mutations in isocitrate dehyrdogenase 1 (mIDH1). Mutation in IDH1 converts α-ketoglutrate (αKG) to 2-hydroxyglutarate (2HG), an oncometabolite that inhibits histone and DNA demethylases, leading to a hypermethylated tumor phenotype. This leads to epigenetic reprograming of the tumor trancriptome. AGI-5198 a specific mIDH1inhibitor blocks the production of 2HG within the mIDH1 glioma cells. Our in-vitro data using AGI-5198 in combination with radiation, which is the standard of care for mIDH1 glioma patients, demonstrated that mIDH1 inhibition confers radiosensitivity to the tumor cells. To determine whether AGI-5198 would be an effective radiosensitizer in-vivo, we used a mIDH1 glioma transplantable mouse model. Animals were implanted with mIDH1 tumor cells and at day seven post tumor implantation; they were treated with radiation followed by administration of AGI-5198. With systemic delivery of AGI-5198, we observed 40% long term survivors(>90 days) in the single modality treatment. Our results also demonstrate that the combination of AGI-5198 and radiation therapy significantly prolongs the median survival (MS) of mIDH1 glioma bearing mice (~1.5 fold vs controls); eliciting strong antitumor activity, eradicating 40% of the established mIDH1 gliomas. In addition, when the long term survivors were rechallenged with mIDH1 tumor cells in the contralateral hemisphere, without further treatment, all the mice remained tumor free, indicating the development of anti-glioma immunological memory. Collectively, these findings support the clinical testing of AGI-5198 as an adjuvant therapy for patients with mIDH1 glioma.
DDIS-14. MODIFIED CARBAZOLES DESTABILIZE MICROTUBULES AND KILL GLIOBLASTOMA MULTIFORM CELLS
Authors: Nephi Stella, Philippe Diaz, Eric Horne, Cong Xu, Ernest Hamel, Mike Wagenbach, Ravil Petrov, Brian Hass, Hothi Parvinder, Linda Wordeman, Rick Gussio
Journal: Neuro-Oncology (2018)

Small molecules that target microtubules (MTs) represent promising therapeutics to treat certain types of cancer, including glioblastoma multiform (GBM). We synthesized modified carbazoles and evaluated their antitumor activity in GBM cells in culture. Modified carbazoles with an ethyl moiety linked to the nitrogen of the carbazole and a carbonyl moiety linked to distinct biaromatic rings exhibited remarkably different killing activities in human GBM cell lines and patient-derived GBM cells, with IC50 values from 67 to > 10,000 nM. Measures of the activity of modified carbazoles with tubulin and microtubules coupled to molecular docking studies show that these compounds bind to the colchicine site of tubulin in a unique low interaction space that inhibits tubulin assembly. The modified carbazoles reported here represent novel chemical tools to better understand how small molecules disrupt MT functions and kill devastating cancers such as GBM.
CMET-01. CLINICAL AND DOSIMETRIC FACTORS RELATED TO RADIATION NECROSIS AFTER FIVE FRACTION RADIOSURGERY FOR RESECTED BRAIN METASTASES
Authors: Zachary Buchwald, Jaymin Jhaveri, Eduard Schreibmann, Jeffrey Switchenko, Roshan Prabhu, Mudit Chowdhary, Mustafa Abugideiri, Bree Eaton, Jeffrey Olson, Hui-Kuo Shu, Ian Crocker, Walter Curran, Kirtesh Patel
Journal: Neuro-Oncology (2018)

Stereotactic Radiosurgery (SRS) is increasingly utilized in the management of resected brain metastases (rBM). A significant complication is radiation necrosis (RN) due to larger target size. Despite dose de-escalation and hypofractionation, rates of RN after SRS to rBM remain high. The aim of this analysis is to evaluate dosimetric parameters associated with RN for rBM. From 2008–2016, 55 rBM in 52 patients at a single institution that were treated with 5 fraction LINAC based SRS (25-35Gy) with a minimum 3 months follow-up were evaluated. For each lesion, variables including clinical target volume (CTV), dose and location/magnitude of hot spots were recorded. Hot spot location was stratified as either within tumor bed (CTV) or within the PTV expansion margin (PTV minus CTV). Overall survival (OS) estimated using Kaplan-Meier method. Cumulative incidence with competing risks was used to estimate rates of RN and local recurrence (LR). Optimal cut-points predicting for RN for hotspot magnitude based on location were identified via maximization of the log-rank test statistic. Median age and OS for all patients was 58.5 years and 16.2 months, respectively. For all targets, the median CTV was 17.53 cc, and mean max hotspot was 113%. At 1 year, cumulative incidence of RN and LR for all patients was 21.8% and 13.1%. Univariate analysis showed max hot spot (hazard ratio (HR): 3.28, p=0.045) and hot spots within PTV expansion margin of 105%, 110% and 111% predicted for RN with HRs of 3.64, 8.47, and 6.90 respectively (all p<0.05), but hot spots within the CTV did not. To our knowledge, this is the first study that investigated dosimetric factors that predict for RN after hypofractionated SRS to rBM. Hot spot location and magnitude appear important for predicting RN risk, suggesting these parameters should be considered during treatment planning.
DDIS-22. WSD0922: A BBB PENETRABLE EGFR/EGFRVIII SMALL MOLECULE FOR THE TREATMENT OF GBM AND METASTATIC CNS TUMOR
Authors: Wei Zhong, Jinqiang Zhang, Zhihua Mu, Claire Sun
Journal: Neuro-Oncology (2018)

Aberrant EGFR signaling caused by mechanisms of overexpression, mutation, or autocrine activation contributes for oncogenesis by inducing cell proliferation and resisting apoptosis. In patients with GBM, an overall frequency of 25–64% mutation is EGFRvIII (exon2-7 deletion). In patients with NSCLC harboring active EGFRm+(Del19 and L858R), up to 65% brain/leptomeningeal metastasis develop ultimately after EGFR TKIs treatment. Current approved EGFR TKIs have demonstrated limited therapeutic efficacy against CNS tumors due to insufficient BBB penetration and/or poor activity against EGFRm+ such as EGFRVIII. The occurrence of GBM and rate of CNS metastases of NSCLC are increasing, thus there is a high unmet medical need for the development of a BBB penetrable EGFR inhibitor (common tumor drivers in the brain: EGFRVIII/Del19/L858R) to clinic. Herein, we report a discovery of brain penetrable EGFR inhibitor WSD0922 for GBM and NSCLC CNS metastasis with IC50 against EGFRm+ ex-vivo GI50 in GBM tissues with EGFRvIII is In-vitro MDCKII transfected cells and Caco-2 assays have shown that WSD0922 is highly permeable (61x10-6 cm/s) and not a substrate of P-gp or BCRP, two main efflux transporters expressed on human BBB. Preclinical CNS PK studies confirmed good brain penetration of WSD0922 with Kp,uu,brain close to unity. Significant TGI or regression for mice bearing GBM PDX model with EGFRVIII was achieved by treatment with WSD0922. Moreover, treatment of mice bearing PC-9 (Del19 in NSCLC) in both subcutaneous and intracranial models with WSD0922 resulted in dose dependent TGI or regression with statistically significant survival benefit. Predicted human PK properties are very promising to offer sufficient target engagement in clinic. Taken together, our data provide a good rationale for WSD0922 to be developed toward clinic for the treatment of patients with GBM and CNS metastasis of NSCLC harboring EGFRm+.
STEM-19. MONOCARBOXYLATE TRANSPORTER-4 DEPLETION INHIBITS STEMNESS, PROMOTES DNA DAMAGE AND RADIOSENSITIZES GLIOBLASTOMA STEM CELLS
Authors: Raffaella Spina, Dillon Voss, Jason W Sohn, Robert Vinkler, Julianna Schraner, Anthony Sloan, Scott Welford, Eli Bar
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults, with a median survival for patients of 12–15 months after diagnosis. Standard therapy includes radiation and chemotherapy, with GBM recurrences refractory to second line treatments. Given the lack of therapeutic opportunities in GBM, new treatment strategies are urgently needed. Glioma stem cells (GSCs) have been shown to support GBM maintenance and exhibit enhanced resistance to ionizing radiation, a cornerstone of GBM therapy. Monocarboxylate transporter-4 (MCT4, SLC16A3) is highly expressed in the vast majority of GBMs and predominantly in cells that congregate in “palisades” around centers of necrosis or in cells where hypoxia-inducible factor-1alpha (HIF-1α) is expressed either due to reduced oxygen levels or other microenvironmental stresses. MCT4 appears to regulate proliferation, survival, and xenograft implantation of GSC neurosphere lines. Importantly, we found these effects to be independent of lactate homeostasis. Gene set enrichment analysis (GSEA) of differentially expressed genes revealed an enrichment of DNA replication stress response pathways including cell cycle (G2/M checkpoint), DNA replication, DNA damage response (DDR), and cellular deoxyribonucleotide metabolism in MCT4-depleted GSCs. To validate these data, after lentiviral silencing of MCT4 expression in two GBM neurosphere lines, we examined DNA repair potential by assessing the resolution of yH2AX and by performing alkaline comet assays. In both assays, reduced MCT4 levels resulted in a dramatic increase in the number of nuclear foci (p < 0.0001) and in the percentage of cells with comet tails (p=0.0003), respectively, confirming that reduced MCT4 expression decreases cellular ability to repair DNA damage. Moreover, we show that conditional MCT4 depletion alone (p=0.0001) or in combination with ionizing radiation (p=0.0006) efficiently enhance survival of mice orthotopically implanted with GSC-derived xenografts. We determined that MCT4 inhibition enhances the radiosensitivity of GBM and should be explored as a treatment strategy to complement conventional treatment.
Abstract P040: GlycA, a Novel Inflammatory Marker, and Subclinical Coronary Atherosclerosis in the Multicenter AIDS Cohort Study (MACS)
Authors: Oluwaseun E Fashanu, Martin Tibuakuu, Di Zhao, James D Otvos, Todd T Brown, Sabina A Haberlen, Eliseo Guallar, Matthew J Budoff, Frank J Palella, Jeremy J Martinson, Akintunde O Akinkuolie, Samia Mora, Wendy S Post, Erin D Michos
Journal: Circulation (2018)

Background: Inflammation may link HIV infection to cardiovascular disease (CVD). GlycA, a novel nuclear magnetic resonance (NMR) biomarker of systemic inflammation, has been associated with incident CVD events in the general population. The relation between GlycA and the presence, extent and composition of subclinical coronary plaque in men with HIV infection (HIV+) or at risk for HIV (HIV-) is unknown. Methods: This is a cross-sectional analysis of 935 men enrolled in MACS with plasma measurement of GlycA and non-contrast cardiac CT and/or coronary CT angiography. We used multivariable adjusted Poisson and linear regression to assess associations of GlycA with prevalent coronary atherosclerosis and plaque extent, respectively. Results: Mean ± SD age was 54 ± 7 yrs; 31% were black, and 63% HIV+ with 81% having undetectable viral load (VL). GlycA levels were higher in HIV+ compared to HIV- men (397 ± 68 vs 380 ± 60 μmol/L, p=0.0001), and higher for those with detectable VL vs. undetectable (413 ± 79 vs 393 ± 65 μmol/L, p=0.004). After adjusting for demographic and CVD risk factors, every 1 SD increment in GlycA was associated with an increased prevalence of coronary artery calcium (CAC&gt;0) (prevalence ratio: 1.09, 95% CI: 1.03-1.15), coronary stenosis ≥ 50% (1.20, 1.02-1.41), and calcified plaque (1.12, 1.02-1.23); p for all &lt; 0.03. These associations remained significant after adjusting for other inflammatory markers and did not differ by HIV status. Among men with plaque, GlycA was positively associated with the extent of CAC, total plaque and mixed plaque ( Table ). Associations were weaker in HIV+ men for total and mixed plaque (P interaction = 0.003 and 0.03, respectively). GlycA was not associated with non-calcified plaque. Conclusion: HIV+ men have higher levels of GlycA than HIV- men. Higher GlycA is positively and independently associated with subclinical coronary atherosclerosis. Whether modification of GlycA through lifestyle or pharmacotherapy can reduce coronary plaque burden and future CVD events requires further study.
ACTR-53. STEAM / EORTC 1608: STUDY OF TG02 IN ELDERLY NEWLY DIAGNOSED OR ADULT RELAPSED PATIENTS WITH ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA - A PHASE 1B STUDY
Authors: Emilie Le Rhun, Tract Parrott, Thierry Gorlia, Beatrice Fournier, Tom Estok, Michael Weller
Journal: Neuro-Oncology (2018)

TG02 is an oral multi-cyclin dependent kinase (CDK) inhibitor that is thought to inhibit tumor growth mainly through CDK9-dependent depletion of oncoproteins such as MCL-1 and MYC. MCL-1 and MYC are frequently overexpressed in glioblastoma (up to 80%). Several studies including analyses of patient-derived glioma cell lines have demonstrated profound inhibitory activity (IC50 range = 25–150 nM). Clinical pharmacokinetics from a phase 1b study in multiple myeloma patients demonstrate that TG02 exposures in humans are sufficient for achieving inhibitory concentrations required in the majority of the glioma cell lines tested. Preclinical studies in mice have demonstrated that TG02 is a good candidate for development in gliomas. Based on these data, the EORTC Brain Tumor Group, in cooperation with Tragara, is currently conducting the phase 1b STEAM trial (EORTC 1608), a three parallel group (A,B,C) open-label, non-randomized, multicenter study. The recommended phase II dose of TG02 in elderly patients with IDH1R132H-non mutant newly diagnosed glioblastoma will be determined in a classical 3 + 3 design dose-escalation and safety study of TG02 in combination with either hypofractionated radiotherapy (RT) or temozolomide (TMZ) in arms A and B. Patient allocation to treatment in arms A and B will be determined by MGMT promoter methylation status centrally determined according to EANO guidelines for the treatment of elderly patients with glioblastoma. Arm C will explore single agent TG02 activity in anaplastic astrocytoma or glioblastoma at first relapse after initial treatment with TMZ/RTTMZ with a primary endpoint of progression-free survival at 6 months. Secondary objectives include efficacy, quality of life, safety, and correlation with molecular markers. The study is currently open in 2 sites and shall be opened until SNO in 5 additional EORTC sites in Europe. Patient enrolment is planned to start in June 2018. An update will be provided at the SNO conference. NCT03224104
GENE-39. MicroRNA-BASED MARKERS IN CEREBROSPINAL FLUID AS POTENTIAL DIAGNOSTIC TOOLS FOR LEPTOMENINGEAL METASTASIS IN LUNG ADENOCARCINOMA PATIENTS
Authors: Zhenyu Pan, Guozi Yang, Lihua Dong, Hua He, Tongchao Jiang, Pengxiang Gao, Zhuo Wang
Journal: Neuro-Oncology (2018)

We hope to identify leptomeningeal metastasis (LM)-related cerebrospinal fluid (CSF) miroRNAs as potential molecular markers contributing to diagnosis of LM patients with lung adenocarcinoma. MATERIAL AND CSF samples were collected from lung adenocarcinoma patients with LM (positive group) and non-LM patients (negative group). Meanwhile, matching CSF samples from other lung adenocarcinoma LM patients were collected before and after effective LM-related treatment. Samples were screening using Agilent Human microRNA arrays. Differentially expressed microRNAs in both of two sets as well as significantly expressed microRNAs in either one set were selected as targets. Whereafter, expression of target CSF miRNAs was determined using quantitative real-time PCR (qRT-PCR). Differential microRNAs expression was analyzed by Mann-Whitney Test. Receiver Operating Characteristic (ROC) curve analysis was used to determine sensitivity and specificity. Twenty samples obtained from 10 LM patients and 10 non-LM controls (5 brain metastasis from lung adenocarcinoma and 5 nonneoplastic disease) were subjected to microRNA arrays. Meanwhile, 6 couples of matching samples were subjected to microRNA arrays.The intersection of significantly differential expression, miR-7977, miR-7975 and miR-4800-5p, were significantly up-regulated in positive group, and down-regulated after effective LM-related treatment. These three microRNAs were selected as targets and subjected to qRT-PCR. Significant increase was noticed in expression of miR-7977 (P=0.001), miR-7975 (P=0.001) and miR-4800-5p (P=0.024) in newly collected samples of 17 LM cases compared with 14 non-LM controls (9 brain metastasis from lung adenocarcinoma and 5 benign brain tumor). ROC analysis indicated that area under curve for miR-7977, miR-7975 and miR-4800-5p was 0.849(P=0.001, 95%CI 0.694–1.0), 0.840(P=0.001, 95%CI 0.688–0.992), and 0.739(P=0.024, 95%CI 0.564–0.915), respectively. The cutoff value, sensitivity and specificity were 48.3, 0.824 and 0.857 for miR-7977, 29.4, 0.824 and 0.929 for miR-7975, and 44.9, 0.765 and 0.643 for miR-4800-5p, respectively. MiR-7977, miR-7975 and miR-4800-5p may serve as molecular markers for diagnosis of LM from lung adenocarcinoma.