tbuckley/cabot-search huggingface dataset:
MNGI-28. CORRELATION OF METHYLATION CLASS AND GENETIC ALTERATIONS WITH PROGRESSION FREE SURVIVAL IN MENINGIOMA
Authors: Anna Berghoff, Gerda Ricken, Ursula Rajky, Christine Marosi, Johannes Hainfellner, Andreas von Deimling, Felix Sahm, Matthias Preusser
Journal: Neuro-Oncology (2018)

Meningioma is a heterogenous disease and precise molecular characterization may support clinical decision-making. Several recurring gene mutations as well as prognostic relevant DNA-methylation classes were recently identified in meningioma. We aimed to validate the recent findings in an independent cohort. Formalin fixed and paraffin emended samples of 127 meningioma patients (Grade I 40.9%; Grade II: 37.8%; Grade III: 21.3%) were retrieved from the Neuro-Biobank, Institute of Neurology, Medical University of Vienna. Methylation classes (MC) were analyzed using 850k EPIC (Illumina, San Diego, CA, USA) according to the Heidelberg Meningioma Classifier. Panel sequencing for genes reported to impact meningioma, namely NF2, TRAF7, KLF4, ARID, SMO, AKT, TERT, PIK3CA and SUFU was performed as previously outlined. The TRAKLS mutation type was characterized by presence of TRAF7, AKT1, KLF4 or/and SMO mutation. Survival data including progression free survival was retrieved from chart review. Meningioma relevant mutations were evident in 96/127 (75.5%) specimens. NF2 (42/127; 33.1%), TRAF7 (40/127; 31.5%), KLF4 (27/127; 21.3%) and ARID (25/127; 19.7%) mutation were the most frequently observed ones. Two or more mutations were observed in 51/127 (40.2%) specimens. MC correlated with presence of target mutations as well as clinical characteristics (p<0.05; Chi Square test). TRAF7, KLF4 and TERT mutations as well as TRAKLS mutation type associated with progression free survival in univariate analysis (<0.05; log rank test), however in multivariable analysis only MC (HR 1.9; 95% CI 1.3–2.8; p=0.001; cox regression model) and presence of TERT mutation HR 24.9; 95% CI 3.9–159.8; p=0.001; cox regression model) remained statically significant. Molecular profiling including methylation class and genetic aberrations and may facilitate more precise prognostic assessment and identification of potential targets for targeted therapy in meningioma patients.
EXTH-04. TARGETING CD97 BY NOVEL FUSION PROTEIN DAF-FC INHIBITS GBM INVASION AND INDUCES ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY
Authors: Alan Nguyen, Michael Safaee, Ankush Chandra, Keith Wycoff, Manish Aghi
Journal: Neuro-Oncology (2018)

The poor prognosis of GBM reflects its capacity to supplement proliferative programs with pro-tumoral interactions with the microenvironment, including invasion and immunosuppression. There is a need to simultaneously target these processes, as they can be temporally, mutually exclusive phenotypes toggling back and forth. We have shown CD97 to be upregulated in GBM and capable of mediating each of these pro-tumoral functions in GBM by binding three ligands: decay accelerating factor (DAF/CD55), chondroitin sulfate, and integrins. To validate CD97 as a therapeutic target in glioblastoma, we partnered with an industry collaborator to produce a DAF-Fc fusion protein in a plant expression system combining DAF with IgG1 Fc to block CD97. CD97 was targeted with siRNA or DAF-Fc. Scratch and matrigel invasion assays were used to assess migration and invasion, respectively. Antibody dependent cellular cytotoxicity (ADCC) assays used NK-92 human natural killer cells as effector cells and GBM or peripheral blood mononuclear cells (PBMCs) as target cells. Intracranial implantation of glioblastoma cells into athymic mice was followed by DAF-Fc or IgG treatment, with IgG1-Fc detected by immunohistochemistry. CD97 expression was elevated in GBM cells versus astrocytes and lymphocytes, and CD97 knockdown by siRNA reduced migration and invasion by 65–75% (p<0.01). Treatment of human and mouse GBM cells with human and mouse DAF-Fc inhibited migration and invasion by 60–80% (p<0.001). There was increased ADCC against GBM cells with increased DAF-Fc concentration and effector to target ratio (p<0.001), but negligible PBMC toxicity at the highest DAF-Fc dose. Systemically delivered DAF-Fc crossed the blood-brain barrier in orthotopic GBM models with specific tumoral uptake compared to normal brain. Our results validate DAF-as a GBM therapeutic with negligible off-target effects against normal astrocytes or PBMCs. Further preclinical evaluation in invasive murine models ahead of a phase I trial is underway.
IMMU-48. GLIOMA IMMUNE PROFILING REVEALS UNIQUE IMMUNE THERAPEUTIC OPPORTUNITIES
Authors: Martina Ott, Shouhao Zhou, Jun Wei, John de Groot, Jason T Huse, Ian McCutcheon, Sujit Prabhu, Sherise Ferguson, Jeffrey Weinberg, Raymond Sawaya, Ganesh Rao, Frederick Lang, Amy Heimberger
Journal: Neuro-Oncology (2018)

There is a rapidly evolving portfolio of immune therapeutic modulators, but the relative incidence of immune targets in human gliomas is unknown. To prioritize available immune therapeutics, comprehensive immune profiling across glioma grades was conducted. CD4+ and CD8+ T-cells and CD11b+ monocytes/macrophages were isolated from the blood of healthy donors (n= 6) and the blood and tumors of newly diagnosed and recurrent grade II (n= 7), III (n= 6) and IV glioma patients (n= 12), and profiled for the expression of 30 immune modulatory targets. In CD4+ and CD8+T-cells, PD-1 and the adenosine pathway showed high expression levels in tumor-infiltrating lymphocytes (TILs) across glioma grades and treatment states. The mean fluorescent intensity (MFI) of A2aR was appreciably upregulated in the TIL and in the CD11b+ glioma-infiltrating monocytes/macrophages (GIM) compared to healthy donors (CD4+ p= 0.0201; CD8+ p= 0.0233; CD11b+ p= 0.0009) and matched peripheral blood (CD4+ p= 0.0054; CD8+ p= 0.019; CD11b+ p< 0.0001). LAG3 and TIM3 TIL expression frequency was low and not associated with glioma grade. TIGIT CD8+TIL were more frequent in high-grade gliomas (grade III and IV). CD39 was upregulated in the TIL compared to healthy donors (CD4+ p=0.0032; CD8+ p=0.0006) and matched peripheral blood (CD4+ p= 0.0002; CD8+ p< 0.0001). B7-H3 (p= 0.0167) and Galectin-9 GIM expression (p= 0.0042) are frequently upregulated in glioblastoma. Regardless of glioma grade, the T-cell co-stimulatory molecule CD86 is down-regulated in the GIM (p= 0.0019). Many immune modulatory markers were not frequently upregulated but exceptionally high in individual patients. Predicated on expression frequency, immune therapeutics targeting PD-1 and the adenosine pathway would be applicable to most glioma patients regardless of grade or prior treatment status. Clinical trials considering the use of other immune targets, such as LAG3, TIM3, TIGIT, BTLA, B7-H3, and Galectin-9 need to consider a companion biomarker for enrollment enrichment.
Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria: Pharmacokinetics and Pharmacodynamics Observed in Two Phase 3 Randomized, Multicenter Studies
Authors: Regis Peffault De Latour, Robert A. Brodsky, Stephan Ortiz, Antonio M. Risitano, Jun-Ho Jang, Peter Hillmen, Aleksandr Kulagin, Rajendra Pradhan, Scott T. Rottinghaus, Rasha Aguzzi, Richard A. Wells, Jeffrey Szer
Journal: Blood (2018)
Abstract 14562: First-in-human Pilot Study of Hydrogen Gas Inhalation for Treatment of Post-cardiac Arrest Syndrome
Authors: Tomoyoshi Tamura, Kei Hayashida, Masaru Suzuki, Motoaki Sano, Joe Yoshizawa, Takayuki Shibusawa, Yosuke Kobayashi, Takeshi Suzuki, Shigeo Ohta, Hiroshi Morisaki, Keiichi Fukuda, Shingo Hori
Journal: Circulation (2016)

Background: Recent proof-of-concept studies in animal models have demonstrated a therapeutic effect of H2 Inhalation (HI) on neurological outcomes following cardiac arrest (CA). In this study, we s...
Abstract 14084: Mobilization of Muse Cells, Pluripotent Stem Cells, by Sphingosine-1-phosphate Receptor 2 Agonist Leading to Cardiomyocyte Regeneration and Functional Recovery After Acute Myocardial Infarction
Authors: Shingo Minatoguchi, Yoshihisa Yamada, Shouhei Wakao, Yoshihiro Kushida, Masamitsu Iwasa, Hiromitsu Kanamori, Masanori Kawasaki, Kazuhiko Nishigaki, Mari Dezawa, Shinya Minatoguchi
Journal: Circulation (2017)

Background: Multilineage-differentiating stress-enduring (Muse) cells, which have a high potential for pluripotency, reside in the bone marrow (BM). Purpose: We examined whether sphingosine-1-phosp...
Abstract 14689: Effects of Statin Therapy on Three-Dimensional Morphology of Fibrous Caps in Lipid Plaques: Analysis Using a Newly Developed Algorithm for OCT
Authors: Zhao Wang, Young-Seok Cho, Tsunenari Soeda, Lei Xing, Haibo Jia, Aaron Aguirre, Rocco Vergallo, Yoshiyasu Minami, Hang Lee, James G Fujimoto, Bo Yu, Ik-Kyung Jang
Journal: Circulation (2015)

Background: The exact dose-dependent mechanism of plaque stabilization with statin therapy remains unclear. The objective of this study is to compare the effects of different doses of statin therapy on 3D morphology of fibrous caps using optical coherence tomography (OCT). Methods: Patients with coronary artery disease were randomized into two groups of treatment: atorvastatin 20 mg/day (moderate intensity) and atorvastatin 60 mg/day (high intensity), and were imaged by OCT at baseline and 12-month follow-up. A total of 31 lipid plaques from 21 patients were analyzed. Fibrous caps were quantified in 3D using a novel computer algorithm. 3D metrics provided comprehensive information on the distribution and surface area of fibrous caps in a thickness category (e.g. &lt;80 μm). Fibrous caps were reconstructed in 3D to assess plaque vulnerability (Fig. 1). Results: Both high and moderate intensity statin therapy increased fibrous cap thickness at follow-up. However, only high intensity statin therapy reduced thin cap (&lt;80 μm) area significantly at follow-up. Conventional metrics such as the minimum cap thickness failed to reveal the differences between the treatment groups (Fig. 2). Instead, 3-D metrics, in particular the thin cap area change showed dose-dependent differences between the treatment groups (p&lt;0.001). 3-D reconstructions further revealed that high intensity statin treatment induced a more rapid transition from thin to thick caps. Conclusions: High intensity statin therapy more effectively stabilized fibrous caps. Thin cap area can be used as a better metric than minimum cap thickness for characterizing vulnerable plaque evolution.
History of Atrial Fibrillation and Trajectory of Decongestion in Acute Heart Failure
Authors: Ravi B Patel, Muthiah Vaduganathan, Aruna Rikhi, Hrishikesh Chakraborty, Stephen J Greene, Adrian F Hernandez, G Michael Felker, Margaret M Redfield, Javed Butler, Sanjiv J Shah
Journal: JACC Heart Failure (2018)
NCMP-09. ISOCITRATE DEHYDROGENASE MUTATIONS AND INCREASED TISSUE 2-HYDROXYGLUTARATE CONCENTRATION MIGHT BE RELATED WITH SEIZURE ONSET IN PATIENTS WITH GLIOMAS
Authors: Makoto Ohno, Mitsuhiro Hayashi, Yuko Matsushita, Yasuji Miyakita, Masamichi Takahashi, Erika Yamazawa, Natsuko Tsushita, Koichi Ichimura, Akinobu Hamada, Yoshitaka Narita
Journal: Neuro-Oncology (2018)

Mutations in isocitrate dehydrogenase 1 or 2 genes (IDH1/2) frequently occur in lower-grade gliomas and secondary glioblastomas. Mutant IDH1/2 proteins gain a new ability to produce the oncometabolite 2-hydroxyglutarate (2HG). Recently, IDH1/2 mutations were suggested to be related with seizure onset through the structural similarity of 2HG to the excitatory neurotransmitter glutamate. Therefore, we sought to investigate the relationship between seizure onset and IDH1/2 status, tissue 2HG concentration and distribution. We assessed 149 patients with WHO grade II-IV glioma, whose IDH1/2 status were identified and measured serum and tissue 2HG concentrations in 123 and 104 patients by using liquid chromatography-tandem mass spectrometry method. The matrix assisted laser desorption and ionization mass spectrometry imaging (MALDI-MSI) was use to analyze tissue 2HG distribution for 12 tissue samples. Seizure onset was observed in 34 among 56 (60.7%) patients with IDH mutant tumor, whereas in 18 among 93 (19.4%) patients with IDH wild-type tumor (p<0.0001). The median tissue 2HG concentrations in patients with seizure onset were significantly higher than in those without seizure onset (2860mg/mg vs 110mg/mg, p<0.0001). Receiver operating characteristic analysis suggested the cutoff value of the tissue 2HG concentration was of 1190mg/mg. Multivariate analysis, including tissue 2HG concentration, serum 2HG concentration, IDH1/2 mutation, tumor histology, WHO grade, tumor location, and patient age, suggested that tissue 2HG concentration and serum 2HG concentration were significantly correlated with seizure onset. The MALDI-MSI showed heterogeneous 2HG distribution in IDH mutant sections. Our results suggest that increased tissue 2HG concentration and heterogeneous distribution might be related to seizure onset in patients with gliomas.
IMMU-42. TTFIELDS INDUCES IMMUNOGENIC CELL DEATH AND STING PATHWAY ACTIVATION THROUGH CYTOPLASMIC DOUBLE-STRANDED DNA IN GBM
Authors: Dongjiang Chen, Nagheme Thomas, Jie Ren, Son Le, Changwang Deng, Dan Jin, Mathew Sebastian, Duy Nguyen, David Tran
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults despite aggressive chemoradiotherapy. Recently, Tumor Treating Fields (TTFields) were approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM patients. The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly, leading to disrupted chromosomal segregation, integrity and stability. In many patients, a transient stage of increased peritumoral edema is often observed early in the course of TTFields treatment followed subsequently by objective radiographic responses, suggesting that a major component of therapeutic efficacy by TTFields may be an immune mediated process. However, the mechanism underlying these observations remains unclear. A panel of GBM cell lines were treated with TTFields at the clinically approved frequency of 200 kHz using the inovitro system. Our data showed TTFields-treated GBM cells had a significantly higher rate (19.9% vs. 4.3%, p=0.0032) of micronuclei structures released into the cytoplasm as a result of TTFields-induced chromosomal instability. Nearly 40% of these micronuclei were co-localized with two upstream dsDNA sensors Interferon (IFN)-inducible protein absent in melanoma 2 (AIM2) and Cyclic GMP-AMP synthase (cGAS), compared to absence of co-localization in untreated cells. TTFields-activated micronuclei-dsDNA sensor complexes led to i) induction of pyroptotic cell death, as measured by a specific LDH release assay, and through AIM2-recruited caspase1 and cleavage of pyroptosis-specific Gasdermin D; and ii) activation of STING pathway components including Type I IFNs and pro-inflammatory cytokines in GBM cells. These results provide compelling evidence that TTFields function as an activator of the immune system in GBM, and present a strong rationale for combining TTFields with immunotherapy aimed at augmenting an anti-tumor immune response such as immune checkpoint inhibitors.
PATH-38. CORRELATION OF ALTERATION OF HLA-F EXPRESSION AND CLINICAL CHARACTERIZATION IN 593 BRAIN GLIOMA SAMPLES
Authors: Gan You, Tingyu Liang
Journal: Neuro-Oncology (2018)

Human gliomas are highly fatal tumor with a significant feature of immune suppression. The immune system in glioma is gradually revealed, and immunotherapy is expected to improve the survival of glioma patients. With a deep understanding of the immune microenvironment of glioma, immunotherapy of gliomas has been increased exponentially in recent years. Searching for key regulators of immune response in glioma will provide clinical targets for immunotherapy. In our research, we focus on human leukocyte antigen (HLA) system, responsible for regulating the immune system, and discovered the relationship between HLA-F expression and clinical prognosis in gliomas. A total of 593 gliomas patients are concluded in our research, 325 patients from Chinese Glioma Genome Atlas (CGGA) and 268 patients from GSE 16011 set. Kaplan-Meier (KM) analysis is performed to explore the prognostic value of HLA-F. T test analysis is used to find the distribution difference in various groups. R language packages are used for other statistical computations and figures drawing. HLA-F was significantly negatively correlated with overall survival (OS) in all grade gliomas and glioblastoma (GBM). Moreover, HLA-F was enriched in GBM and IDH1 wild-type group, and HLA-F was a mesenchymal subtype marker. Pearson correlation test showed that HLA-F was correlated with other HLA-I molecules. HLA-F expression was positively with malignant phenotype and negatively with OS indicating that HLA-F could predict the immune state in glioma, and might be a clinical target of glioma immunotherapy. Key Words: HLA-F; glioma; immunotherapy; OS
TMIC-45. OLIGODENDROCYTE PROGENITOR CELLS AND MACROPHAGES/MICROGLIA INDUCE CHEMO-RADIORESISTANT ABILITIES IN GLIOMA CELLS AT THE TUMOR BORDER
Authors: Takuichiro Hide, Yoshihiro Komohara, Hideo Nakamura, Keishi Makino, Shigetoshi Yano, Ichiyo Shibahara, Toshihiro Kumabe, Akitake Mukasa
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) usually develops in adult brain white matter and shows rapid growth and invasion. Even after complete resection, GBM recurs around the tumor removal cavity, where GBM cells acquire chemo-radioresistance and survive. Characterization of the tumor border microenvironment is critical for improving prognosis in patients with GBM. Here, we compared microRNA (miRNA) expression in samples from the tumor, tumor border, and peripheral region far from tumor mass by miRNA microarray. The top three miRNAs showing higher expression in the tumor border were related to oligodendrocyte differentiation, and pathological oligodendrocyte lineage cells increased in the border, where numbers of macrophages and microglia also colocalized. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, similar to that produced by FGF1, EGF and HB-EGF, IL-1β, corresponding to OPCs and macrophages, respectively. Thus, OPCs and macrophages/microglia may form a glioma stem cell niche at the tumor border, representing a novel, promising target for prevention of recurrence.
RTHP-06. RANDOMIZED PROSPECTIVE TRIAL OF STEREOTACTIC RADIOSURGERY VERSUS CHEMOTHERAPY FOR RECURRENT MALIGNANT GLIOMA AFTER SECOND-LINE CHEMOTHERAPY
Authors: Ankit Modh, David Bergman, Lonni Schultz, James Snyder, Tom Mikkelsen, Samuel Ryu, M Salim Siddiqui, Tobias Walbert
Journal: Neuro-Oncology (2018)

PURPOSE: Outcomes for patients with recurrent malignant glioma are dismal. Fractionated radiosurgery (FSRS) has been shown to be feasible and safe when delivered in this setting, but prospective evidence is lacking. We conducted a single-institutional randomized trial on the use of FSRS versus chemotherapy for recurrent malignant glioma after second-line chemotherapy.
Nonalcoholic Fatty Liver Disease
Authors: Xiao Jing Wang, Harmeet Malhi
Journal: Annals of Internal Medicine (2018)

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. Most cases are diagnosed incidentally in the primary care or hospital setting on the basis of elevated liver enzyme levels or hepatic steatosis on imaging. NAFLD encompasses a wide spectrum: The vast majority of patients have nonprogressive nonalcoholic fatty liver, and a few of those develop progressive liver injury, inflammation, and fibrosis, a condition termed nonalcoholic steatohepatitis. Cardiovascular disease is the leading cause of death in patients with nonalcoholic fatty liver disease. Persons with nonalcoholic steatohepatitis have increased liver-related mortality. In the absence of regulatory agency–approved drugs, lifestyle modification and weight loss remain the cornerstones of NAFLD therapy.
CBMT-16. A COMBINATION STRATEGY TO COUNTERACT PTEN-DEFICIENCY BY TARGETING THE S6 AND TAM KINASES IN GLIOBLASTOMA
Authors: Kelli Ennis, Pranjal Sarma, Collin Wetzel, Catherine A. Behrmann, David Plas
Journal: Neuro-Oncology (2018)

PTEN deficiency affects the majority of glioblastomas, triggering signal transduction pathways that induce anabolic metabolism and apoptosis resistance. The mTOR complex 1 (mTORC1) and S6 kinases (S6Ks) are key mediators of metabolic reprogramming and apoptosis resistance in PTEN-deficient cells. S6K1 can be inhibited using LY2584702, a selective inhibitor that has been tested in Phase 1 clinical trials. We show here that LY2584702 can be used in combination with the TAM tyrosine kinase inhibitor BMS777607 to interfere with anabolic metabolism and restore cell death pathways in PTEN-deficient glioblastoma cells. In vivo, combination treatment reduced the growth rate of PTEN-deficient glioblastoma cells in both subcutaneous and orthotopic tumor settings. The data indicate that the TAM kinases, consisting of the tyrosine kinases TYRO3, AXL, and MERTK, can be targeted together with the S6Ks to counteract PTEN-deficiency in glioblastoma.
Abstract 16545: Shared Heart Failure Knowledge and Self-Care in Patient-Caregiver Dyads
Authors: Julie T Bidwell, Melinda K Higgins, Carolyn M Reilly, Sandra B Dunbar
Journal: Circulation (2017)

Introduction: Patient heart failure (HF) knowledge contributes to successful HF self-care, but less is known about the additive influence of caregivers (CGs). The purpose of this analysis was to ch...
MNGI-17. THE ROAM / EORTC 1308 INFORMATION STUDY RESULTS: HOW QUALITATIVE RESEARCH METHODS CAN OPTIMISE PATIENT RECRUITMENT FOR MENINGIOMA TRIALS
Authors: Michael Jenkinson, Frances Sherratt, Brian Haylock, Damien Weber, Bridget Young
Journal: Neuro-Oncology (2018)

ROAM/1308 is an international randomised controlled phase III trial comparing radiation to observation following complete surgical resection of atypical meningioma. We embedded a qualitative sub-study within ROAM/1308 with the aim of optimising patient recruitment. Patients approached to participate in the ROAM trial and recruiting clinicians were enrolled into the qualitative sub-study in 11 UK sites. Audio-recorded recruitment consultation (n=30), and semi-structured interviews with clinicians (n=17) and patients (n=23), including decliners and consenters. Analysis of transcribed audio-recordings was informed by content and thematic analysis. Ethics approval was granted for the study. Analysis identified areas where communication was problematic. Giving patients their pathology results immediately before discussing ROAM left them overwhelmed and unable to absorb trial information. Clinicians presentation of the trial arms often lacked balance with a tendency to emphasise the positive aspects of active monitoring (i.e. no additional treatment) while the negative aspects of tumour recurrence were rarely discussed. Conversely the negative aspects of radiotherapy were emphasised whilst neglecting to discuss that radiotherapy may confer better disease control. Patients exhibited bias against radiotherapy citing concerns about side effects, and this perception was rarely challenged by recruiting clinicians. Several patients viewed the prospect of radiotherapy as illogical, in part, due to earlier conversations with neurosurgeons who indicated further treatment was unnecessary following resection. Embedded qualitative studies can address barriers to recruitment in meningioma trials. The patient information leaflet has been amended and a patient-facing video added to the trial website. Workshops and a webinar for healthcare professionals (surgeons, oncologists research nurses) to enhance communication about ROAM/1308 have been conducted. Subsequent recruitment consultations had a more balanced discussion and clinicians felt more confident approaching patients about ROAM/1308. Ongoing support will be provided to sites to assist them in implementing and maintaining changes in the recruitment consultation.