tbuckley/cabot-search huggingface dataset:
STEM-11. DIRECTED NEURONAL DIFFERENTIATION AS A THERAPEUTIC STRATEGY FOR MALIGNANT GLIOMAS
Authors: Alessandra Audia, Visweshwaran Ravikumar, Zhong Deng, Vineeth Murali, Veerakumar Balasubramaniyan, John de Groot, Arvind Rao, Krishna Bhat
Journal: Neuro-Oncology (2018)

IDH-mutant (IDH-MUT) glioma patients show highly improved prognosis compared to those with wild-type IDH. However, IDH mutations are rare in the more aggressive grade IV glioblastomas and introducing IDH mutations in mouse neural cells does not induce gliomagenesis. This is a paradox, given that IDH mutation is considered an early oncogenic event and the mutated IDH produces the oncometabolite 2-hydroxyglutarate. Here we identify a previously unknown mechanism that explains this paradox. We found that IDH-MUT patient tumors expressing a molecular signature enriched in genes associated with neuronal differentiation survive the longest (~11 years) and these same tumors have significantly lower expression of the Mesenchymal master regulator TAZ, which is epigenetically silenced. Concordantly, IDH-MUT/TAZ-low glioma stem-like cells (GSCs) show remarkable neuronal differentiation induced by retinoic acid, whereas IDH-WT/TAZ-high GSCs are resistant to this process implying that IDH status and TAZ levels dictate propensity to neurogenesis. TAZ overexpression in IDH-MUT GSCs caused inhibition of retinoic acid neuronal differentiation and conversely CRISPR/Cas9-mediated knockout of TAZ in IDH-WT GSCs promotes this process as judged by alteration in genes regulating neurogenesis as well as cellular morphology resembling neurons (dendritic branching etc.). Preliminary data on the mechanism of TAZ inhibition, indicate that TAZ might directly act as inhibitor of gene expression via formation of a complex with HDAC-1 and -2. Verteporfin, a FDA approved inhibitor of TAZ caused reduction of tumor volume and improved survival in xenograft bearing mice. We are currently evaluating brain penetrating HDAC inhibitors for their ability to induce neuronal differentiation and tumor inhibition in intracranial models of GBM. Taken together, our studies uncover a role for TAZ as a barrier for terminal neuronal differentiation and that differentiation therapy TAZ or HDAC inhibitors is possible for IDH-WT gliomas if combined with retinoids.
CSIG-25. EPIDERMAL GROWTH FACTOR RECEPTOR EXTRACELLULAR DOMAIN MISSENSE MUTATION A289V AS A DRIVER OF GLIOBLASTOMA INVASION AND PROLIFERATION
Authors: Zev Binder, Amy Thorne, Spyridon Bakas, E Paul Wileyto, Hamed Akbari, Saima Rathore, Sung Min Ha, Logan Zhang, Ahmed Idbaih, Stephen Bagley, Jennifer Morrissette, MacLean Nasrallah, Jianhui Ma, Ciro Zanca, Andrew Scott, Christos Davatzikos, Frank Furnari, Donald O’Rourke
Journal: Neuro-Oncology (2018)

Epidermal Growth Factor Receptor (EGFR) missense-mutations in glioblastoma (GBM) typically occur within the extracellular domain (ECD) and, to-date, have not shown a clinical impact. These ECD mutations, while not as common as wild-type amplification or EGFRvIII, do represent a distinct patient population in need of investigation. This study investigates the oncogenic effect of the most common EGFR ECD missense-mutations (R108K, A289D/T/V, and G598V) in a retrospective cohort of 260 de novo GBM patients from the University of Pennsylvania. Extrapolation of each individual missense-mutation revealed a significant reduction in patient survival for the EGFRA289D/T/V mutants (p=0.028). This effect was confirmed with a follow-up cohort of 111 patients. The Cancer Imaging Phenomics Toolkit (CaPTk – www.cbica.upenn.edu/captk) was used to extract 2104 quantitative imaging phenomic (QIP) features, from multiparametric magnetic resonance imaging, across the various tumor sub-regions comprising the enhancing and non-enhancing tumor core, as well as the peritumoral edematous/invaded tissue. Multivariate machine learning techniques integrated these features, revealing radiographic signatures suggestive of increased invasion and proliferation for patients bearing the A289 mutation. The underlying mechanism of EGFRA289V in tumor growth was examined using engineered U87 glioma cells and patient-derived HK281 glioma spheres simulating expression of wild-type-EGFR or EGFRA289V. Corroborating our findings in patients, mice bearing intracranial tumors with EGFRA289V mutations revealed significantly worse survival accompanied by highly invasive tumors. Cells expressing EGFRA289V yielded a highly active EGFR/ERK signaling pathway, resulting in increased expression and functionality of the matrix metalloproteinase MMP1, which can be attenuated by the use of ERK pathway inhibitors. Collectively, the findings of this study highlight a highly invasive and proliferative phenotype associated with the EGFRA289V missense-mutation. Moreover, given the tumor-specific and extracellular nature of the mutation, we postulate that it may be amenable to targeted therapy. Key data presented is from a manuscript with preliminary acceptance to Cancer Cell. *equal contribution
ACTR-33. TUMOR TISSUE PENETRATION AND PHARMACODYNAMICS OF ONC201 IN ADULT RECURRENT GLIOBLASTOMA PATIENTS
Authors: Isabel Arrillaga-Romany, Yazmin Odia, Joshua Allen, Varun Vijay Prabhu, Rohinton Tarapore, Debora Vendramini Costa, Neelima Shah, Edna Cukierman, Wolfgang Oster, Minesh Mehta, Patrick Wen, Tracy Batchelor
Journal: Neuro-Oncology (2018)

ONC201 selectively antagonizes DRD2, crosses the blood-brain barrier and induces apoptosis in high grade gliomas and other advanced cancers. ONC201 efficacy is pronounced in glioma cells that harbor low DRD5 expression and is associated with induction of the ATF4/CHOP/DR5-mediated integrated stress response pathway. DRD2 antagonism also induces activation of NK and other immune cells. We previously reported the single agent activity of ONC201 in 17 adult patients with recurrent glioblastoma that demonstrated the safety, systemic pharmacodynamics, and a durable objective response when administered orally once every 3 weeks. Here, we evaluated the intratumoral drug concentrations and pharmacodynamic activity of ONC201 in adult recurrent glioblastoma patients that were treated on a weekly schedule. Six patients >18 years old with first recurrence of glioblastoma who were eligible for salvage surgical resection were enrolled. ONC201 was administered orally as 625 mg once a week. Salvage surgery was performed approximately 24 hours after the second dose of ONC201 and patients continued on ONC201 until radiographic and/or clinical progression. Tumor tissue was flash-frozen and formalin-fixed for assessment of intratumoral drug concentrations by LC-MS and pharmacodynamics by IHC, respectively. Of the 6 enrolled patients, 5 had sufficient tissue for evaluation. Intratumoral drug concentrations exceeded therapeutic thresholds: median 1.5 µM (range 600 nM 9.3 µM). Investigation of biomarkers related to downstream signaling induced by ONC201 revealed heterogeneous intratumoral induction of ATF4/CHOP/DR5 expression and tumor cell apoptosis (TUNEL). Stronger induction of the pharmacodynamic signaling was associated with stronger induction of apoptosis and inversely associated with DRD5 expression, but not with drug concentration. No drug-related adverse events were reported in this cohort. Evaluation of immune cytokines and effectors molecules in serum and immune infiltration into the tumor is ongoing. ONC201 is biologically active and well tolerated in recurrent glioblastoma tumors when administered to adults.
TMIC-43. A TENSION-MEDIATED GLYCOCALYX FEEDBACK LOOP PROMOTES A MESENCHYMAL, STEM-LIKE PHENOTYPE IN GLIOBLASTOMA
Authors: Shelly Kaushik, James Matthew Barnes, Russell O Bainer, Jason K Sa, Elliot C Woods, FuiBoon Kai, Laralynne Przybyla, Jonathon N Lakins, Joanna J Phillips, Do-Hyun Nam, Carolyn R Bertozzi, Valerie M Weaver
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is one of the deadliest central nervous system cancers, difficult to treat and largely impossible to cure. A considerable challenge in GBM therapy is treatment resistance and tumor recurrence, resulting in dismal patient prognosis. GBM aggression is often associated with a mesenchymal phenotype, increased expression of glycoproteins and the presence of tumor-initiating “stem-like” cells. Using patient-derived xenograft models, and immune competent syngeneic and transgenic glioma mouse models, we show that GBMs demonstrate increased contractility, and their tumors are surrounded by a stiffer ECM, that maintains and even further enhances integrin mechanosignaling. As a result of increased integrin signaling, these tumors also harbor a mesenchymal-like gene signature and phenotype, possess a bulky glycocalyx and demonstrate a stem-like phenotype. Bioinformatics analysis, expression profiling and limiting dilution studies reveal that these mechanically challenged tumors express more “bulky” glycoproteins such as mucins and CD44, as well as glycocalyx regulators, galectins. Considering that a large proportion of these bulky glycoproteins are also stem markers, we show that upregulation of the glycoproteins and their modulators leads to enhanced GBM stem-ness. Our findings suggest that there is a dynamic and reciprocal link between integrin mechanosignaling and a bulky glycocalyx, which promotes a mesenchymal, stem-like phenotype in GBMs. Thus, therapeutic strategies to target GBM tissue tension could reduce mortality and improve patient outcome.
CMET-10. RISK OF RADIATION NECROSIS FOLLOWING REPEAT STEREOTACTIC RADIOSURGERY FOR RECURRENT BRAIN METASTASES
Authors: Daria Krivosheya, Hamid Borghei-Razavi, Michael Vogelbaum, Lilyana Angelov, Gene Barnett, Jennifer Yu, Samuel Chao, Erin Murphy, Manmeet Ahluwalia, John Suh, Alireza Mohammadi
Journal: Neuro-Oncology (2018)

Stereotactic radiosurgery (SRS) has become the standard of care for the treatment of many patients with oligo-metastases of the brain with a local control rate of 80–90% and radiation necrosis rate of 7% per lesion. Per patient, the rate of radiation necrosis is 10–15% with half being symptomatic. We sought to determine outcomes of stereotactic radiosurgery for treatment of recurrent brain metastases after failure of initial SRS. Retrospective review of all patients that underwent Gamma Knife radiosurgery at our institution between 2000 and 2018 was conducted. We screened 2,671 patients and identified 51 lesions in 39 patients that recurred after the first treatment and received a second single-fraction stereotactic radiosurgery dose to the same lesion. The median patient follow-up after the second radiosurgery treatment was 10.2 months (1.1–60.5 months). The median time between the two treatments was 16.8 months (range: 2.5–75.3 months). The diagnosis of progression was based on imaging changes on PET and CBV or biopsy. The average radiation dose at first and second treatments was 21 Gy and 19 Gy, respectively. Out of 51 lesions that received two SRS treatments, 25 (49%) increased in size within a median of 4.8 months post second treatment (range: 1.0–29.4 months). Of these, 18 lesions (35%) in 17 patients (43%) were diagnosed as radiation necrosis based on either a pathological examination (7 lesions), or a combination of radiographic findings (11 lesions). The rates of symptomatic radiation necrosis were 16% per lesion and 21% per patient. Repeat SRS treatment of recurrent brain metastases is associated with a higher rate of radiation necrosis. Increase in size post repeat SRS is more likely radiation necrosis than recurrence. Strategies such as dose reduction, fractionated treatments, or combination with laser ablation may improve outcomes and reduce the rate of subsequent radiation necrosis.
TMOD-09. TARGETING THE PI3K-mTOR PATHWAY AND ELUCIDATING MECHANISMS OF RESISTANCE IN A NOVEL AND RELEVANT ANIMAL MODEL OF GLIOBLASTOMA
Authors: Brittany Dey, Michelle Wassell, Jennifer Perez, Ann-Catherine Stanton, Stephen Mack, Ian Pollack, Sameer Agnihotri
Journal: Neuro-Oncology (2018)

Pediatric glioblastoma (pGBM) and adult glioblastoma (aGBM), henceforth collectively referenced as GBM are incurable brain tumors with variable prognosis and response to treatments due to the intermolecular heterogeneity. In particular, the GBM MYCN subtype is a highly aggressive genetic group in both pediatrics and adults where patients have a dismal median survival of only 14 months. Furthermore, this subtype is enriched with loss of the tumor suppressor genes TP53 and PTEN, leading to PI3K-AKT pathway activation and DNA-checkpoint abnormalities. Here, we report the generation of a novel syngeneic GBM mouse model of the MYCN subtype. We isolated and transduced C57BL/6 Sox2-CRE neural stem cells (NSCs) with inverted retroviral-cassettes of the murine Mycn oncogene and shRNA targeting tumor suppressor genes p53 and Pten. The retroviral-cassettes are flanked by tandem LoxP sites arranged so that CRE recombinase expression inverts the cassettes in frame allowing for MYCN protein expression and loss of the P53 and PTEN proteins. Transgene activation is accompanied with selectable cell surface markers and fluorescent tags enabling for fluorescent activated cell sorting (FACS) of desired cell populations. MYCN protein expression with concomitant silencing of P53 and PTEN protein leads to increased proliferation and formation of invasive high-grade gliomas when implanted into the frontal cortex of immune competent C57BL/6 mice and NOD-SCID mice. Using several next generation brain penetrant small molecule inhibitors of the PI3K-AKT pathway, we show tumor regression in vivo. Moreover, we have identified several novel mechanisms of PI3K-AKT treatment resistance and are currently identifying therapies that may overcome this resistance. In summary, well defined genetic drivers of GBM can lead to informed mouse model generation to test promising therapies.
CSIG-31. MUTATION OF PIM1 GENE IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA INHIBITS CELL DEATH THROUGH CHANGE IN SUBCELLULAR LOCALIZATION OF PIM-1 AND INCREASE OF BAD PHOSPHORYLATION
Authors: Nobuyoshi Sasaki, Koichi Ichimura, Motoo Nagane, Arata Tomiyama
Journal: Neuro-Oncology (2018)

In a study of Next Generation Sequencing in primary central nervous system lymphoma (PCNSL), we have previously reported several mutations of high frequency, in comparison with systemic diffuse large B cell lymphoma (DLBCL)s. Consequences of these specific mutations in PCNSL are unknown. In this study, we have analyzed the functional consequence of mutations in the PIM1 gene, observed in 100% of PCNSL patients, which encodes a serine/threonine kinase and is known to drive tumorigenesis in several malignancies. Four most frequent mutations of PIM1 in PCNSL, S77N, K115N, P216S, L275F, were chosen from our previous study, and each mutant was generated by site directed mutagenesis in PIM1 cDNA cloned in an expression vector. Resulting vectors were transiently transfected into human cancer cell lines. Cell death of the cells expressing each mutant was evaluated by dye-exclusion method under treatment of chemotherapeutic agents. Alteration of molecular signaling was evaluated by immunoblotting. Among the four mutants, increased phosphorylation of BCL-2 associated death promoter (BAD) at Ser112, which is a phosphorylation target of Pim-1, was observed by expression of K115N mutant compared with wild type PIM1 in Nagai and Hela cells expressing endogeneous BAD. Decreased cell death under campthotethin treatment was also observed in K115N mutant expressing Nagai cells compared with wild type PIM1-expressed cells. Moreover, we observed a significant shift in subcellular localization of Pim-1 carrying K115N mutant; from the nucleus, main sublocalization for wild type Pim-1, into the cytosol determined by immunocytochemistry and immunoblotting of nuclear and cytosolic fraction of the cells. DISCUSSION: It is suggested that PIM1 K115N mutant may drive chemoresistance through increased BAD phosphorylation that suppresses cell death compared with wild-type PIM1 through modification of its subcellular localization.
COMP-04. R TOOLS FOR EXPLORATORY ANALYSIS OF PUBLICLY AVAILABLE DATA: HPAANALYZE AND BEYOND
Authors: Anh Tran, Anita Hjelmeland
Journal: Neuro-Oncology (2018)

The Human Protein Atlas (HPA) is a comprehensive resource for exploration of human proteome which contains a vast amount of proteomics and transcriptomics data generated from antibody-based tissue micro-array profiling and RNA deep-sequencing. Data from the HPA are freely available via proteinatlas.org, allowing scientists to access and incorporate the data into their research. Previously, the R package hpar has been created for fast and easy programmatic access of HPA data. Here, we introduce HPAanalyze, an R package aims to simplify exploratory data analysis from those data, as well as provide other complementary functionality to hpar. HPAanalyze is an R package for retrieving and performing exploratory data analysis from HPA. It provides functionality for importing data tables and xml files from HPA, exporting and visualizing data, as well as download all staining images of interest. The package is free, open source, and available via Github. CONCLUSIONS: HPAanalyze intergrates into the R workflow via the tidyverse philosophy and data structures, and can be used in combination with Bioconductor packages for easy analysis of HPA data.
TMOD-16. COMPARING THE EFFECTS OF CIRCUMSCRIBED VERSUS INFILTRATIVE TUMOR GROWTH PATTERNS ON FUNCTIONAL CONNECTIVITY, HEMODYNAMIC PARAMETERS, AND BEHAVIOR IN A MOUSE GLIOMA MODEL
Authors: Inema Orukari, Annie Bice, Grant Baxter, Adam Bauer, Joshua Rubin, Joseph Culver
Journal: Neuro-Oncology (2018)

Gliomas can cause significant changes in normal brain function leading to behavior deficits. Functional connectivity (fc) disruptions may contribute to these deficits. However, investigating the effects of glioma growth on fc in humans is complicated by heterogeneity in lesion size, type, and location across subjects. In this study, we evaluated the effects of different patterns of growth on fc, hemodynamic parameters, and behavior in a controlled mouse glioma model. 5x104 glioma cells growing in either a circumscribed (U87 PDE7B H217Q, n=13) or infiltrative (U87 PDE7B WT, n=14) pattern were stereotactically injected into the forepaw somatosensory cortex of adult nude mice. We monitored tumor burden with weekly bioluminescence imaging (BLI). Additionally, we evaluated fc with weekly functional connectivity optical intrinsic signal imaging (fcOIS). Fc was calculated between homotopic brain regions. Furthermore, cerebral blood flow (CBF) and hemodynamic lags were assessed. Lastly, we assessed performance on a somatomotor behavior battery during the 7th week post-injection. Mice with infiltrative tumors had more tumor burden then mice with circumscribed tumors. Furthermore, infiltrative tumors disrupted fc and produced hemodynamic lags earlier than circumscribed tumors. However, infiltrative tumors didn’t change CBF, while circumscribed tumors increased CBF near the injection site. Lastly, mice with infiltrative tumors exhibited somatomotor deficits, while mice with circumscribed tumors performed similar to sham mice (n=20). We were able to detect differences in fc disruptions in mice with gliomas growing in different patterns with fcOIS. Infiltrative tumors produced greater tumor burden and fc disruptions than circumscribed tumors. Additionally, hemodynamic lag was a better indicator of tumor burden than CBF. Lastly, infiltrative tumors induced behavior deficits during this study, while circumscribed tumors did not. A better understanding of how fc disruptions contribute to behavior deficits in glioma patients may lead to better patient risk stratification and improved behavior outcomes.
Prefibrotic myelofibrosis: treatment algorithm 2018
Authors: Guido Finazzi, Alessandro M. Vannucchi, Tiziano Barbui
Journal: Blood Cancer Journal (2018)

Abstract Prefibrotic myelofibrosis (pre-PMF) is a distinct entity among chronic myeloproliferative neoplasm diagnosed according to the revised 2016 WHO classification. The clinical picture is heterogeneous, ranging from isolated thrombocytosis, mimicking essential thrombocythemia (ET), to symptoms of high-risk PMF. Retrospective studies showed that survival of patients with pre-PMF is worse than that of ET and better than overt PMF. Whilst a specific prognostic score is lacking, the International Prognostic Scoring System is able to predict survival in pre-PMF patients, yet failing to separate intermediate-1 and -2 groups, and can be used in clinical practice. Each patient should be evaluated for, and interventions adapted to, both life-expectancy and the risk of bleeding and thrombosis. In low-risk patients with expected long survival, observation only is recommended; in cumulated intermediate-1 and -2 risk cases, whose median survival is projected at more than 10 years, treatment is based on symptoms; in high risk cases, with median survival lower than 5 years, intensive management is required. A pragmatic approach to address the risk of bleeding and thrombosis includes: no treatment or low-dose aspirin in asymptomatic patients; aspirin or oral anticoagulation if previous arterial or venous thrombosis, and hydroxyurea as first-line cytoreduction in case of thrombocytosis or leukocytosis.
Congenital brain abnormalities during a Zika virus epidemic in Salvador, Brazil, April 2015 to July 2016
Authors: Mariana Kikuti, Cristiane W. Cardoso, Ana P.B. Prates, Igor A.D. Paploski, Uriel Kitron, Mitermayer G. Reis, Ganeshwaran H. Mochida, Guilherme S. Ribeiro
Journal: Eurosurveillance (2018)

Background North-eastern Brazil was the region most affected by the outbreak of congenital Zika syndrome that followed the 2015 Zika virus (ZIKV) epidemics, with thousands of suspected microcephaly cases reported to the health authorities, mostly between late 2015 and early 2016. Aim: To describe clinical and epidemiological aspects of the outbreak of congenital brain abnormalities (CBAs) and to evaluate the accuracy of different head circumference screening criteria in predicting CBAs. Method Between April 2015 and July 2016, the Centers for Information and Epidemiologic Surveillance of Salvador, Brazil investigated the reported cases suspected of microcephaly and, based on intracranial imaging studies, confirmed or excluded a diagnosis of CBA. Sensitivity, specificity and positive and negative predictive values of different head circumference screening criteria in predicting CBAs were calculated. Results Of the 365 investigated cases, 166 (45.5%) had confirmed CBAs. The most common findings were intracranial calcifications and ventriculomegaly in 143 (86.1%) and 111 (66.9%) of the 166 CBA cases, respectively. Prevalence of CBAs peaked in December 2015 (2.24 cases/100 live births). Cases of CBAs were significantly more likely to have been born preterm and to mothers who had clinical manifestations of arboviral infection during pregnancy. None of the head circumference screening criteria performed optimally in predicting CBAs. Conclusion This study highlights the magnitude of neurological consequences of the ZIKV epidemic and the limitations of head circumference in accurately identifying children with CBA. Gestational symptoms compatible with ZIKV infection should be combined with imaging studies for efficient detection of suspect CBAs during ZIKV epidemics.
Abstract 13912: Impact of Thrombus Sidedness on Presentation and Outcomes of Patients With Proximal Lower Extremity Deep Vein Thrombosis: An Analysis From RIETE Registry
Authors: Behnood Bikdeli, Babak Sharif-Kashani, Bavand Bikdeli, Reina Valle, Conxita Falga, Antoni Riera-Mestre, Lucia Mazzolai, Peter Verhamme, Phillip S Wells, Juan Francisco Sánchez Muñoz Torrero, Luciano Lopez, Manuel Monreal
Journal: Circulation (2017)

Introduction: Prior small studies have suggested differences in demographics and outcomes between left-sided deep and right-sided deep vein thrombosis (DVT), and also unilateral vs. bilateral DVT. ...