tbuckley/cabot-search huggingface dataset:
EXTH-78. PARP INHIBITION IMPROVES RADIOTHERAPY EFFECTIVENESS IN MENINGIOMA CELL CULTURE.
Authors: Randy Jensen, Jon Harper
Journal: Neuro-Oncology (2018)

Biological effects of AC electric fields at frequencies between 100-300 kHz discovered a decade ago are being applied to cancer cells as a therapeutic modality in the treatment of glioblastoma multiforme (GBM).They are called Tumor Treating Fields (TTFields) as they disrupt cell division.Based on our electro-conductive measurements and modeling, we provide an assessment of possible molecular-level mechanisms.Computer simulations and experimental measurements carried out for microtubules and actin filaments are presented.Charge and dipole values for monomers and dimers as well as polymerized forms of these proteins are summarized.Continuum approximations for cable equations describing actin filaments and microtubules compare favorably to measurements in buffer solutions showing soliton waves and transistor-like amplification of ionic signals, respectively.AC Conductivity and capacitance of tubulin and microtubules have been measured and modeled in the range of frequencies between 100 kHz and 1 MHz.A dramatic change in conductivity occurs when tubulin forms microtubules.In living cells, this signals a conductive phase transition coinciding with mitosis in dividing cells.This process is allowed by TTField penetration into the cleavage furrow in dividing cells and provides the most significant mechanistic explanation of the observed effects.We provide estimates of the forces, energies and power involved in the action of TTFields on microtubules and kinesin motors.These calculations are compared and contrasted with typical values experienced at a cell level and provide strong arguments for real physical effects of TTFields in dividing cells.We also show results of DLS and TEM measurements on microtubules and tubulin oligomers in solution, which allow us to quantify these processes under controlled conditions.In conclusion, the most likely candidates to provide a quantitative explanation of these effects are ionic condensation waves around microtubules as well as dielectrophoretic effects on the dipole moments of microtubules.
CBMT-40. A SOX2-EXPRESSING PERICYTE PRECURSOR CONSTITUTES A NEW AND EFFICIENT TARGET FOR ANTI-ANGIOGENESIS IN GLIOMAS
Authors: Roland Kälin, Yuping Li, Cai Linzhi, Michael Synowitz, Jörg-Christian Tonn, Wolfgang Enard, Eloi Montanez, Rainer Glass
Journal: Neuro-Oncology (2018)

Pericytes are essential for maintaining the stability of CNS blood-vessels and the blood-brain-barrier. They are closely associated with endothelia and can be identified by a set of markers. New pericytes are required during neo-angiogenesis but how pericytes are generated in the adult brain is largely unknown. We investigated neoplastic vascularization of the adult brain in a transgenic lineage-tracing model. We observed that the vast majority of mature pericytes originates from a newly identified precursor cell-type. These precursors are characterized as pericyte marker-negative cells of non-hematopoietic origin, which are distant from blood-vessels and highly proliferative. Immunofluorescence analysis of pericyte precursors was corroborated by single-cell transcriptomic data. Pericyte precursors, but not mature pericytes, express the transcription factor SOX2, which has a role in maintaining a stem-like identity. In particular, we observed that traced, SOX2+ cells are confined to a non-vascular localization and do not express pericyte-markers (PDGFRB, Desmin, NG2 or CD146). Whereas mature, traced pericytes were Sox2-negative, expressed the entire set of pericyte-markers and had a perivascular position. Conditional knockout of Sox2 in pericyte precursors resulted in largely reduced numbers of traced cells and blocked the formation of new pericytes. This indicates that new intratumoral pericytes are generated by a previously uncharacterized, Sox2-positive avascular pericyte precursor cell. Lineage ablation experiments in brain tumor models showed that pericyte precursors are necessary for angiogenesis and tumor expansion. All in all, this shows that pericyte precursors are a new and promising target for glioma-therapy.
GENE-04. CHARACTERISTICS OF PATIENTS WITH A PRIMARY BRAIN TUMOR UNDERGOING HEREDITARY CANCER MULTI-GENE PANEL TESTING
Authors: Sarah Azam, Krista Qualmann, Syed Hashmi, Aarti Ramdaney, David Rodriguez-Buritica, Leslie Dunnington, Michelle Jackson
Journal: Neuro-Oncology (2018)

Currently, no germline genetic testing guidelines exist for patients with a primary brain tumor (PBT). Patient-specific characteristics of PBT patients in relation to genetic etiology are understudied; therefore we aimed to describe these variables based on hereditary cancer multi-gene panel test (MGPT) results among patients with a PBT. A total of 654 consecutive subjects were referred for MGPT at a diagnostic laboratory between March 2012-June 2016. Clinical data were ascertained from test requisition forms. Statistical analyses were completed using STATA (v.13, College Station, TX). In our cohort, 67% (339/506) were diagnosed under 50 years of age. MGPT identified 104/654 (16%) patients with germline mutations. Of these, 35 (34%) had an isolated PBT with no additional primary cancers. Half of identified genes predisposed a risk to PBTs, while the other half did not. Test result positive astrocytomas were diagnosed at significantly younger ages than patients with negative and variant of uncertain significance results (p=0.021). No association between tumor grade and genetic testing outcome was observed. Of 165 patients with available family history, 95% (n=157) reported a family history of some cancer and 18% (n=30) reported family history of brain tumors. While no germline genetic testing criteria currently exist for PBTs, our data suggest younger age of diagnosis is being utilized as an indicator for testing. Particular PBT pathologies have been associated with specific hereditary cancer syndromes; therefore, pathology can be helpful in narrowing down the differential diagnosis. In addition, more research is necessary to better understand the relationship between tumor grade and testing outcomes. Family history evaluation of both PBTs and systemic cancer is a beneficial risk assessment tool, particularly until testing criteria are developed. Further research is necessary for the development of solidified genetic testing criteria in the PBT population and more robust identification of at-risk individuals.
PATH-52. UTILIZING NEXT GENERATION SEQUENCING REPORTS IN CLINICAL DECISION MAKING: REPORT FROM THE NATIONAL INSTITUTES OF HEALTH (NIH) NEURO-ONCOLOGY BRANCH (NOB) NATURAL HISTORY STUDY (NHS) PRIMARY BRAIN TUMOR PANEL (PBTP)
Authors: Christine Siegel, Orwa Aboud, Miranda Brown, Hye-Jung Chung, Mark Raffeld, Sonja Crandon, Ming Ji, Jason Levine, Elizabeth Vera, Snehal Patel, Jennifer Reyes, Terri Armstrong, Liqiang Xi, Alvina Acquaye, Lisa Boris, Nicole Briceno, Nancy Garren, Carlos Romo, Martha Quezado, Jing Wu, Brett Theeler, Mark Gilbert
Journal: Neuro-Oncology (2018)

The use of molecular diagnostics is an integral component of CNS cancer care. The NIH NOB PBTP includes 80 alterations (55 mutations/copy number variations and 25 gene fusions) identified as relevant to the primary CNS patient population. We have previously reported on the diagnostic utility. Identified therapeutic target results from the PBTP are reported here. PBTP results from patients enrolled on the NOB NHS are reported. Targetable alterations were defined using the NCI MATCH trial list. The proportion of cases with identified alterations based on recognized diagnostic histology and recurrence are reported. 190/282 (67%) PBTPs reported significant alterations; 132 from initial diagnosis and 58 recurrent samples;10 had two sequential samples analyzed. Astrocytoma, grade 2–4 (126/190, 66%), was the most common histologic tumor type. Over 60% of cases had a unique alteration profile, appearing only once in the data set. At diagnosis 74% had 1–3 alterations. At recurrence 45% had >3, and 9% had > 7 alterations. New and increasing alterations were seen in 80% (8/10) of sequential cases, with 1 case showing an entirely different alteration pattern. Targetable alterations were identified in 87/190 (46%) PBTP results. Exclusively in astrocytomas, EGFR (19%), and CDK4/CDK6 (12%) were found. Less frequent were: BRAF (5%) (8 astrocytomas, 2 pleomorphic xanthoastrocytoma), FGFR (3%) (5 GBM, 1 rosette-forming glioneuronal tumor), MET (3%) (3 GBM, 1 anaplastic oligodenroglioma, 1 anaplastic ependymoma), PTCH1 (3%) (3 astrocytoma, 1 ependymoma, 1 medulloblastoma), NTRK (2%) (2 astrocytomas, 1 oligodendroglioma). CONCLUSIONS: The PBTP has demonstrated diagnostic and therapeutic utility, with actionable targets found in nearly half of analyzed samples. The profile and number of alterations was higher at recurrence, underscoring the need for contemporary resampling and analysis. Importantly, 2/3 of the results showed a unique alteration profile highlighting the unique nature of each patients tumor.
CSIG-41. ONCOGENE ADDICTION SWITCH FROM NOTCH TO PI3K REQUIRE SIMULTANEOUS TARGETING OF DUAL PATHWAY INHIBITION IN GLIOBLASTOMA
Authors: Norihiko Saito, Kazuya Aoki, Nozomi Hirai, Ryo Suzuki, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Takatoshi Sakurai, Satoshi Iwabuchi
Journal: Neuro-Oncology (2018)

Notch signaling pathway regulates normal stem cells in the brain and glioma stem cells (GSCs). However, blocking the proteolytic activation of NOTCH with γ-secretase inhibitors (GSIs) fails to alter the growth of some GSCs as GSIs seem to be active in only a fraction of GSCs lines with constitutive NOTCH activity. Here we report loss of PTEN as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of “oncogene addiction” from the NOTCH to the phosphoinositol-3 kinase (PI3K) pathway. We investigated the effects of Notch inhibition in GSC using GSI. Drug cytotoxicity test on 16 GSCs show differential growth response to GSI stratifying GSCs into two groups: responders vs non-responders. Active Notch signaling seems to be important features for the GSC as Notch inhibition only affected GSCs defined as having increased Notch activity. However in the responder group GSCs with the PTEN mutation seems to be less sensitive to GSI treatment. Here we show that NOTCH regulates the expression of PTEN and the activity of the PI3K signaling pathway in GSCs since treatment with GSI attenuated Notch signaling and increases PTEN expression. NOTCH regulates PTEN expression via Hes-1 as knockdown of either Notch or Hes1 led to increase expression of PTEN.This novel observation suggests the need to simultaneous inhibition of both pathways as a means to improve therapeutic efficacy in human glioblastoma.
PDTM-13. OVEREXPRESSION OF MYC ALONE IS SUFFICIENT TO INITIATE GROUP 3 MEDULLOBLASTOMA
Authors: Ran Tao, Najiba Murad, Zhenhua Xu, Peng Zhang, Konstantin Okonechnikov, Marcel Kool, Samuel Rivero-Hinojosa, Christopher Lazarski, Pan Zheng, Charles Eberhart, Brian Rood, Roger Packer, Yanxin Pei
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant brain tumor in children. Among the four molecular subgroups of MB (WNT, SHH, Group 3 and Group 4), patients with Group 3 MB exhibit the worst prognosis. Group 3 MB is associated with amplification and overexpression of the MYC oncogene. However, whether MYC overexpression alone is sufficient to induce Group 3 MB tumorigenesis in specific cell type(s) in the cerebellum remains unclear. The study of the etiology of Group 3 MB and the development of effective, targeted therapies for this disease has also been impeded by lack of appropriate disease models that faithfully recapitulate Group 3 MB. Here, we generated a novel mouse model for Group 3 MB and demonstrated that overexpression of MYC alone is sufficient to transform astrocyte progenitors and granule neuron progenitors in the early postnatal cerebellum. The resulting tumors resemble human Group 3 MB in terms of histology and gene expression profiles, making this animal model a valuable tool for the development and testing of new therapies. To identify potential therapeutic targets, we analyzed dysregulated gene expression and revealed that the genes involved in the glucose metabolism pathways were significantly upregulated in murine and human Group 3 MB compared to normal cerebellar cells or SHH Group MB. Among these genes, expression of lactate dehydrogenase A (LDHA), which catalyzes the conversion of pyruvate to lactate during energy metabolism, is associated with poor prognosis in Group 3 MB. Inhibition of LDHA by either RNA interference or pharmacological agents significantly reduced growth of both mouse and human Group 3 tumor cells, without affecting SHH Group MB, suggesting that LDHA is a potential specific target for treating Group 3 MB.
ANGI-12. MRI-BASED CELL TRACKING WITH INDIVIDUAL CELL SENSITIVITY FOR MEASURING CANCER CELL INVASION
Authors: Dorela Shuboni-Mulligan, Barbara Blanco-Fernandez, Shatadru Chakravarty, Erik Shapiro
Journal: Neuro-Oncology (2018)

PURPOSE: GBM cell invasion is particularly aggressive and leads to poor prognosis. In vitro and in vivo cell tracking techniques for studying tumor progression could facilitate drug discovery. Here we demonstrate the utility of MRI-based cell tracking as a tool for in vitro testing of inhibitors for cancer cell invasion. Iron oxide particles are the core technology that enables single-cell tracking, as labeled cells can be visualized as hypo-intensive spots using MRI. The technique provides a robust method to easily visualize cell invasion in 3D and can be applied in vivo to track invasion of labelled cells within the brain. We developed an in vitro MRI assay capable of detecting invasion inhibition for human (U87MG) and rodent (RG2) glioma cell lines. We first established magnetic labelling efficiency (microscopy and ICP-OES) and cell viability/proliferation (MTT assay and PKH26 labelling) to determine optimal labelling concentration. Next, to visualize tumor cell invasion, magnetically labelled cells were formed into spheroids and embedded into a collagen matrix; samples were then scanned with a 7T MRI in a custom 3D printed holder. Cell invasion was visualized with and without inhibitor (CEP-1347, 400nM) and compared to traditional microscopy. Two scan sequences, T1 FISP and FLASH, effectively visualized our 3D invasion assay; producing 3D images that demonstrated suppression of tumor cell invasion with inhibitor, equivalent to those observed with 2D microscopy. Further, cell viability and proliferation were not significantly impacted at 72hrs below bead concentrations of 0.1ug/mL. Tumor spheroids size was impacted by concentration (F=4.820, p=0.001)but not for cells labelled at the optimal 25pg/cell concentration. CONCLUSION: MRI can be used as a tool to monitor GBM invasion in vitro and can effectively test inhibitors for cancer invasion. This technique provides a powerful tool that can be used to observe invasion in vitro and in vivo.
Abstract 14470: Recalibration of the ACC/AHA ASCVD Risk Estimator for Primary Prevention in a Large, Multiethnic Community-Based Population
Authors: Alan S Go, Grace H Tabada, Marc Jaffe, Joan C Lo, Matthew D Solomon, Sue Hee Sung, Jamal S Rana
Journal: Circulation (2017)

Introduction: While the 2013 ACC/AHA Pooled Cohort ASCVD Risk Estimator was an important advance in predicting risk of ASCVD events, several studies have demonstrated suboptimal accuracy and calibr...
PATH-30. RECONSIDERATION FOR POOR PROGNOSIS OLIGODENDROGLIAL TUMOR CASES BASED ON WHO2007 AND WHO 2016
Authors: Takashi Maruyama, Yoshihiro Muragaki, Masayuki Nitta, Soko Ikuta
Journal: Neuro-Oncology (2018)

Mounting evidence suggests that oligodendroglial tumor is associated with a more favorable prognosis comparing with astrocytic tumor. Treatment strategy of our department is as follows 1) grade 2 oligodedroglioma with less than 90% resection are treat with post operative radiation following with RTOG 9802. 2)grade 3 anaplastic oligodendroglioma are treated with ACNU and radiation therapy. Instead of better prognosis of oligodendroglial tumor, there are several patients with unfavorable clinical course of malignant transformation. In this study, we retrospectively analyse clinical data of unfavorable oligodendroglioma cases diagnosed by WHO2007 and WHO2016. Overall 237 cases of newly diagnosed by WHO2007 in 2001 to 2014 were further analysed. Fetal cases were diagnosed as Oligodendroglioma(OL) 5, Oligoastrocytoma(OA) 3, Anaplastic oligodendroglioma(AO) 13 and Anaplastic oligoastrocytoma(AOA) 3 in WHO2007. These tumor were re-evaluated with WHO2016 (OL 120, AO 65, NOS 22). Fetal cases of oligodedroglial tumor were OD-mt 5, AO-mt 4, NOS 1 and the lest were all astrocytic tumor, Diffuse astrocytoma(DA)-mt 3, DA-wt 1, Anaplastic astrocytoma(AA)-mt 2 and AA-wt 7 cases. OS of all oligodendroglial tumor was not reached, PFS was 8.5 months in OD and not reached in AO. Median OS and median PFS were 57,1 and 40,1 months in OD fetal cases and 31,3 and 18,6 months in AO fetal cases. Five OD fetal cases were all partial removal and 3 were treated by post-operative therapy. One out of four AO fetal cases was total removal and all cases were treated with post-operative therapy. There were several poor prognosis oligodendroglial tumor instead of their genomic alteration such as 1p19q LOH and IDH-mt. Aggressive tumor resection may also alter the natural history of unfavorable oligodendroglial tumor.
Efficacy and safety of the histamine H4 receptor antagonist ZPL-3893787 in patients with atopic dermatitis
Authors: Thomas Werfel, Gary Layton, Michael Yeadon, Lyndsey Whitlock, Ian Osterloh, Pablo Jimenez, Wai Liu, Victoria Lynch, Aliya Asher, Athanasios Tsianakas, Lynn Purkins
Journal: Journal of Allergy and Clinical Immunology (2018)
Meeting the Criteria of Medication Therapy Management—Reply
Authors: Stephen D. Persell, Michael S. Wolf
Journal: JAMA Internal Medicine (2018)

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EPID-13. ANTI-ANGIOGENIC THERAPY FOR HIGH-GRADE GLIOMA: A META-ANALYSIS
Authors: Malaka Ameratunga, Nick Pavlakis, Helen Wheeler, Robin Grant, John Simes, Mustafa Khasraw
Journal: Neuro-Oncology (2018)

We have previously published a Cochrane meta-analysis of the efficacy of anti-angiogenic therapy (AAT) in high grade glioma (HGG) in 2014. Since this time, a number of key trials have been published. An updated meta-analysis was performed to account for these new results. The primary analysis was to evaluate the pooled overall survival (OS) of AAT in HGG and the secondary analysis was to evaluate the pooled progression-free survival (PFS) of AAT in HGG. Subgroup analyses were performed according to treatment setting and AAT combined with chemotherapy versus chemotherapy alone. Searches were conducted to identify randomised controlled trials (RCTs) including CENTRAL, MEDLINE and Embase to August 2017. Proceedings of oncology conferences and trial registries were also searched. 11 eligible RCTs were identified (N=3743). There was no improvement in OS with the addition of AAT (pooled hazard ratio (HR) of 0.95, 95% confidence interval (CI) 0.88, 1.02; p=0.16) overall, or in the adjuvant or recurrent settings (HR 0.93, 95% CI 0.86, 1.02; p=0.12 and HR 0.99, 95% CI 0.85–1.16; p = 0.90). Pooled analysis of OS for AAT with chemotherapy compared to chemotherapy also did not show an improvement (HR 0.92, 95% CI 0.85–1.00; p=0.05). Pooled analysis of PFS from ten studies showed improved PFS with AAT (HR 0.73; 95% CI 0.68, 0.79; p < 0.00001). These improvements in PFS occurred in the adjuvant (HR 0.75, 95% CI 0.69–0.82; p < 0.00001) and recurrent settings (HR 0.64, 95% CI 0.54–0.76; p< 0.00001) and when AAT was combined with chemotherapy compared to chemotherapy alone (HR 0.72, 95% CI 0.66–0.77; p <0.00001). CONCLUSIONS: The use of anti-angiogenic therapy does not improve survival in newly diagnosed people with GBM, despite improved progression free survival. There is no evidence of a survival advantage for anti-angiogenic therapy over chemotherapy in recurrent GBM.
RDNA-16. THE ROLE OF RAD52 IN GENOMIC INSTABILITY AND THERAPEUTIC RESISTANCE OF MALIGNANT GLIOMAS
Authors: Diana Aguilar-Morante, Kirstine Juul Elbæk, Alex Frias, Petra Hamerlik
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the deadliest and most common primary brain tumor with median survival rates of less than two years. GBM is defined by hallmarks such as uncontrolled cellular proliferation, diffuse infiltration, propensity for necrosis, robust angiogenesis, resistance to apoptosis and rampant genomic instability. Inter- and intra-tumoral heterogeneity, cellular plasticity and de-regulated signaling pathways are plausible causes of resistance to existent therapies in GBM. As current therapies offer only limited survival benefits, the identification and validation of new approaches in glioblastoma management is of highest importance. RAD52 is one of the key homologous recombination (HR) proteins. Rad52 binds to single strand DNA (ssDNA) and so plays a crucial role in most HR events as well as restart of collapsed replication forks in response to oncogene-induced replication stress. Our recent findings show significantly higher Rad52 mRNA levels in malignant gliomas compared to normal brain, where its levels negatively correlate with GBM patient survival. Experimental data show that the inhibition of RAD52 by 6-Hydroxy-DL-Dopa (6OH-Dopa) impairs GBM cell survival due to increase in replication-transcription collisions leading to accumulation of DNA damage. These preliminary findings support for first time a novel role of RAD52 in glioblastoma. We believe that Rad52 targeting may hold promise in future therapeutic intervention in GBM