tbuckley/cabot-search huggingface dataset:
P08.32 Selective MET kinase inhibition in MET-dependent glioma models
Authors: W. P. Leenders, C. van den Heuvel, A. Navis, K. Rex, A. Coxon
Journal: Neuro-Oncology (2017)

Background: Grade IV diffuse gliomas (glioblastomas) are notoriously difficult to treat. Many studies aim at targeting tumor-specific aberrations, such as mutations in genes encoding oncogenic receptor tyrosine kinases (RTKs). Of high interest as a tumor target in diffuse glioma is the RTK MET, which is amplified in a significant proportion of glioblastomas, and a number of MET inhibitors have been developed. However, most RTK inhibitors available in the clinic today, including those inhibiting MET, are not entirely selective and inhibit additional kinases at the doses used. They therefore may induce potentially undesired off-target effects, such as blood-brain barrier normalization in the case of concomitant VEGFR2 inhibition. Methods: We studied the effects of the novel, selective MET-kinase inhibitor (Compound A) and the combined VEGFR2/RET/MET inhibitor cabozantinib on MET activation and proliferation in the MET-amplified E98 astrocytoma cell line in vitro, using western blot analysis and MTT proliferation assays. Effects of compound A were also studied in mice carrying orthotopic xenografts of the same E98 cell line. Survival was monitored and effects of MET inhibition were investigated by immunohistochemistry using phospho-specific antibodies. Results: E98 cells were highly sensitive to treatment with Compound A in vitro (IC50~9.4 nM). Furthermore, Compound A effectively inhibited phosphorylation of MET in orthotopic E98 xenografts. In contrast, we have previously shown that after treatment with cabozantinib in the same model the high levels of phosphorylated MET were maintained. While treatment with Compound A significantly prolonged the survival of E98-xenograft bearing mice, tumors still developed and showed extensive AKT phosphorylation in the absence of MET phopshorylation, suggesting in vivo therapy resistance mechanisms. Interestingly, resistance to Compound A was not seen in vitro in an E98 cell line derived from Compound A-resistant tumor xenografts. Conclusions: Compound A is a promising, highly selective MET kinase inhibitor with activity against gliomas with constitutive MET signaling. Selective MET kinase inhibitors may be more suited for treatment of glioma than combined VEGFR2/MET inhibitors, as the latter may induce vessel normalization resulting in poor tumor penetration. Similar to clinical experience, E98 tumor-bearing mice ultimately develop resistance to TKIs. Combination therapies targeting both MET and potential resistance pathways may be required to allow long-term tumor treatment.
P12.15 Long term experience of Atypical Meningioma: Survival and Prognostic Factors
Authors: O. Kim
Journal: Neuro-Oncology (2017)

Objective: This retrospective study analyzed the prognostic factors, the effect of different methods of treatments and the behavior of atypical meningioma. Methods: Fourty one patients were diagnosed as atypical meningioma, among 273 patients who were given a diagnosis of meningioma in the period of 2002 to 2015. Age, gender, tumor location, Ki 67, Simpson grade and treatment received were analyzed. We studied the correlation between these factors with recurrence, overall survival rate and progression free survival. Results: Mean patient ages was 57.8 ± 13.4 and mean follow up period was 63.9 ± 55.4 (moths). Mean overall survival rate and progression free survival rate are 73.6 ± 55.2 and 60.9 ± 52.6 (months)Better survival was observed for patients less than 50 years old but with no statistical significance (P = 0.096). And patients with total resection compared with subtotal resection also better survival rate but no statistical significance (P < 0.720). Patients with a tumor located in brain convexity, parasagittal and skull base also no statistical significance (P = 0.386). Progression-free survival showed a significant relationship with total resection compared with subtotal rescection (P = 0.008). Conclusions: Independent prognostic factors affecting overall survival are not founded in our study. But we confirmed that Simpson grade was significant factor for statistically affect to progression free survival. Overall survival was not affected statistically by patient age, gender, tumor location, Ki 67, Simpson grade and treatment received in this study. This is may be due to most of patients are still alive. With long-term follow up period, it would be able to observe more independent prognostic factors clearly.
P18.06 Quality of life and neurocognitive performance of patients with glioma surviving longer than five years after surgery and radiotherapy
Authors: K. Eichbichler, J. Dorozinski, J. Furtner, A. Wöhrer, K. Dieckmann, C. Caucig-Lütgendorf, D. Prayer, M. Preusser, J. Hainfellner, C. Marosi
Journal: Neuro-Oncology (2017)

Quality of life (QoL) and neurocognitive performance of patients with glioma surviving longer than five years after surgery and radiotherapy (RT) is not well established. Long term effects of radiotherapy (RT) and side effects of chemotherapy (CT), corticoids and anti-epileptic drugs might compromise patient’s outcomes. The aim of this study is to correlate the white matter lesion volume and the remaining volume of unchanged brain tissue with the cognitive status and QoL of long-term brain tumor survivors. PATIENTS AND METHODS: We tested patients surviving for at least five years for a histologically proven glioma, who have been treated with surgical resection, RT or RT and CT. Imaging data from the MRI at diagnosis and the actual MRI for this study were analyzed using the free neuroimaging software “MRIcron”. Furthermore, the patients were assessed with the EORTC QlQ30, the brain cancer module BN20, and neurocognitive testing using the Hopkin´s verbal learning test (HVLT), Trail making tests A and B (TMT A&B) and the controlled word association test (COWA). Results: At this moment 31 patients are included in the study, 20 female and 11 male patients, aged from 20 to 85 years, in median 49 years. 6 patients were diagnosed with diffuse oligodendroglioma, 6 with oligoastrocytoma WHO grade II, 4 with diffuse astrocytoma, 4 with anaplastic oligodendroglioma, 2 with anaplastic oligoastrocytoma, 5 with anaplastic astrocytoma and 4 with glioblastoma. Despite having to deal with more negative symptoms patients report a better global health status than the healthy population. Professionally active patients reported a higher QoL than non-working patients. QoL results were not influenced by the volume of normal appearing brain tissue in MRI. The cognitive tests however showed that patients with a volume of normal appearing brain higher than average remember 1-2 words more in HVLT than patients with lower than average unchanged brain volume and are able to name 3 more words in the COWA. The TMT A (27 sec vs. 62 sec) and TMT B (66 sec vs 139 sec) were significantly different.The volume of gliosis visible in the MRI affected QoL as well as the cognitive status. Visible active tumor did not affect the cognitive status, but lowered the global health status. Conclusions: QoL and neurocognitive outcomes show a high variety in long term surviving glioma patients. Testing patient´s reported outcomes and their cognitive performance adds valuable information allowing a more comprehensive view than imaging data only and should help to plan individually suitable support and rehabilitation measures.
OS08.3 Genomic landscape of meningiomas
Authors: W. L. Bi, N. F. Greenwald, M. Abedalthagafi, P. Agarwalla, P. Horowitz, S. Santagata, O. Al-Mefty, R. Beroukhim, I. F. Dunn
Journal: Neuro-Oncology (2017)

Meningiomas are the most common primary brain tumor. The majority are benign, low-grade lesions which can be effectively managed with surgery. However, around 15% are high-grade tumors, which have a nearly 100% recurrence rate, and demonstrate an aggressive clinical course despite administration of high-dose adjuvant radiation. While much is known about the genetic events which constitute low-grade meningiomas, relatively little is known about the genomic drivers of high-grade tumors. We analyzed the genomes of 274 high-grade meningiomas and compared this information with data from 456 low-grade meningiomas. High-grade meningiomas had a higher mutation burden than low-grade meningiomas but did not harbor any statistically significant mutated genes aside from NF2, which is the most frequently altered gene in low-grade tumors. High-grade meningiomas possessed significantly elevated rates of chromosomal gains and losses, especially among tumors with monosomy 22. Across serial recurrences, genomic disruption preceded the emergence of nearly all mutations, remained largely uniform across time, and when present in low-grade meningiomas, correlated with subsequent progression to a higher grade. We observed a striking degree of mutational heterogeneity across tumor recurrences, which was likely due to extensive geographic heterogeneity in the primary tumor. Although we observed significantly fewer mutations amenable to targeted inhibition among high-grade meningiomas, we found that they contained numerous mutations predicted to be neoantigens, suggesting that efforts to harness the power of the immune system may be beneficial.
Efficacy and Safety Following Bosutinib Dose Reduction in Patients with Philadelphia Chromosome‒Positive Chronic Myeloid Leukemia
Authors: Vamsi Kota, Tim H. Brümmendorf, Carlo Gambacorti-Passerini, Jorge E. Cortes, Jeffrey H. Lipton, Hagop M. Kantarjian, Dong-Wook Kim, Fiona An, Eric Leip, Rocco J. Crescenzo, Mabel Woloj, Mark Shapiro, H. Jean Khoury
Journal: Blood (2016)
P09.03 Bevacizumab in glioma: An experience from Tata Memorial Hospital
Authors: M. Boppana, R. Tonse, V. Patil, R. Krishnatry, T. Gupta, R. Jalali
Journal: Neuro-Oncology (2017)

BACKGROUND: Optimal management of recurrent high grade gliomas continues to be challenging, with Bevacizumab as one of the modalities increasingly used in the last few years. The current audit looks at the pattern of use and its results from a major tertiary care center in India. METHODS: Patients who received Bevacizumab as salvage treatment for recurrent high grade glioma between January 2015 to August 2016 were included for this analysis. The demographics, characteristics at recurrence, symptomatic response, adverse events, and survival were noted. SPSS version 16 was used for analysis. Descriptive statistics was performed and Kaplan Meier time to event estimation method was used for estimation of progression free survival and overall survival. Results: Twenty seven patients were selected for this analysis. The median age was 47 years and 23 patients were males (85.1%). The histopathology was grade IV glioma in 21 patients (77.7%) and grade 3 in 6 patients (22.3%). Bevacizumab was used as 2nd line treatment in 22 patients, 3rd line in 4 patients and 4th line in 1 patient. It was administered as single agent in 11 patients and with chemotherapy in rest of the patients (CCNU in 2 patients and irinotecan in rest). The median number of cycles administered were 6 (1-12). Twenty two patients were eligible for symptomatic response assessment and 15 patients (68.1%) had symptomatic benefit. The median progression free survival was 145 days (57-232) and median overall survival was 164 days (123-204) respectively. The toxicity was limited to febrile neutropenia in 1 patient, bleeding episode in 1 patient and dyslipidemia in 1 patient. There was no episode of intracranial bleed or hypertension noted. There was a trend towards decrease in steroid use with bevacizumab. Conclusions: In Indian context Bevacizumab is well tolerated. Bevacizumab was associated with symptomatic improvement in recurrent high grade glioma. The ability of this drug to improve survival still remains questionable.
Abstract 121: GRK5-NT Regulates the Activity of Calcium-Calmodulin-Dependent Transcription Factors
Authors: Daniela Sorriento, Anna Fusco, Gaetano Santulli, Bruno Trimarco, Guido Iaccarino
Journal: Circulation Research (2012)

We have demonstrated that the amino terminal domain (GRK5-NT), which includes the RH domain and the region of binding to calmodulin, is able to regulate cardiac hypertrophy through inhibition of NFκB. Several studies indicate that mechanical stress and neuro-hormonal activation (Angiotensin, phenylephrine, endothelin) increase the levels of intracellular calcium, therefore activating calcineurin, a serine/threonine phosphatase that dephosphorylates nuclear factor of activated T cells (NFAT). Aim of this study is to evaluate the possibility that GRK5-NT regulates calcium-calmodulin dependent transcription factors. To this aim, we infected cardiomyoblasts in culture with an adenovirus encoding for GRK5-NT (AdGRK5-NT) or treated with a synthetic protein (TAT-RH), which reproduce the only RH domain of GRK5. Hypertrophic responses were induced by chronic stimulation of α 1 adrenergic receptors with phenylephrine (PE 10 -7 M,24h) and the levels of GATA4 and NFAT3 were assessed by western blot. PE induces activation and nuclear translocation of GATA4 and NFAT3 (NFAT:+38±3%;GATA4:+46±3% vs control), the treatment with AdGRK5-NT, but TAT-RH, reduces this effect (NFAT:-68±5%;GATA4:-56±2% vs PE). These data suggest that GRK5-NT using the NT domain regulates the activation of calcium-calmodulin dependent transcription factors through a mechanism of competition for binding to calmodulin. To confirm these data, we evaluated the effect of GRK5-NT in vivo in spontaneously hypertensive and hypertrophic rats (SHR). The overexpression of GRK5-NT in the heart was induced by intracardiac injection of 10 10 pfu/ml of AdGRK5-NT. The treatment inhibits nuclear translocation of NFAT3 and GATA4 (NFAT:-55±1%;GATA4:-34±3% vs PE) and is associated with a reduction in their DNA binding activity, as assessed by EMSA (NFAT:-47±1.5%;GATA4:-33±1% vs EP). In conclusion, our data indicate that GRK5-NT is able to regulate cardiac hypertrophy in two ways: inhibition of NFκB through binding and stabilization of IκB nuclear and inhibition activity of calcium- calmodulin dependent transcription factors, possibly by competing with calmodulin binding.
Low-Dose Decitabine Improves Platelet Recovery in Patients with Isolated Thrombocytopenia after HSCT
Authors: Yue Han, Yaqiong Tang, Ying Zhao, Man Huang, Jia Chen, Jiaqian Qi, Ying Wang, Xiaojin Wu, Xiao Ma, Feng Chen, Xuefeng He, Changgeng Ruan, Depei Wu
Journal: Blood (2016)
P16.07 Individual task specific testing associated with intra-operative MRI during awake craniotomy surgery for low grade gliomas to improve extent of resection and minimize morbidity
Authors: D. A. Gripp, P. H. P. Aguiar, M. V. C. Maldaun, L. R. Mathias, S. M. Verst, M. Docema
Journal: Neuro-Oncology (2017)

Brain low grade lesions of glial origin (LGG) especially those located in or near eloquent areas pose a challenging task for neurosurgeons operating such tumors. Even after the new classification of LGG, age, IDH status and extent of resection (EOR) seem to represent the main points that stratify patients in low or high risk. Often, surgery is the first step in the treatment and may positively impact the overall survival if extensive resection can be achieved with lowest morbidity. Therefore, neurophysiologic monitoring and intra operative MRI can be considered valuable tools in aiding maximal safe resection. Awake surgery has an important role when left side low frontal or posterior temporoparietal gliomas are to be operated on and individualized testing may influence, to our knowledge, on the extent and quality of resection, since anatomic variability may be encountered on different individuals during awake mapping. Materials and methods: a total of 16 LGG (10 astrocytomas, 4 oligoastrocytomas and 2 oligodendroglioma) were submitted to surgery, using awake craniotomy, neurophysiologic monitoring and intra operative MRI. Depending on each patient personal background, when appropriate and with personal consent prior to surgery, individualized testing based on mainly labor activities and hobbies such as playing the guitar and singing, praying, and oral math calculations were conducted and evaluated by a neurophysiologist, in conjunction with brain intra operative cortical and subcortical mapping. 9 patients were male and 7 were female. Median age was 38, maximal age was 54 and the minimal age was 28. All patients had lesions located in or near eloquent speech and/or motor areas. All patients were submitted to immediate post operative CT scan prior to UCI care and all were submitted to control MRI scan to estimate the EOR. 70% patients presented with headache, 62, 5% with seizure, only 1 patient presented as an incidental finding. Post operatively, 10 patients were neurologically intact, 5 had transient worsening of the previous neurological deficit and only one did not totally recover after 3 months post operation. The use of iMRI was helpful to improve EOR in 37,5% cases and positive mapping using individual speech testing that limited resection occurred in 56,25% cases. Gross total resection was achieved in 10 patients. ­CONCLUSION: brain mapping is an essential tool when performing awake surgery and may be even more specific when combined to individualized intra operative testing. Intra operative MRI, in our cases, combined to neuromonitoring, was a valuable tool when seeking maximal safe LGG resection.
P08.60 RAMBO (rapid anti angiogenesis mediated by oncolytic virus) decreased bevacizumab-induced glioma cell invasion
Authors: Y. Tomita, K. Kurozumi, T. Shimizu, T. Oka, Y. Otani, J. Ishida, K. Fujii, B. Kaur, I. Tomotsugu, I. Date
Journal: Neuro-Oncology (2017)

INTRODUCTION: Anti-VEGF therapies such as bevacizumab have been shown to attenuate VEGF-mediated angiogenesis, to decrease vascular permeability, and to inhibit tumor growth in malignant glioma. Conversely, bevacizumab has also been reported to induce invasive proliferation. Oncolytic viral therapy is considered to be a promising treatment modality for malignant glioma. Previous studies indicate that RAMBO (rapid anti angiogenesis mediated by oncolytic virus), a vasculostatin-expressing Herpes simplex virus (HSV)-1-derived oncolytic virus, has potent anti tumor activity against malignant glioma. In this study, the effects of RAMBO on bevacizumab-induced invasive changes in glioma were evaluated. MATERIALS AND METHODS: RAMBO is composed of the cDNA encoding for human vasculostatin (Vstat120), driven by the HSV-1 IE4/5 promotor, within the backbone of an attenuated HSV-1 virus (HSVQ). Experiments were conducted using the human malignant glioma cell lines U373 and U87deltaEGFR, and Vstat120 expression in the supernatant was assessed by western blotting. The effect of the combination of RAMBO with bevacizumab was assessed by cytotoxicity assays, scratch wound assays, and Matrigel invasion assays. RESULTS: Vasculostatin was detected in cell lysates and secreted CM at 14 hours after infection with RAMBO. The cytotoxicity assay demonstrated that bevacizumab did not increase the cytotoxicity of RAMBO against glioma cells. Conversely, in the scratch wound assay, RAMBO CM significantly reduced both the number of migrating cells and the rate of migration compared with saline used as control. Furthermore, the number and the rate of migrating cells induced by bevacizumab treatment was reduced by RAMBO CM. In the Matrigel invasion assays, the number of invasive cells induced by bevacizumab was reduced by RAMBO CM. CONCLUSIONS: These results demonstrated that RAMBO suppressed bevacizumab-induced glioma invasion, which may lead to a promising approach for the treatment of malignant glioma.
OS07.7 Patterns of diagnostic marker assessment in adult diffuse glioma - a survey of the European Confederation of Neuropathological Societies
Authors: A. Woehrer, B. W. Kristensen, A. Vital, J. A. Hainfellner
Journal: Neuro-Oncology (2017)

Introduction: The 2016 update of the WHO classification has introduced an integrated diagnostic approach that incorporates both tumor morphology and molecular information. This conceptual change has far reaching implications especially for neuropathologists who are in the forefront of translating molecular markers to routine diagnostic use. Adult diffuse glioma is a prototypic example for a group of tumors that underwent substantial regrouping, and it represents a major workload for surgical neuropathologists. METHODS: We conducted a survey among members of the European Confederation of Neuropathological Societies (Euro-CNS) in order to assess 1) the extent to which molecular markers have already been incorporated in glioma diagnoses, 2) which molecular techniques are in daily use, and 3) to set a baseline for future surveys in this field. Results: Based on 130 responses from participants across 40 nations neuropathologists uniformly rate molecular marker testing as highly relevant and already incorporate molecular information in their diagnostic assessments. At the same time however, the survey documents substantial differences in access to crucial biomarkers and molecular techniques across geographic regions and within individual countries. Concerns are raised concerning the validity of test assays with MGMT, 1p19q, and ATRX being perceived as most problematic. Conclusions: Together neuropathologists advocate the need for international harmonization of standards and consensus guidelines, and the majority is willing to actively engage in quality control.
OS06.4 Identification of novel NTRK fusion in glioneuronal tumors and radiographic response following therapy with an NTRK inhibitor
Authors: P. K. Brastianos, C. Alvarez-Breckenridge, J. J. Miller, N. Nayyar, C. Gill, D. Dias-Santagata, S. Santagata, P. Multani, S. Yip, D. Cahill, A. J. Iafrate, T. Batchelor
Journal: Neuro-Oncology (2017)

Glioneuronal tumors constitute a histologically diverse group of primary CNS neoplasms, with no effective systemic therapy after surgery has failed. To further characterize this group of tumors, we collected a cohort of 26 glioneuronal tumors and performed in-depth genomic analysis. We identified mutations in BRAF (34%) and oncogenic fusions (30%). In addition, we discovered novel oncogenic fusions involving members of the NTRK gene family in a subset of our cohort. One patient with BCAN exon 13 fused to NTRK1 exon 11 initially underwent a subtotal resection for a 4th ventricular glioneuronal tumor but ultimately required additional therapy due to progressive, symptomatic disease. Given the patient's targetable fusion, the patient was enrolled on a clinical trial with entrectinib, a pan-Trk, ROS1 and ALK inhibitor. The patient was treated for 11 months and during this time volumetric analysis of the lesion demonstrated a maximum reduction of 60% in the contrast-enhancing tumor compared to his pre-treatment MRI. The radiologic response was associated with resolution of his clinical symptoms and was maintained for eleven months on treatment. This represents the first report of BCAN-NTRK1 fusion in glioneuronal tumors and highlights its clinical importance as a novel, targetable alteration.
Vorinostat Does Not Improve Outcome in Patients with Acute Myeloid Leukemia and High Risk Myelodysplasia Treated with Azacitidine: Results of the UK Trials Acceleration Programme Ravva Trial
Authors: Charles Craddock, Aimee E Houlton, Paul Ferguson, Manoj Raghavan, Sonia Fox, Louise Dudley, Lynn Swun Quek, Jamie D. Cavenagh, Michael Dennis, Mary Frances McMullin, Srinivas P Pillai, Richard Kelly, Shamyla Siddique, Keith Wheatley, Paresh Vyas
Journal: Blood (2016)
Lateral thinking – Interocular symmetry and asymmetry in neurovascular patterning, in health and disease
Authors: James R. Cameron, Roly D. Megaw, Andrew J. Tatham, Sarah McGrory, Thomas J. MacGillivray, Fergus N. Doubal, Joanna M. Wardlaw, Emanuele Trucco, Siddharthan Chandran, Baljean Dhillon
Journal: Progress in Retinal and Eye Research (2017)