tbuckley/cabot-search huggingface dataset:
MNGI-24. PREDICTORS OF VISUAL OUTCOMES IN SPHENO-ORBITAL MENINGIOMA SURGERY ENDORSE EARLY MAXIMUM SAFE SURGERY AND INTENSIVE FOLLOW-UP OF PATIENTS WITH MULTIPLE MENINGIOMA
Authors: Amir Zamanipoor Najafabadi, Stijn Genders, Wouter van Furth
Journal: Neuro-Oncology (2018)

Most Spheno-Orbital Meningioma (SOM) series include patients over a period of multiple decades, while surgical techniques have improved over the years. In addition, predictors of visual outcomes and progression free survival (PFS) have not yet been systemically assessed. The aim of this study was to assess predictors of visual outcomes and PFS in a recent SOM cohort. Consecutive patients operated by a team of a neurosurgeon and orbital surgeon in the Leiden University Medical Center between June 2015-December 2017 were included. Pre- and postoperative visual acuity (Snellen chart), visual field deficit (Humphrey field analyser, in decibel [dB]), and relative proptosis (exophthalmometry) were compared with the Wilcoxon signed-rank test. Predictors of visual outcomes were assessed with linear regression analysis. Predictors of PFS (definition: need for reintervention) with the log-rank test. Eight patients presented with impaired visual acuity, which improved in 88% (preoperative: 0.8, postoperative: 1.1, p=0.012). All 16 patients presented with visual field deficits, which improved in 86% (preoperative: -8.4dB, postoperative: -3.8dB, p=0.008). Also all patients presented with proptosis, which improved in 86% (preoperative: 4.5mm, postoperative: 2.9mm, p=0.013) Strongest predictors for postoperative visual acuity, visual field deficits and persistent proptosis were preoperative visual acuity (p=0.001), visual field (p<0.001) and proptosis (p=0.017), respectively. Predictors for PFS were Simpson grade (p=0.048) and number of meningioma tumours (p=0.017). In our cohort, all visual outcomes and proptosis improved significantly after surgery. We recommend early surgery after diagnosis, as patients who present with greatly impaired or deteriorated visual function are less likely to have normal postoperative visual outcomes. In addition, we recommend more frequent and tailored follow-up for patients after a Simpson grade II-V resection of the SOM or with multiple meningioma.
Abstract MP03: Plasma Sphingolipids and Risks of Heart Failure and Atrial Fibrillation in Older Adults: The Cardiovascular Health Study
Authors: Rozenn N Lemaitre, Paul N Jensen, Barbara McKnight, Andrew Hoofnagle, Irena B King, Susan R Heckbert, Nona Sotoodehnia, Dariush Mozaffarian, Bruce M Psaty
Journal: Circulation (2018)

Introduction: Ceramides and sphingomyelins (sphingolipids) are circulating lipids involved in multiple physiological pathways relevant to heart failure (HF) and atrial fibrillation (AF), including apoptosis, oxidative stress, and inflammation. Experimental studies suggest that sphingolipids with different saturated fatty acids exhibit different biological activities, but their relationships with HF and AF are unknown. Hypothesis: Higher levels of plasma ceramide and sphingomyelin that contain the fatty acid 16:0 are associated with higher risks of HF and AF; and higher levels of ceramides and sphingomyelins that contain the fatty acid 20:0, 22:0 or 24:0 are associated with lower risks. Methods: We measured sphingolipids in the Cardiovascular Health Study (CHS) in plasma samples from 1994-95 (N=4026) or from 1992-93 (N=586). We assessed the separate associations of the levels of 8 sphingolipids with risks of incident HF and incident AF using Cox regression. A p-value threshold of 0.006 was used to account for multiple testing. Results: Among 4,612 participants, 1179 incident HF and 1198 incident AF occurred during &gt;40,000 person-years of follow-up. In adjusted analyses, higher levels of Cer-16 (ceramide with 16:0) and SM-16 (sphingomyelin with 16:0) were associated with higher risk of incident HF, but not with risk of incident AF (Table). In contrast, higher levels of Cer-20, Cer-22 and Cer-24 were each associated with lower risk of AF, but not with risk of HF. Higher levels of SM-20, SM-22, and SM-24 tended to be associated with lower risks of AF and HF, with only the association of SM-20 with AF significant. Conclusions: Plasma levels of ceramide and sphingomyelin with 16:0 show different associations with HF and AF than species with 20:0, 22:0 or 24:0. Associations of Cer-16 and SM-16 specifically with higher risk of HF may be due to a role of apoptosis in HF. The novel findings that Cer-20, Cer-22, and Cer-24 are associated with lower risk of AF warrant further examination of the role of these sphingolipids in protecting from AF.
Psoriasis and Atherosclerosis
Authors: Hasan K. Siddiqi, Paul M Ridker
Journal: Circulation Research (2018)

P atients with psoriasis have elevated atherosclerotic risk. 1 Although inflammation is thought to be a contributing factor, the specific pathways through which psoriasis increases vascular risk is uncertain.Patients with psoriasis tend to have significant comorbidities, such as hypertension, diabetes mellitus, and obesity, that predispose to atherosclerotic cardiovascular disease (ASCVD). 2 Yet, after adjustment for these comorbidities, patients with psoriasis continue to be at high risk in a manner reflecting the severity and duration of psoriasis.
AB0843 Effect of tnf inhibitors on bone microarchitecture in patients with ankylosing spondylitis: a longitudinal study based on high-resolution peripheral quantitative based (HRPQCT)
Authors: N. Nigil Haroon, E. Szabo, A.M. CHEUNG, R. Inman
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Ankylosing spondylitis (AS) is associated with high risk of fractures. BMD, bone microarchitecture and strength are negatively affected in AS. TNF inhibitors such as etanercept, adalimumab, golimumab and infliximab are the mainstay of treatment in AS. However no data is available on the effect of TNF inhibitors on bone microarchitecture and strength. <h3>Objectives</h3> This study aimed to assess the effect of TNF inhibitors on bone microarchitecture in patients with AS. <h3>Methods</h3> AS was defined by Modified New York criteria. Areal BMD was measured by DXA. Volumetric BMD (vBMD) and bone microarchitecture were measured using highresolution peripheral quantitative CT (HRpQCT) at the radius and tibia at baseline and after one year of treatment with TNF inhibitors. Intake of calcium and vitamin D were optimised. <h3>Results</h3> There were 31 subjects (58% men). Mean (+SD) age and BASDAI were 40+14 years and 4.1+2.1 respectively. Median duration of disease was 14 (IQ: 6.5–25.5) years. Mean duration of follow-up was 15 months. Areal BMD (n=22) at lumbar spine (1.053+0.235 vs. 1.049+0.202,p=0.89), total hip (0.944+0.152 vs. 0.912+0.164,p=0.5), and femoral neck (0.955+0.151 vs. 0.954+0.191,p=0.2) did not change significantly. HRpQCT (n=31) on follow-up demonstrated that total, trabecular and cortical volumetric BMD were unchanged at both radius and tibia (table 1). Also, HRpQCT based trabecular parameters such as trabecular number, thickness and separation, BV/TV and cortical parameters such as cortical porosity and thickness remained stable (table 1). FEA estimates of bone stiffness and stress tended to be lower at the radius on follow-up however these parameters were not significantly different at the tibia (table 1). <h3>Conclusions</h3> This is the first study to document the changes in bone strength in AS patients with the use of TNF inhibitors. Treatment with TNF inhibitors might maintain bone microarchitecture at cortical and trabecular sites in patients with AS. <h3>Disclosure of Interest</h3> N. Nigil Haroon Consultant for: AMGEN Canada, E. Szabo: None declared, A. CHEUNG Consultant for: AMGEN, ELI LILLY, R. Inman Grant/research support from: AMGEN, Consultant for: AMGE, ABBVIE, NOVARTIS, JANNSEN, MERCK
COMP-06. GLIOBLASTOMA DEVELOPMENT MIRRORS THE DEVELOPING BRAIN
Authors: Charles Couturier, Shamini Ayyadhuri, Phuong Le, Jean Monlong, Redouane Allache, Salma Baig, Gabriele Riva, Mathieu Bourgey, Bratislav Misic, Marie-Christine Guiot, Jack Antel, Guillaume Bourque, Jiannis Ragoussis, Kevin Petrecca
Journal: Neuro-Oncology (2018)

Intratumoral and interpatient heterogeneity are characteristics of glioblastoma and constitute important challenges in overcoming treatment resistance and developing new, more effective therapies. Using single-cell RNA sequencing, we characterized 60 933 cells from 4 developing fetal brains and 8 glioblastomas. By using fetal brain development as a road map, we show a tri-lineage (astrocytic, oligodendrocytic, and neuronal) hierarchical organization in all glioblastomas. In each patient, a population of progenitor cancer cells was found at the apex of this hierarchy. These cells were enriched in our patient-derived glioma stem cell samples, and, like progenitors in the developing brain, were the main dividing cell population within the cancer. Using expression signatures obtained from single-cell RNA-sequencing, we isolated progenitor cancer cells and compared them to other glioblastoma cell types. We showed the progenitors are the most resistant to chemotherapy and the most tumorigenic in mouse xenograft models. This newly found conserved developmental organization points to the cell of origin and suggests new therapeutic approaches.
CMET-08. BRAIN METASTASES AS PRIMARY PRESENTATION OF SOLID TUMORS: A DESCRIPTIVE ANALYSIS OF THE NATIONAL CANCER DATABASE (NCDB)
Authors: Catherine Garcia, Stacey Slone, William St Clair, Eric Durbin, Thomas Pittman, Donita Lightner, John Villano
Journal: Neuro-Oncology (2018)

Survival of cancer patients with brain metastases (BM) has increased with novel therapies. Previous analyses have focus on radiation treatment or predate novel systemic therapies that have improved survival outcomes. We analyzed the National Cancer Database from 2010–2014, for all patients with metastatic disease to the brain to analyze patterns of care across the United States. 88,459 cases were included. The majority of patients were male (51.7%), white (84.2%), and non-Hispanic (92.6%), with a median age of 65 years. The most common primary cancer sites included lung and upper airway cancer (82.5%), breast cancer (4.2%), skin cancer (3.5%), and gastrointestinal tumors (2.3%). Hepatobiliary cancer patients had a higher frequency of comorbidities (9.6% with a Charlson-Deyo score ≥3). Patients were more likely to be treated in community centers (64.0%) and lived in metropolitan areas (79.0%). Overall 72.6% received any form of radiation, 53.5% received radiation to the brain, 52.1% received chemotherapy, 2.3% received immunotherapy, and 13.3% underwent surgical procedure to distant metastatic site. The most common radiation modality was whole-brain radiation (58.4%), followed by stereotactic radiosurgery (11.6%), other (0.65), and brachytherapy (0.1%). The type of radiation was unknown in 2.0% of the patients. Radiation to the brain was more common in skin cancer (63.4%). The use of chemotherapy was significantly lower in patients with hepatobiliary cancer (34.2%). Immunotherapy was used in 2.3% of patients, mainly in melanoma (13.6%), and breast cancer (8.15%). Median survival for all cases was 5 months, and was significantly higher in male reproductive system cancer (16.3 months), and lower in hepatobiliary cancer (2.7 months). CONCLUSIONS: The increased survival of BM in the current era exceeds historical RTOG recursive partitioning analysis. Large scale data, such as NCDB, is essential for single tumor analysis with treatment and survival data, and provides a reference for future investigations.
CBMT-02. miR-124, -128, AND -137 COMBINATION THERAPY AGAINST GLIOBLASTOMA
Authors: Adam Kosti, Mei Qiao, Erzsebet Kokovay, Luiz Penalva
Journal: Neuro-Oncology (2018)

miRNAs are critical regulators of tumorigenesis, acting as oncogenes or tumor suppressors. Previous work, by us and others, have demonstrated that miR-124, -128, and -137 are key players in controlling neurogenesis and gliomagenesis. Together these miRNAs promote differentiation of neural stem cells (NSCs), while in gliomas their dysregulation contribute to the glioma phenotype. The three miRNAs display strong expression correlation in GBM cohorts and synergize to drive neuronal differentiation of NSCs by regulating a shared network of genes. Individually ectopic overexpression of these miRNAs induces significant changes in proliferation, and differentiation of GBM cells; however, it is unclear if they synergize to produce a stronger effect as observed in NSCs. We tested the combination of miR-124, -128, and -137 in glioblastoma cell lines and found that together they produce a synergistic effect, decreasing cell proliferation and we will test this synergy in other systems. In NSCs we found an interconnected transcription factor (TF) network to be important targets of miR-124, -128, and -137. Due to their importance in NSCs, we hypothesized that these TFs are critical in gliomas. We performed a siRNA screen against the TFs network in GBM cell lines and examined the impact of knockdown on cell proliferation, viability, and apoptosis. While several genes were important in maintaining the glioma phenotype, knockdown of ETS-related transcription factor Elf-4 (ELF4) produced the strongest phenotype changes. We will next characterize ELF4’s transcriptional influence utilizing ChIP-seq paired with RNA-seq. Overall our initial data suggests that this miRNA-Transcription factor network is important in the glioma phenotype, and that combination of the three miRNAs is synergistic. Furthermore, we find the ELF4 is a critical TF from this network and regulates the glioma phenotype.
QOLP-20. QUALITY OF LIFE IN THE PHASE III CeTeG/NOA-09 TRIAL RANDOMIZING CCNU/TEMOZOLOMIDE (TMZ) COMBINATION THERAPY VS. STANDARD TMZ THERAPY FOR NEWLY DIAGNOSED MGMT-METHYLATED GLIOBLASTOMA
Authors: Johannes Weller, Theophilos Tzaridis, Joachim Steinbach, Uwe Schlegel, Peter Hau, Dietmar Krex, Oliver Grauer, Roland Goldbrunner, Oliver Bähr, Martin Uhl, Clemens Seidel, Ghazaleh Tabatabai, Lars Bullinger, Norbert Galldiks, Christina Schaub, Walter Stummer, Matthias Simon, Rolf Fimmers, Schmid Matthias, Christoph Coch, Martin Glas, Ulrich Herrlinger, Niklas Schäfer
Journal: Neuro-Oncology (2018)

The CeTeG/NOA-09 trial demonstrated a significant survival benefit of radiotherapy with CCNU/temozolomide (TMZ) combination therapy compared to standard TMZ therapy as first-line treatment of O6-methylguanine-DNA methyltransferase (MGMT)-promotor hypermethylated glioblastoma. Quality of life (QoL) assessment was a secondary objective to investigate if CCNU/TMZ combination chemotherapy has a detrimental effect on patient’s QoL. PATIENTS AND Patients (n=141) received standard radiotherapy and were randomized (1:1) for CCNU/TMZ or standard TMZ. The modified intention-to-treat population consisting of 129 patients was analyzed. At least every three months, Karnofsky performance score (KPS) was determined and QoL was measured using the EORTC-QLQ C30 and BN20 questionnaires. A longitudinal mixed-model analysis was used to evaluate differences between treatment arms in the course of KPS and QoL over time. Time to first deterioration was analyzed using a Cox regression model. Over a period of four years, longitudinal mixed-model analysis detected no significant impairment of QoL or KPS in the CCNU/TMZ arm as compared to the TMZ arm. Time to deterioration was prolonged in one QoL domain, motor dysfunction, for patients in the experimental arm. Intensified alkylating chemotherapy with CCNU/TMZ for patients with MGMT promotor-methylated glioblastoma did not lead to a reduction of QoL or KPS compared to TMZ standard therapy.
CADD-49. IDENTIFICATION AND VALIDATION OF AZOLES AS HK2 INHIBITORS IN GLIOBLASTOMA <i>IN VITRO</i> AND <i>IN VIVO</i>
Authors: Sameer Agnihotri, Sheila Mansouri, Kelly Burrell, Mira Li, Jeff Liu, Romina Nejad, Sushil Kumar, Shahrzad Jalali, Sanjay Singh, Alenoush Vartanian, Eric Xueyu Chen, Severa Bunda, Alireza Mansouri, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2018)

Hexokinase I and 2 (HK1/HK2) catalyze the first committed step in glucose metabolism, ensuring a sustained glucose concentration gradient. Glioblastomas (GBMs) over-express HK2, and we have previously shown that its loss sensitizes GBM cells to treatment. In this study, we have conducted a systematic small-drug screen to identify potential HK2 inhibitors. Pathway analysis was conducted using Gene Set Enrichment Analysis on differentially expressed genes in control and HK2 siRNA-treated samples. The top 200 up- and down-regulated genes were used to query the Connectivity Map database for potential inhibitors. 15 candidate drugs were identified and their EC50 was determined in glioma cell lines, glioma stem cells (GSCs), and normal human astrocytes. Dynamic metabolic flux analysis with 13C-glucose labeling followed by liquid chromatography-mass spectrometry (LC-MS) was used to assess effect of candidate drugs on tumor cell glycolytic intermediates. Xenograft mice bearing glioma stem cells or U87 cells were treated with vehicle, ketoconazole, or posaconazle (25mg/kg). Mice were sacrificed when moribund and immunohistochemistry was used to assess proliferation (Ki67) and apoptosis (TUNEL assay). Mouse brain tissue drug concentration was determined using HPLC-MS/MS. HK2 knockdown affected glycolysis and angiogenesis. The EC50 of ketoconazole and posaconazole was within clinically achievable doses and below the concentration needed to affect normal human astrocytes or stem cells (<15µM). Compared to control, a significant decreased in several intermediate metabolites of glycolysis was also observed in vitro. Vehicle treated xenografts had a significantly shorter survival (44 ± 2 days) compared with mice treated with ketoconazole (54 ± 4 days, p<0.05) or posaconazole (56 ± 4 days, p<0.05). Both drugs led to significant reduction in proliferation and increase in apoptosis. Azoles can target genes and pathways regulated by HK2. These pre-clinical results support the value of investigating azoles as repurposed drugs in clinical trials.
Predictors of 1-year compliance with adaptive servoventilation in patients with heart failure and sleep disordered breathing: preliminary data from the ADVENT-HF trial
Authors: Elisa Perger, Owen D. Lyons, Toru Inami, Stephanie Smith, John S. Floras, Alexander G. Logan, T. Douglas Bradley
Journal: European Respiratory Journal (2018)

<b>Adherence to sleep apnoea treatment is essential to evaluate trials involving cardiovascular end-points. In patients with heart failure and obstructive or central sleep apnoea in the ADVENT-HF trial, adherence to adaptive servoventilation was very good.</b>http://ow.ly/5sNz30mDj2W
INNV-28. EXTENT OF RESECTION IN NEWLY DIAGNOSED GLIOBLASTOMA: INCORPORATING CLINICAL AND MOLECULAR DATA TO PREDICT OUTCOME
Authors: Julie Semenchuk, Marco Essig, Katie Galloway, Pascal Lambert, Marshall Pitz
Journal: Neuro-Oncology (2018)

The benefits of increasing extent of resection (EOR) for both overall survival and progression-free survival (PFS) in glioblastoma has been well documented. However, models predicting surgical outcomes have failed to incorporate a patients IDH status, a known prognostic factor. We isolate the impact of IDH on surgical outcomes. We determine the effect modification of increasing EOR and decreasing residual tumor volume (RTV) on IDH status. We performed a retrospective cohort study of 98 patients with glioblastoma who had undergone either biopsy or surgical resection. Tumor volumes were determined by volumetric analysis. Univariable and multivariable Cox PH Regression models were built using overall survival and PFS as endpoints. Increasing EOR and decreasing RTV were both associated with prolonged overall survival and PFS. When IDH status was added to multivariable models, the model utilizing RTV provided a slightly better fit compared to EOR. An interaction term between RTV and IDH status was characterized, such that at low RTVs the prognosis of an IDH mutant is significantly better than that of an IDH wild-type, an effect that is less important as RTV increases. The significance of this term was confirmed by improved fit upon insertion into multivariable models. Minimizing RTV and increasing EOR are important prognostic factors for both IDH wild-type and IDH mutant glioblastoma. The protective benefit of the IDH mutation at lower RTVs suggests these patients are the best candidates for aggressive surgical resection.
Wellbeing support for general practitioners
Authors: Mark Sage
Journal: BMJ (2018)

Although resilience is undoubtedly needed among healthcare professionals, this is only one piece of the puzzle.1 It puts the onus on the individual, implying that lack of resilience is further evidence that doctors are failing, when they are probably already at a low ebb. Doctors’ suicide rates are appalling and should focus minds,2 but whole system change is a …
EXTH-33. COMPREHENSIVE TARGETING OF NOVEL MASTER REGULATORS OF CANCER STEM CELLS TO TREAT GLIOBLASTOMA – IN VIVO STUDY
Authors: Changwang Deng, Mathew Sebastian, Son Le, Dan Jin, Dongjiang Chen, Nagheme Thomas, David Tran
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most prevalent and aggressive brain cancer in adults. GBM is enriched with glioma stemlike cells (GSCs) that contribute to tumor initiation and treatment resistance and thus a natural focus for therapeutic development. However, targeting GSCs has been a challenge because of the dearth of knowledge of master regulators specific to GSCs and not to normal brain cells. Therefore systematic elucidation of the GSC specific core regulatory program will improve our understanding of GSC biology and provide an opportunity to develop novel GSC specific therapy with maximal efficacy and minimal toxicity. To accomplish these objectives, we have recently developed two innovative computational platforms, GeneRep and nSCORE and experimentally validated them in several published datasets. With this platforms, a cluster of 6 interrelated master subnetworks emerged, which were functionally grouped into the stemness and cancer pathways, some of which are known Olig and Myc factors. By enforcing the expression of this cluster in normal Human Astrocytes, we were able to reprogram these normal cells into GSC-like cells as measured by the neurosphere formation and in vivo tumorigenesis assays, confirming the contribution of this cluster for the GSC development. Furthermore, this cluster was present and functioned cooperatively to maintain GSCs in patient derived GSC lines. Functionally blockage individually or two of them by shRNA significantly reduces neurosphere formation and promotes cell death. Intracranial Injection of those gene-modified-GSCs into NSG mouse, dramatically double the mouse survival time. Most promising, preliminary data shows that in vivo tumor growth could be inhibited by either modulation of gene expression or via cancer vaccine. Our data establish a novel set of genes controlling GSCs survival and provide a compelling rationale for its therapeutic targeting to reduce tumor growth.