tbuckley/cabot-search huggingface dataset:
GENE-07. GENOMIC ENHANCER METHYLATION IS ASSOCIATED WITH BIOLOGICAL AND CLINICAL FEATURES IN PITUITARY TUMORS
Authors: Maritza Mosella, Tathiane Malta, Thais Sabedot, Michelle Felicella, Todd Aho, Laila Poisson, Ana deCarvalho, James Snyder, Ian Lee, Steven Kalkanis, Tobias Walbert, Houtan Noushmehr, Jack Rock, Ana Valeria Castro
Journal: Neuro-Oncology (2018)

The importance of enhancers has been recently highlighted in a pan-can transcriptomic analysis that revealed causal interaction between active enhancers and actionable genes as well as their prognostic value. DNA methylation is associated with enhancer activity and its interplay with the transcriptional machinery. However, pituitary tumors (PT) were not included in the pan-can study and the role of enhancer in these tumors is unknown. In order to address the methylation profile of causal (CausEnhs) and prognostic enhancers (PrognEnhs) described in the pan-can analysis, we analyzed the DNA methylome of two cohorts - an internal one comprised of 9 macroadenomas (6 nonfunctioning pituitary tumors-NFPT and 3 functioning - FPT; 5 invasive) and 5 non-tumoral pituitary specimens (NT) and an external cohort comprised of 24 PTs (18 NFPT + 6FPTs). Unsupervised analysis showed that PrognEnhs clustered according to PT functional status and were mainly hypermethylated in NFPT in relation to FPT, in both cohorts. PrognEnhs overlapped with differentially methylated enhancers (DME) that we previously identified in a supervised analysis comparing NFPTs and FPT from our cohort (p < 0.03). Among the 6758 PrognEnhs, 177 overlapped hypermethylated enhancers and 8 overlapped hypomethylated enhancers in NFPTs. Motif analysis of the ProgEnhs that overlapped hypermethylated enhancers identified a DNA signature including the core Basic Leucine Zipper Domain (bZIP domain), binding site for the transcription factors Fra-1/Fra-2,AP-1, Fosl2 and ATF3 (p-value < 0.0001), related to various oncogenic processes. In both cohorts, probes nearest or overlapping CausEnhs were mostly hypermethylated but not significantly associated with any clinical feature. These preliminary findings suggest that DNA methylation of enhancers associated with prognosis in other tumors may be involved in the functional status and oncogenic pathways in PT.
CADD-05. A NEW BIOANALYTICAL METHOD AND SINGLE-DOSE PHARMACOKINETICS FOR OXALOACETATE
Authors: David Conway, Alan Cash
Journal: Neuro-Oncology (2018)

As reported at SNO 2017, oxaloacetate was found to increase survival in mice implanted with human glioblastoma multiforme by its pharmacologic activity as a potent “glutamate scavenger.” The pharmacokinetics of oxaloacetate is not well understood in part due to a lack of bioanalytical methods. As such, a novel sensitive and specific LC–CMS/MS method was developed for the quantification of oxaloacetate in mouse plasma. The optimal chromatographic behavior was achieved using Venusil ASB Phenyl, 4.6 X 100mm, 5µ, 150ºA using reversed phase chromatography. Sample preparation was done via protein precipitation with a derivatization reagent. Detection was performed by negative ion electrospray ionization in MRM mode, monitoring the transitions m/z 326.129→83.9 and m/z 320.917→152.100. The calibration curve showed good linearity within the range of 256.728 to 10269.100 ng/mL (r2 ≥0.9940). The plasma pharmacokinetic profile of oxaloacetate was determined in healthy male BALB/c mice following oral administration at the doses of 250 and 1000 mg/kg body weight, respectively. Plasma pharmacokinetic parameters were determined by non-compartmental analysis using WinNonlin 6.3. Non-linear pharmacokinetics was demonstrated. At 250 mg/kg body weight, oxaloacetate pharmacokinetics was plasma exposure 4392.15 h*ng/mL, T1/2 0.2 hours, Cmax 12063 ng/mL and mean retention time was 0.30 h. At 1000 mg/kg body weight dose the plasma exposure was 27695.99 h*ng/mL, T1/2 0.14 hours, Cmax 80299 ng/mL and the MRT was 0.26 hours. Oxaloacetate, with its rapid pharmacokinetics, may offer a safe adjunctive therapy to patients with GBM.
PATH-12. CHARACTERISTICS OF GIANT CELL MORPHOLOGY IN LONG-TERM SURVIVORS OF GLIOBLASTOMA: CONSIDERATION OF SEX DIFFERENCES
Authors: Sandra Johnston, Spencer Bayless, Maciej Mrugala, Joshua Rubin, Peter Canoll, Kristin Swanson
Journal: Neuro-Oncology (2018)

The hallmark of glioblastoma (GBM) is poor survivorship. However, a small subset (5%) of patients live greater than 5 years (extreme survivors (ES)). The pathological and tumor determinants of ES are unknown. Giant cell (GC) morphology occurs in < 1% of all GBM, is typically IDH1 wildtype, shows a high frequency of p53 mutations, and is reportedly associated with a somewhat better survival than other IDH1-wildtype GBM. However, the clear association between ES and GC GBM has not be established. We aimed to describe the characteristics of ES tumors that presented with GC GBM features and examine sex differences. In our retrospective multi-institutional database, we identified 90 ES patients with GBM. We reviewed neuropathological reports for the diagnosis of GC GBM or pathology description that included the descriptor(s) of GC: monstrocellular or giant cell or bizarre multinucleated and evaluated phenotypical features in order to describe ES with GC GBM. Values are presented as means. Sixteen (17.8%) ES patients were characterized as GC GBM (males (n=9, 56.25%), females (n=7, 43.75%)). Males were significantly younger than females (39.67 vs 56.29, p=0.018). Females presented with significantly smaller tumors than males (F: 9.49 mm, M: 21.14 mm, p=0.0008). Males less often presented with seizures (33.33%) compared to females (42.86%, p=0.7686). Calculations of invasion/proliferation ratios from our mathematical model revealed no statistically significant differences between females and males. Overall survival between males and females was not statistically significant. Across the board, GC GBM occurred most often in frontal lobes (All: 56% (n=9), 66.67% of males (n=6), and 42.86% of females (n=3)). Extreme survivors of GBM exhibit giant cell features at greater than five-fold incidence than the general GBM population. Sex differences warrant significant attention in future explorations of pathological and tumor characteristics in GC GBM.
Predicting Outcome in Head and Neck Cancer: miRNAs with Potentially Big Effects
Authors: David A. Clump, Curtis R. Pickering, Heath D. Skinner
Journal: Clinical Cancer Research (2018)

A five-miRNA signature for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) identifies patients at risk for inferior outcomes. Combining established clinical variables with this novel miRNA signature affords an opportunity to personalize and intensify treatment strategies in this high-risk patient population.See related article by Hess et al., p. 1505.
STEM-08. MODULATION OF RADIATION-INDUCED MESENCHYMAL STEM CELL MIGRATION IN GLIOBLASTOMA
Authors: Henry Ruiz-Garcia, Rachel Sarabia-Estrada, Anna Harrell, Mondal Sujan, Keila Alvarado-Estrada, Alfredo Quinones-Hinojosa, Daniel Trifiletti
Journal: Neuro-Oncology (2018)

Glioblastoma is the most common primary adult brain tumor and carries a devastating prognosis. Mesenchymal stem cell (MSC) therapies offer a new strategy that could provide a novel treatment approach; however, it is unknown how MSC therapy should be integrated into the current standard of care: radiation and chemotherapy. AIMS: Study the modulatory effect of ionizing radiation (IR) on MSC migratory patterns. METHODS AND To confirm IR-induced lethality, alamarBlue assay of radiated patient-derived glioblastoma brain tumor initiated cells (BTICS) showed decreased viability after 10 Gy and 20 Gy IR when measured at 48 hours (p=0.006). MSCs were transduced with a lentiviral vector for expression of iRFP and, ex vivo implantation of MSCs was carried out on organotypic slices of normal mouse brain to evaluate engraftment and migration in the setting of IR delivery, groups of 0 Gy, 2 Gy, 5 Gy and 10 Gy were compared via confocal microscopy using 3D time lapse and daily qualitative evaluation of migratory patterns. Migratory distances showed a positive correlation with increasing dose of IR compared to control. Additionally, to assess the effect of IR on MSC migration, transwell assays were performed, in quadruplicate, using the radiated conditioned media from patient-derived glioblastoma BTICs; after incubating for 24 hours, migration was assessed by directly counting DAPI-labeled nuclei via fluorescent microscopy. Reduced MSC transwell migration was found after 10 Gy IR compared to the control, 2 Gy IR, and 5 Gy IR groups (p=0.008, p=0.002, and p=0.010, respectively). MSC migration to BTIC-conditioned media decreases when BTICs are exposed to high dose IR, however migration of MSCs seems to follow a positive relationship with the delivery of IR on an ex vivo mouse model. This suggests that low dose, but not high dose, radiation could ‘prime’ the tumor microenvironment for MSC delivery.
SURG-10. MICROSURGERY OF LIMBIC AND PARALIMBIC GLIOMAS: EXTENT OF RESECTION, MORBIDITY AND SURVIVAL
Authors: Cristina Goga, Martin Stienen, Nicholas Smoll, Alessandro Moiraghi, Karima Tizi, Shahan Momjian, Karl Schaller
Journal: Neuro-Oncology (2018)

OBJECT: To describe the authors experience with microsurgical resection of limbic and paralimbic gliomas by retrospectively analyzing surgical results, neurological and survival outcomes. Adults who had undergone resections of limbic and paralimbic gliomas of all grades were included. Tumor location was differentiated according to the Yasargil classification. The extent of resection (EOR) was assessed using a quantitative, semiautomated volumetric analysis of pre and postoperative MR images. Fifty-six consecutive patients, with a median age of 48.8 years, a Karnofsky Performance Score (KPS) of 90 and a median tumor volume of 38.9 cm3 were followed for 2.9 years (median). The majority of gliomas involved combinations of the frontoorbital-insula-mediobasal temporal areas (53%, Type 5), followed by the mediobasal temporal (25%, Type 1), insular region (18%, Type 3), and cingulate gyrus (14%, Type 2). An EOR> 90% was achieved in 55% of the procedures with a median EOR of 91.8%. Permanent disabling motor and language deficits were recorded in 3.6% and 1.8% of patients. The 5-year overall survival (OS) was 90% for Grade II gliomas. Median OS was 15 months and 14 months for Grade III and IV gliomas. A multivariate analysis of various prognostic variables (age, preoperative KPS score, preoperative tumour volume, EOR, residual tumour volumes,IDH1/IDH2 status, 1p19q status, MGMT methylation, postoperative chemotherapy and radiation therapy) showed that WHO grade, poor preoperative KPS decreased postoperative KPS performance predicted survival and disease progression CONCLUSIONS: Extensive resection is often achievable and is relatively safe even in patients with limbic and paralimbic gliomas of all grades. The prognosis of these tumor may not differ substantially from those of hemispheric gliomas located elsewhere and microsurgical resection may not substantially influence their clinical course. It remains unclear, which subset of patient or tumor characteristics may benefit more and which EOR cut-off provides the optimal benefit.
GENE-33. MECHANISM OF ACQUIRED MUTATION AFTER TMZ TREATMENT
Authors: Kuniaki Saito, Saki Shimizu, Eriko Nozaki, Keiichi Kobayashi, Satoshi Kume, Tomohiro Chiba, Junji Shibahara, Yoshiaki Shiokawa, Motoo Nagane
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is poor-prognosis cancer and tumor recurrence is inevitable despite intensive chemoradiotherapy. Thus, insights into the mechanism of tumor recurrence are critical for improved patient treatment. Here, we describe our integrated genomic analyses using next-generation sequencing of the paired samples from initial and recurrent tumors. We collected paired GBM samples in patients who recurred after temozolomide (TMZ) treatment. Mutation analysis of the cancer-related genes was performed using Ion Ampliseq Cancer Hotspot Panel v2. In addition, MGMT promoter methylation and expression of mismatch repair (MMR) protein such as MLH1, MSH2, MSH6, and PMS2 were analyzed by pyrosequencing and Western blotting, respectively. Sixty tumor samples from 29 patients were included in this study. Mutation acquisition of cancer-related genes was observed only in 12 (41%) patients while remaining 17 (59%) patients were mutationally stable even after TMZ treatment. Mutations were gained in 5 MGMT methylated tumors and 7 unmethylated. Remarkably, 70% of acquired mutations in MGMT methylated tumor were C> T at non-CpG sites whereas only 8% in MGMT unmethylated tumors. Acquired mutations in the recurrent sample after radiotherapy only were C> T at CpG site despite the tumor was MGMT methylated. In mutation gain group, MMR expression decreased significantly after treatment (p=0.0120.048). Furthermore, in contrast to MGMT unmethylated tumors, MGMT methylated tumors showed marked MMR inactivation (40% vs. 7.5%, p=0.078). Progression-free survival (PFS) and overall survival (OS) did not differ significantly between mutation-gain group and mutation-stable group (p=0.89 for PFS, p=0.67 for OS). We showed different types of the mutation acquisition after TMZ treatment according to MGMT status, providing further insights into the mechanism of TMZ resistance to improve treatment of the patients with GBM.
THU0100 Work impairment in rheumatoid arthritis is highly correlated with depression
Authors: A.D. Houssien, J. Galloway
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Work outcomes are highly relevant in rheumatoid arthritis. Almost a third of people are no longer in employment by 2 years after diagnosis. Remaining in the workforce has positive attributes in terms of health outcome and quality of life. <h3>Objectives</h3> We set out to study the relationship between work and depression in rheumatoid arthritis. <h3>Methods</h3> We used routinely collected data from a hospital rheumatoid arthritis cohort that has systematically collected longitudinal data on disease measures, mental health, and work impairment. The Work and Social Adjustment Scale was used to estimate work impact, and we used question 2 (scale 0–8, above 6 indicating severe impairment) for analyses. Mood was assessed using the PHQ2. Cross sectional analyses were used to describe the relationship between work impairment and depression, adjusting for disease severity factors. We then analysed the temporal relationship between work impairment and mood. <h3>Results</h3> In total 283 patients had data available for analysis. Mean age was 53 years (SD 15), 81% were female, median disease duration 6 years (IQR 0 to 10). 74% were seropositive (RF or CCP), mean baseline DAS28 score 3.8 (SD 1.7), baseline HAQ 1.2 (SD 0.9). At baseline 69% reported no depression, 13% reported some symptoms, 18% had probable major depression. 72% of patients reported some degree of work impairment, 14% reported severe impairment. There was a strong relationship between baseline depressive symptoms and work impairment: coefficient 2.4, 95% CI 1.7 to 3.0, p&lt;0.001. Adjusting for age, gender, DAS28, HAQ: 1.3, 95% CI 0.5 to 2.0, p=0.004. Over time work impairment increased (linear regression coefficient: 0.2 per year 95% CI 0.1 to 0.4), see figure 1. People with baseline low mood had an accelerated worsening of work impairment. <h3>Conclusions</h3> Work impairment is highly prevalent in contemporary rheumatoid arthritis patients. It is significantly correlated with mental health, even after adjusting for disease severity factors. Baseline mental health also predicts progression of work impairment. The relationship is likely bidirectional, and future research is justified to evaluate whether mental health interventions could improve work outcomes. <h3>Disclosure of Interest</h3> None declared
Abstract 19761: Contemporary Nationwide Outcomes of Acute Ischemic Stroke in Patients on Maintenance Hemodialysis
Authors: Sami Aljohani, Fahad Alqahtani, Tatiana Busu, Khaled Boobes, Ali Hama Amin, Ahmad Almustafa, Abdulrahman Tarabishy, Mohamad Adnan Alkhouli
Journal: Circulation (2017)

Introduction: the management of acute ischemic stroke (AIS) in hemodialysis patients is challenging. Methods: we utilized the nationwide inpatient sample to examine contemporary trends in the incidence, management patterns and outcomes of AIS in hemodialysis patients. Results: 930,010 patients were admitted with AIS between 2003-2014, of whom 10186 (1.1%) were on dialysis. Dialysis patients were younger (67±13 vs. 71±15, p<0.001), had a higher percentage of black patients that the non-dialysis group (36.2% vs. 16.8%, p<0.001), and a higher prevalence of major comorbidities. The utilization of thrombolysis and mechanical thrombectomy increased overtime (Figure1). Adjusted in-hospital mortality was higher in the dialysis group (6.9% vs. 5.6%, p<0.001), however this mortality gap narrowed overtime (Figure1). Adjusted bleeding complications, surrogates of moderate-severe disability were similar to non-dialysis patients (Table1). However, dialysis patients had higher rates of sepsis and blood transfusion and h...
Lithium-containing biomaterials stimulate bone marrow stromal cell-derived exosomal miR-130a secretion to promote angiogenesis
Authors: Lu Liu, Yaqin Liu, Chun Feng, Jiang Chang, Runqing Fu, Tingting Wu, Fei Yu, Xiaoting Wang, Lunguo Xia, Chengtie Wu, Bing Fang
Journal: Biomaterials (2018)
CMET-47. CLINICAL EVALUATION OF FITNESS TO DRIVE IN PATIENTS WITH BRAIN METASTASES
Authors: Cristina Valencia-Sanchez, Steven Schild, Sujay Vora, Jonathan Ashman, Thomas Daniels, Michele Halyard, William Rule, Nan Zhang, Richard Butterfield, Akanksha Sharma, Maciej Mrugala, Alyx Porter
Journal: Neuro-Oncology (2018)

Brain tumors can result in focal neurological and cognitive deficits which may impair the ability to drive. There are no evidence-based recommendations on driving restrictions for patients with brain metastases. Recommendations vary per practice, with extrapolation based on local driving and epilepsy laws. Occupational Therapy driving assessment (OTDA) may provide insight into limitations for this population. To determine whether clinical neurologic examination is sufficient to predict suitability to drive in patients with brain metastases. We assessed the concordance between Neurology assessment of suitability to drive (pass/fail) and OTDA in individuals with brain metastases. 40 subjects were prospectively enrolled. Neurooncology evaluation was performed as standard of care, including an interview and neurological examination. Subjects subsequently underwent OTDA during which a battery of objective measures of visual, cognitive and motor skills related to driving was administered. Preliminary results from the first 29 patients included are reported. Mean age was 68 years. Lung was the primary location of the tumor in 62% cases. More patients in the group that failed OTDA had bilateral brain metastasis (77.3% vs 42.9%,p=0.0478). The sensitivity of the Neurology assessment to predict driving fitness compared to OTDA was 22.7% and the specificity 71.4%. The 22 patients who failed OTDA were more likely to fail on Vision Coach (81.8%), MOCA (68.2%) and Trail Making (50%) tests. There was poor correlation between the assessment of suitability to drive by Neurology and the outcome of the OTDA in patients with brain metastases. Subtle deficits that may impair the ability to drive safely may not be evident on neurologic examination. The Vision Coach, MOCA and Trail Making tests were the most sensitive tests to predict driver safety. The results raise questions about the choice of assessments in making recommendations about fitness to drive in people with brain metastases.
NIMG-55. RADIOMICS ANALYSIS FOR DETECTION OF IDH MUTATION OF GLIOMA USING DIFFUSION TENSOR AND KURTOSIS IMAGES
Authors: Satoshi Takahashi, Wataru Takahashi, Shota Tanaka, Akihiro Haga, Takahiro Nakamoto, Akitake Mukasa, Shunsaku Takayanagi, Yuichi Suzuki, Tsukasa Koike, Yosuke Kitagawa, Taijyun Hana, Takahide Nejo, Masashi Nomura, Nobuhito Saito
Journal: Neuro-Oncology (2018)

Creating a machine learning model using diffusion tensor and kurtosis images are effective for malignancy diagnosing of glioma. However, it is unknown whether an IDH mutation, which is the most important mutation in glioma, can be predicted using diffusion tensor and kurtosis images. The purpose of our research was to predict the IDH mutation by using diffusion tensor and kurtosis images based on a machine learning. Between August 2014 and July 2017, 38 consecutive patients with suspected glioma and preoperative MRI including diffusion coefficient (ADC), fractional anisotropy (FA), mean kurtosis (MK), were included in the study. All IDH mutations were identified by Sanger sequencing. A volume of interest (VOI) was created manually and applied to T2-weighted images, diffusion-weighted images (DWI), ADC, FA, MK. 476 per imaging sequence and 2856 features were extracted. 39 datasets were obtained. The number of cases for the IDH mutation and wild-type was 21 cases of the IDH1 mutation (3 diffuse astrocytoma, 8 anaplastic astrocytoma, 4 oligodendroglioma, 3 anaplastic oligodendroglioma, 3 glioblastoma, 18 cases of wild-type(2 anaplastic astrocytoma, 16 glioblastoma). An IDH2 mutation was not observed in our cases. Features were selected by using recursive feature elimination (RFE). The most accurate machine learning model was created using the extracted eight features from ADC, Fa, and MK. The best AUC was 0.95 ± 0.02 in a support vector machine (SVM). Discussion: Imaging sequences useful for the IDH1 mutation identification are ADC, MK, FA, similar to malignancy diagnosing of glioma. However, useful features were different. The machine learning models using diffusion images may be useful for identifying the IDH1 mutations.