tbuckley/cabot-search huggingface dataset:
HOUT-10. SELECTIVE SEROTONIN REUPTAKE INHIBITOR (SSRI) TREATMENT IS ASSOCIATED WITH IMPROVED SURVIVAL AMONG ELDERLY PATIENTS DIAGNOSED WITH GLIOBLASTOMA
Authors: Sebastian Otto-Meyer, Erik Ladomersky, Denise Scholtens, Lijie Zhai, Kristen Lauing, Christina Amidei, Rimas Lukas, Derek Wainwright
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is an incurable primary brain tumor with a median age of diagnosis at 64 years old. Previous studies have suggested an association between psychosocial factors and GBM patient outcomes. Here, we retrospectively investigated the relationship between SSRI treatment and overall survival (OS) in deceased GBM patients previously cared for in our hospital system. Medical records of 449 patients diagnosed with GBM after the year 2000 were obtained from our hospital systems data warehouse. Patient ages ranged from 18 to 86 (median=59 years old) and were 60.6% male. All patients received temozolomide and were excluded if they had a clinical history of progression from a lower-grade glioma. Patients were stratified into 2 groups: (i) with or (ii) without SSRI treatment (defined as at least 1 recorded SSRI prescription post-diagnosis). OS was analyzed with a Kaplan-Meier survival curve and compared with the log-rank test. GBM patients with SSRI treatment (n=151) have an increased median OS of 537 days, as compared to 431 days among untreated patients (n=298) (P=0.0011). Stratifying by age reveals a striking OS benefit, with a median survival of 486 days among elderly (60 years old) patients treated with an SSRI (n=83) versus untreated patients (n=137) with a median survival of 329 days (P=0.0009). Although less robust, there is also a 59.5 day median OS improvement in younger (<60 years old) GBM patients treated with SSRIs (n=68), as compared to untreated individuals (n=161) (P=0.0379). GBM patients treated with SSRIs possess significantly improved OS, with an enriched effect among elderly individuals for whom therapies are often less effective and/or limited. These preliminary results require further modeling to definitively interpret the direct effects of SSRIs on GBM and the immune response against GBM, while we also plan clinical trials to further elucidate these exciting observations.
AZD2171, an orally active inhibitor of VEGFR tyrosine kinase activity, reduces polyp burden in a mouse model of intestinal cancer
Authors: Robert Goodlad, A. James Watkins, Richard Poulsom, Anderson J. Ryan, Stephen R. Wedge, Ian T. Pyrah, Nikki Mandir, Robert W. Wilkinson
Journal: Cancer Research (2005)

5841  AZD2171 is a novel, highly potent and orally active inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase activity, and inhibits VEGF-induced proliferation of human primary endothelial cells at subnanomolar concentrations. The effect of inhibiting VEGF signaling with AZD2171 was studied in a mouse model of multiple intestinal neoplasia (ApcMin/+) mice. These mice inherit a mutant copy of the adenomatous polyposis coli (APC) gene and develop numerous benign polyps in the gastrointestinal (GI) tract following loss of APC heterozygosity in GI epithelial cells. The mutation in APC is analogous to that occurring in patients with familial adenomatous polyposis. In addition, mutations in APC have also been described in many sporadic colorectal cancers. Two studies were performed, in 6-week old and 10-week old C57BL/6J-ApcMin/+ mice. In both studies, mice received AZD2171 (5 mg/kg/day) or vehicle by oral gavage for 28 days (n = 14-16 per group). At the end of each experiment, the intestines were fixed and the number and size of polyps in the small and large intestines were scored. Vascularity (by von Willebrand factor) was assessed by immunohistochemical methods, and VEGFR-2 mRNA was detected by in situ hybridization. In 6-week old mice, AZD2171 reduced polyp number in the small bowel and colon by 46% and 62%, respectively (P
CBMT-17. NOVEL APPROACH OF UTILISING SERUM/PLASMA EV AND CELL-FREE RNA FOR TREATMENT MONITORING IN GLIOBLASTOMA PATIENTS
Authors: Theophilos Tzaridis, Katrin Reiners, Ulrich Herrlinger, Hartmann Gunther, Björn Scheffler, Martin Glas, Christoph Coch
Journal: Neuro-Oncology (2018)

INTRODUCTION: Glioblastoma (GBM) is a malignant primary brain tumour with dismal prognosis. Treatment monitoring remains a challenge in clinical routine, since brain imaging cannot reliably differentiate between true progression and treatment-associated changes. In this project, we evaluate different methods of extracellular vesicles (EV) purification, in order to specifically isolate GBM-EVs from human serum/plasma and introduce EVs, as well as cell-free RNA as possible biomarkers for treatment monitoring in GBM patients. EVs from primary GBM cells and the Gaussia luciferase expressing Gli36-GLuc cells were isolated via size-exclusion chromatography (SEC) and ultracentrifugation. EV-surface markers were evaluated by flow cytometry. Gli36-GLuc EVs containing GLuc mRNA were spiked in healthy plasma. Thereafter, plasma EVs were isolated via ultracentrifugation, SEC and immunoprecipitation. Subsequently, RNA was isolated from vesicles and evaluated for GLuc levels via qRT-PCR. Total cell-free RNA from serum of GBM patients was tested for different mRNAs and micro-RNAs at different disease stages. EVs from GBM cells expressed high levels of CD29 and CD44, when compared to EVs from healthy donor plasma. Gli36-GLuc EVs spiked in healthy plasma were more effectively isolated with CD44-based immunoprecipitation than with ultracentrifugation or SEC, as shown by higher GLuc RNA levels in the corresponding vesicles. When compared to total cell-free RNA extracted from this plasma, RNA from EVs exhibited a higher GLuc yield. In cell-free RNA from GBM patients, MGMT levels alone were not capable of detecting progressive disease. 1. CD44 could serve as a novel, promising target for GBM-EV and be utilised for immunoprecipitation-based EV capturing. 2. Using the appropriate EV purification method possibly affects their potential as biomarkers for GBM. 3. MGMT levels alone in cell-free RNA of GBM patients did not correlate with disease status contrary to previous reports.
ATIM-19. RESULTS OF THE GLOBE STUDY: A PHASE 3, RANDOMIZED, CONTROLLED, DOUBLE-ARM, OPEN-LABEL, MULTI-CENTER STUDY OF VB-111 COMBINED WITH BEVACIZUMAB VS. BEVACIZUMAB MONOTHERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Timothy Cloughesy, Andrew J Brenner, Nicholas Butowski, Yael C Cohen, Noa Lowenton-Spier, Patrick Wen
Journal: Neuro-Oncology (2018)

Ofranergene obadenovec (VB-111) is a viral cancer-therapy with a dual mechanism: vascular disruption and induction of a tumor directed immune response. In a phase 2 trial, recurrent GBM (rGBM) patients treated with VB-111, followed at progression with VB-111 in combination with bevacizumab (BEV), had durable tumor growth attenuation, associated with prolonged overall survival (OS) of 15 months. A phase 3 multisite international randomized open-labeled controlled trial. Patients with rGBM were randomized 1:1 to receive VB-111 at 10e13VPs q8W in combination with BEV 10mg/Kg q2W vs. BEV 10mg/Kg q2W. Primary endpoint was OS. 256 patients (128 per arm) were enrolled in 57 sites. The mean age was 55, 67% were male. 74% were in 1st progression, KPS < 80 found in 23% of patients. In the combination arm vs the BEV arm: baseline tumor volume > = 15cm3 in 49% vs 41%; Grade 3–4 adverse events reported among 61 % (mostly CNS and febrile) vs 34%, and pyrexia in 39% vs 4% of patients; ORR was 27.3% vs 21.9% and median duration of response was 3.7 vs 2.2 months. Median OS was 6.8 vs 7.9 months in the combination vs BEV arms, HR 1.2 [95% CI 0.910–1.59, p=NS]. In the subgroup of patients with baseline tumors< 15 cm3, OS was 9.2 vs 8.3 months [p=NS], and 12 month OS was 38.9% vs 26.9% [p=NS]. Among patients in the combination arm, OS was 7.9 vs 5.5 in patients with and without a febrile reaction. In this trial, VB-111 in combination with BEV failed to increase OS in patients with rGBM. Lack of VB-111 priming, as done in the phase II trial may explain the differences with the favorable outcomes in the latter. Patients with large progressive tumors may precluded sufficient drug exposure. Additional exploratory analyses are ongoing.
INNV-15. ANALYSIS OF CHALLENGES TO ACCRUAL IN CLINICAL TRIALS FOR NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Nicholas Metrus, Ahmad Daher, Rebecca Harrison, Nazanin Majd, Stefania Maraka, Joo Yeon Nam, Christopher Trevino, Shiao-Pei Weathers, Barbara O’Brien, Carlos Kamiya-Matsuoka, Monica Loghin, Kristin Alfaro, Kathy Hunter, W K Alfred Yung, John de Groot, Marta Penas-Prado
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common glioma, with an incidence of 3.2 per 100,000 adults, and approximately 12,500 new diagnoses each year in the US. With limited treatment options, there is a constant push to improve patient outcome by testing experimental therapies in clinical trials. However, it is estimated that only 8%-11% of patients with newly diagnosed GBM enroll to clinical trials. In an effort to better prioritize patients into appropriate clinical trials and understand barriers to trial enrollment, a weekly Tumor Planning Conference was instituted at MD Anderson Cancer Center in August 2016 to discuss eligibility of each patient with newly diagnosed GBM for available clinical trials. We performed a retrospective review of 112 patients presented over the course of 17 months; data collected included age, gender, date, location and extent of surgery, post-operative day at time of conference, available molecular data and the date(s) it was reported, patients residence and Karnofsky Performance Scale score. A total of 2 to 4 clinical trials for newly diagnosed GBM were available for enrollment at any one time during the analysis. Of the total patients consented for trial participation, 8 were ultimately enrolled and treated into clinical trials (7.14%). The primary reason for no trial participation was study-specific eligibility/ineligibility criteria (such as lack of necessary molecular markers) (46.3%), followed by being out-of-window for trial enrollment (27.4 %). The weekly tumor planning conference did not improve the number of accruals to trials for newly diagnosed GBM compared to what has been previously reported. However, it provided valuable insights about barriers to trial enrollment, such as the importance of timely outside referrals, efficient new patient scheduling, and need for expedited trial-specific molecular testing.
STEM-16. Stox2, A NEW REGULATOR FOR GBM STEM CELL MAINTENANCE AND IMMUNE RESPONSE
Authors: Dan Jin, Son Le, Changwang Deng, Dongjiang Chen, Mathew Sebastian, Nagheme Thomas, Duy Nguyen, David Tran
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) stem-like cells (GSCs) are highly radio- and chemoresistant and thought to be the main source of tumor relapses. Therapeutic targeting of GSC has vital significance. However, the mechanism regulating GSCs’ survival remains incompletely understood, making eradicating GBM difficult to attain. Here, we describe a identification and characterization of a novel master regulator of GSCs discovered using a computational approach. STOX2 a little known protein was found to be upregulated specifically in GSC compared to normal neuronal stem cells and be exquisitely fundamental to the maintenance and survival of GSCs in general. We demonstrated in several patients derived GSC xenografts. that STOX2 depletion in GSCs quickly pushed cell into apoptosis, most likely through the downregulation of a key stem-ness program. Additionally, expression of PD-L1, an immune suppressing ligand, in GBM required high level of STOX2, indicating a dual function for STOX2 in maintaining GSC stem-ness while preventing them from being recognized by the immune system. Thus STOX2 is a novel GSC master regulator that is indispensable for GSC maintenance and may represent a new therapeutic target for the treatment of GBM.
HOUT-22. TWO CASE REPORTS OF PATIENTS WITH SUPERIOR SEMICIRCULAR CANAL DEHISCENCE AND EHLERS-DANLOS SYNDROME
Authors: Komal Preet, Courtney Duong, Methma Udawatta, Vera Ong, Jacky Chen, Quinton Gopen, and Isaac Yang
Journal: Neuro-Oncology (2018)

Superior semicircular canal dehiscence (SSCD) is a rare bony defect that results in an opening between the inner ear and middle cranial fossa, which often results with patients presenting with auditory and vestibular symptoms. Ehlers-Danlos Syndrome (EDS) is an inherited connective tissue disorder that is characterized by joint hypermobility and skin extensibility. We previously reported the case of a 50-year-old woman with a 15-year history of auditory and vestibular symptoms. Computed tomography confirmed the presence of bilateral dehiscence in her superior semicircular canals. Past medical history was significant for Ehlers-Danlos Syndrome (EDS) Hypermobility Type. We present a new case presentation of a 36-year-old female with similar symptoms and a medical history significant for EDS-Hypermobility and confirmation of bilateral superior semicircular canal dehiscence. Both patients were treated via middle fossa craniotomy, with follow-up visits indicating symptom improvement. Because of their rarity, this study highlights the possibility of a connection between the two diagnoses.
Abstract 17282: Concordance of Mitral Leaflet Chordal Measurements Using Different Echocardiographic Techniques and Surgical Approaches: Implications for Mitral Valve Repair
Authors: Hoda Javadikasgari, A M Gillinov, Tomislav Mihaljevic, Brian P Griffin, Milind Y Desai
Journal: Circulation (2015)

Objectives: In patients with significant primary mitral regurgitation (PMR), the success of mitral valve repair (MVr) depends upon precise preop planning, including accurate assessment of chordal length. Both 2-dimentional (2D) &amp; 3-dimentional (3D) transthoracic (TTE) &amp; transesophageal (TEE) echocardiography visualize anterior and posterior chords. We sought to assess concordance of echo-based MV chordal measurements against direct intraop (robotic vs. midline) measurements. Methods: After informed consent, we prospectively enrolled 56 consecutive patients (59±11 years, 86% men) who underwent MVr (52% robotic, 48% sternotomy) between 12/14-6/15 by a single experienced surgeon. The lengths of anterior &amp; posterior MV chords were measured in 2-, 3-, &amp; 4-chamber views on preop 2D/3D TTE &amp; 2D/3D TEE (Philips &amp; General Electric) &amp; were compared to intraop length of the most perpendicular normal anterior &amp; posterior chords. All measurements were performed in a blinded manner &amp; noninvasive measurements were compared against intraop measurements using intraclass correlation coefficient (ICC). Results: Intraoperatively, the mean lengths of anterior &amp; posterior chords were 2.02±0.4 &amp; 1.81±0.4 cm, respectively. For the anterior chords, the mean lengths on 2D &amp; 3D TTE were 1.96±0.3 &amp; 1.96±0.3 cm, respectively, while they were 1.99±0.3 &amp; 1.93±0.3 cm on 2D &amp; 3D TEE, respectively. Similarly, for posterior chords, the mean length on 2D &amp; 3D TTE was 1.90±0.3 &amp; 1.89±0.3 cm, while they were 1.91±0.3 &amp; 1.90±0.3 cm on 2D &amp; 3D TEE, respectively. Data on ICC’s (for the concordance of the whole group &amp; separated on different surgical approaches) are shown in Figure. Conclusion: There is high concordance in measurement of anterior MV chords by 2D/3D TTE/TEE with surgical techniques. However, concordance for posterior chord measurement is less accurate, especially when a robotic approach is used. In such patients, precise preop planning using imaging (including tomography) may be crucial.
Myocardial Inflammation, Measured Using 18‐Fluorodeoxyglucose Positron Emission Tomography With Computed Tomography, Is Associated With Disease Activity in Rheumatoid Arthritis
Authors: Isabelle Amigues, Aylin Tugcu, Cesare Russo, Jon T. Giles, Rachelle Morgenstein, Afshin Zartoshti, Christian Schulze, Raul Flores, Sabahat Bokhari, Joan M. Bathon
Journal: Arthritis & Rheumatology (2018)

Objective To determine the prevalence and correlates of subclinical myocardial inflammation in patients with rheumatoid arthritis ( RA ). Methods RA patients (n = 119) without known cardiovascular disease underwent cardiac 18‐fluorodeoxyglucose ( FDG ) positron emission tomography with computed tomography ( PET ‐ CT ). Myocardial FDG uptake was assessed visually and measured quantitatively as the standardized uptake value ( SUV ). Multivariable linear regression was used to assess the associations of patient characteristics with myocardial SUV s. A subset of RA patients who had to escalate their disease‐modifying antirheumatic drug ( DMARD ) therapy (n = 8) underwent a second FDG PET ‐ CT scan after 6 months, to assess treatment‐associated changes in myocardial FDG uptake. Results Visually assessed FDG uptake was observed in 46 (39%) of the 119 RA patients, and 21 patients (18%) had abnormal quantitatively assessed myocardial FDG uptake (i.e., mean of the mean SUV [ SUV mean ] ≥3.10 units; defined as 2 SD above the value in a reference group of 27 non‐ RA subjects). The SUV mean was 31% higher in patients with a Clinical Disease Activity Index ( CDAI ) score of ≥10 (moderate‐to‐high disease activity) as compared with those with lower CDAI scores (low disease activity or remission) ( P = 0.005), after adjustment for potential confounders. The adjusted SUV mean was 26% lower among those treated with a non–tumor necrosis factor–targeted biologic agent compared with those treated with conventional (nonbiologic) DMARD s ( P = 0.029). In the longitudinal substudy, the myocardial SUV mean decreased from 4.50 units to 2.30 units over 6 months, which paralleled the decrease in the mean CDAI from a score of 23 to a score of 12. Conclusion Subclinical myocardial inflammation is frequent in patients with RA , is associated with RA disease activity, and may decrease with RA therapy. Future longitudinal studies will be required to assess whether reduction in myocardial inflammation will reduce heart failure risk in RA .
QOLP-05. THE EFFECT OF RESILIENCE ON QUALITY OF LIFE IN PATIENTS WITH HIGH GRADE GLIOMAS AND THEIR CAREGIVERS
Authors: Laura Donovan, Adela Joanta-Gomez, Teri Kreisl, Andrew B. Lassman, Mary Welch, Fabio Iwamoto
Journal: Neuro-Oncology (2018)

Quality of life is often impaired in patients with high grade gliomas (HGG) and their caregivers. Resilience refers to one’s ability to maintain or improve their emotional wellbeing in the setting of extreme stressors. In patients with chronic illnesses including cancer, higher levels of resilience are correlated with improved quality of life. This has not been well studied in HGG patients or their caregivers. We designed a prospective cohort study to assess this relationship in 50 patient-caregiver dyads. All patients were diagnosed with HGG in the past 6 months. Caregivers were self-identified by patients as the primary person providing physical or emotional support since diagnosis. Resilience was assessed using the Connor Davidson Resilience Scale (CD-RISC) in patients and caregivers. Quality of life was assessed using the EORTC-QLQ30 and BN-20 scales in patients and the Caregiver Quality of Life Cancer scale (CQOLC) in caregivers. After obtaining informed consent, demographic information was collected and participants completed the CD-RISC and QOL surveys. IRB approval was granted in May 2018 and in the 3 weeks following approval, 15 dyads have been consented and 3 have completed surveys. To date, median age of both patients and caregivers is 55.6 years. All patients carry a diagnosis of glioblastoma and all caregivers identify as spouses or long-term partners. Caregivers report impaired QOL with an average score of 67 out of a possible 140 points (higher scores indicating better QOL). Median global quality of life score in patients is 80 which is higher than previously reported medians. There are currently too few patients to draw correlations; however, based on the current rate of participation, we anticipate accrual will complete within 5 months. We will present the updated data. If positively correlated, interventions targeting resilience may also improve quality of life in this population.
Abstract 16416: Predictors of Discordance Between Instantaneous Wave-Free Ration and Fractional Flow Reserve
Authors: Natsuko Satomi, Issei Ishida, Hiroyuki Arashi, Junichi Yamaguchi, Yutaka Konami, Hiromu Kadowaki, Kazuki Tanaka, Shintaro Haruki, Hisao Otsuki, Masashi Nakao, Kentaro Jujo, Yuichiro Minami, Hiroshi Ogawa, Nobuhisa Hagiwara
Journal: Circulation (2017)

Background: The instantaneous wave-free ratio (iFR) is an index of the functional severity of coronary stenosis. Recently, cut-off point of iFR was proposed based on randomized control trials. Frac...
IMMU-08. THE ROLE OF WNT SIGNALING ON T-CELL INFILTRATION IN GLIOBLASTOMA
Authors: Shweta Tiwary, Jun Wei, Rave Ezhilasaran, Erik Sulman, Suyun Huang, Sherise Ferguson
Journal: Neuro-Oncology (2018)

Glioblastomas (GBMs) are considered immunologically cold tumors, making it difficult to apply immunotherapeutic strategies. Oncogenic pathways intrinsic to the tumor or the microenvironment can influence T-cell infiltration. WNT/β catenin is one such pathway implicated in modulating T-cell infiltration in other solid malignancies. In this study, we examine the influence of WNT signaling on the infiltration of T-cells in GBM. Using the TCGA dataset, we analyzed the mRNA expression of both β-catenin dependent (canonical) and independent (non-canonical) WNT ligands and CTNNB1 (β-catenin) in GBM. The expressions of these components were correlated with a T-cell signature (CD3e, CD3d, CD3g, CD4, CD8a, and CD8b) and survival. Additionally, multiple GSC cell lines, derived from human GBM samples, were profiled for different WNT ligands and cells with the highest and lowest expression were selected for further experiments. In vitro, we also utilized a T-cell migration assay to measure the effect of WNT ligands (WNT3a and WNT5a) on T-cell migration towards a GL261 monolayer. In silico analysis of the TCGA dataset revealed downregulation of most WNTs in GBM and in 49 evaluated GSC cells lines. In cases with evidence of a T-cell signature, disease-free progression was 2-fold higher than those without evidence of a T-cell infiltration. Additionally, we observed a mutual exclusivity between the T-cell signature and β -catenin expression. WNT5a (non-canonical WNT ligand) had a significantly higher expression in the low-risk group (higher survival *p=1.42e-33) in GBM. Furthermore, in vitro, we observed a 2-fold increase in the migration ability of effector T-cells (CD4+ CD8+) towards the GL261 monolayer in presence of WNT5a. This data suggest that the WNT/β-catenin dependent pathway negatively regulates T-cell infiltration whereas the β-catenin independent pathway may have a promoting role.