tbuckley/cabot-search huggingface dataset:
CSIG-23. miR-146a PREDICTS BETTER OVERALL SURVIVAL AND ACTS AS A TEMOZOLOMIDE (TMZ) SENSITIZER THROUGH TARGETING MULTIPLE SIGNALING PATHWAYS IN GLIOBLASTOMA
Authors: Tiantian Cui, Erica Hlavin Bell, Kevin Liu, Joseph McElroy, Marjolein Geurts, Ashley Gray, Aline Becker, Jessica Fleming, Sasha Beyer, Jahar Haque, Pierre Robe, Arnab Chakravarti
Journal: Neuro-Oncology (2018)

Glioblastomas (GBMs) are the most aggressive primary brain tumors, with an average survival of less than 15 months. microRNAs (miRNAs) are emerging as promising, novel prognostic biomarkers in GBM. miRNA-146a acts as a tumor suppressor in different cancer types. This purpose of this study is to assess the prognostic value of miR-146a and investigate its role in tumor growth and therapeutic sensitivity and the underlying cellular and molecular mechanisms in GBM. To determine the correlation between expression of miR-146a and overall survival (OS) of GBM patients, total RNAs were isolated from 268 FFPE GBM tumor samples (IDH1/2 WT) for miR expression analysis (simultaneously) using the nCounter human miRNA v3a assay (NanoString Technologies), then, univariable and multivariable analyses were performed. Furthermore, functional studies were conducted to define the role of miR-146a in GBM tumorigenesis and therapeutic response and the underlying molecular mechanisms in established and patient-derived primary GBM cells. Univariable analyses demonstrated that miR-146a is correlated with better prognosis in GBM patients (HR=0.66, p=9.21E-05), which was independent of the promoter methylation of O6-methylguanine-DNA methyltransferase by multivariable analyses (p<0.001). Interestingly, expression of miR-146a was downregulated in a majority of GBM cells compared with normal human astrocytes, as well as GBM tissues compared with paired non-tumor tissues. Functionally, overexpression of miR-146a significantly inhibited proliferation and invasion of both established and patient-derived primary GBM cells in vitro. Importantly, we also found that miR-146a overexpression increased the sensitivity of GBM cells to temozolomide (TMZ) and potentiated TMZ-induced apoptosis in vitro. While conducting downstream targeting and mechanistic studies, we found that overexpression of miR-146a significantly inhibited the NF-κB, AKT, and ERK pathways through targeting novel targets in GBM. CONCLUSION: Our data suggest that miR-146a predicts favorable prognosis for GBM patients and may serve as a therapeutic target in GBM.
PDTM-29. CSF H3F3A K27M CIRCULATING TUMOR DNA COPY NUMBER QUANTIFIES TUMOR GROWTH AND TREATMENT RESPONSE
Authors: Stefanie Stallard, Masha G. Savelieff, Brendan Mullan, Zachary Miklja, Amy Bruzek, Taylor Garcia, Kyle Wierzbicki, Benjamin Singer, Rintaro Hashizume, Angel Montero Carcaboso, Kaitlin Q. McMurray, Jason Heth, Karin Muraszko, Patricia L. Robertson, Rajen Mody, Sriram Venneti, Hugh Garton, Carl Koschmann
Journal: Neuro-Oncology (2018)
STEM-24. IDENTIFICATION OF SERPIN B3 AS A JUNCTIONAL ADHESION MOLECULE A BINDING PARTNER IN GLIOBLASTOMA CANCER STEM CELLS
Authors: Josephine Volovetz, Soumya Turaga, Ulhas Naik, Justin Lathia
Journal: Neuro-Oncology (2018)

Cancer stem cells (CSCs) in glioblastoma (GBM), the most lethal primary brain tumor, contribute to tumor progression and therapeutic resistance. While we previously demonstrated that junctional adhesion molecule A (JAM-A), a cell adhesion molecule, is necessary and sufficient for CSC maintenance, the signaling networks underlying this function have yet to be elucidated. JAM-A has several known binding partners in endothelial cells. To identify GBM CSC-specific binding partners, we introduced JAM-A into CSCs, conducted a pull-down assay, and determined binding partners via mass spectrometry. The top candidate identified was Serpin B3, a serine/cysteine proteinase inhibitor and key regulator of epithelial to mesenchymal transition. We validated the endogenous interaction between JAM-A and Serpin B3 via co-immunoprecipitation and confirmed binding dynamics in vitro via surface plasmon resonance. Like JAM-A, Serpin B3 was enriched in CSC patient-derived xenograft models. Immunostaining revealed colocalization of Serpin B3 and JAM-A, in vitro and in vivo. Overexpression of Serpin B3 was found to increase stem cell marker expression. Ongoing studies are assessing proliferation, self-renewal, and tumor initiation in the context of Serpin B3 overexpression in non-CSCs and Serpin B3 knockdown in CSCs. Additional mechanistic studies using JAM-A mutant constructs will determine the precise binding site between JAM-A and Serpin B3 and serve as the basis for developing therapeutics that inhibit the interaction between JAM-A and Serpin B3. Our findings provide a novel JAM-A binding partner and reveal a putative interaction that may be disrupted to compromise CSC maintenance.
SURG-04. SURVIVAL BENEFIT ASSOCIATED WITH GROSS TOTAL RESECTION IN GRADE II ASTROCYTOMAS: AN INTEGRATED ANALYSIS OF THE SEER AND TCGA DATABASE
Authors: Ali Alattar, Kate Carroll, Alex Bryant, Brian Hirshman, Rushikesh Joshi, Bob Carter, Olivier Harismendy, Clark Chen
Journal: Neuro-Oncology (2018)

We used the Surveillance, Epidemiology, and End Results (SEER) to determine the survival benefit associated with gross-total resection (GTR) of grade II diffuse astrocytoma (DA) stratified by age and tumor location. We further correlated these findings to the prevalence of isocitrate dehydrogenase mutations (mIDH) in similarly age- and location-stratified DA patients from The Cancer Genome Atlas (TCGA). The SEER database was used to assess GTR associated survival benefits relative to subtotal resection (STR), and TCGA database was used to determine the prevalence of IDH mutation. Survival analysis was accomplished using Kaplan-Meier curves, log-rank tests, and multivariable Cox proportional hazards models. GTR was associated with significant survival benefit for all DA patients with frontal tumors irrespective of age (age < 50, HR 0.56, p=0.002; age > 50, HR 0.41, p< 0.001). However, in patients with non-frontal tumors, only those < 50 derived a survival benefit from GTR (< 50 HR 0.55, 95%, p=0.002; > 50 HR 0.78, 95% p=0.114). This pattern of GTR-associated survival in DA patients differed significantly from our previous finding in AA patients, where significant survival benefit was only observed in patients < 50 with frontal tumors who underwent GTR. While the prevalence of mIDH status in the TCGA DA and AA’s generally tracked with the above described survival patterns, notable exceptions were observed. For instance, while the prevalence of mIDH in patients age > 50 with non-frontal tumor were comparable for DA and AAs (82% versus 75%), the GTR associated survival benefit in these patients differed significantly. Our results suggest that the survival benefit of GTR, prevalence of mIDH, and relationship of these variables to patient age and tumor location differs between DA and AA. While mIDH status generally correlated with survival patterns, instances where these patterns differed suggests complex interactions between age, location, mIDH status and tumor grade as prognostic factors.
Protocol Deviations, Reanalyses, and Corrections to PREDIMED Trial Derivative Study on Peripheral Artery Disease
Authors: Miguel A. Martínez-González
Journal: JAMA (2018)

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MNGI-23. PREOPERATIVE QUANTITATIVE IMAGING FEATURES ARE PROGNOSTIC FOR MENINGIOMA OUTCOMES
Authors: Oliver Morin, William Chen, Efstathios Gennatas, Stephen Magill, Ashley Wu, Gilmer Valdes, Arie Perry, Penny Sneed, Michael McDermott, Timothy Solberg, Nancy Ann Oberheim Bush, Steve Braunstein, Javier Villanueva-Meyer, David Raleigh
Journal: Neuro-Oncology (2018)

OBJECTIVES: Quantitative radiologic and radiomic features can identify brain tumors at risk for poor outcomes. Here, we investigate prognostic models for meningioma grade, local failure (LF) and overall survival (OS) based on demographic, radiologic, radiomic and therapeutic data. We developed a database that was enriched for high grade meningiomas from 219 patients who underwent surgery for 229 meningiomas from 1990 to 2015 who had comprehensive clinical, pathologic and radiologic information available for retrospective review. The median imaging follow up was 4.3 years, and there were 112 WHO grade I (49%), 93 grade II (41%) and 24 grade III (10%) meningiomas. Two neuro-radiologists independently annotated 17 radiologic features, and 154 radiomic features were extracted from preoperative post-contrast 3D SPGR MR images for each meningioma. Random forest models were trained using nested resampling, and the performance of each model was assessed by calculating feature importance, mean balanced accuracy (BA) and area under the curve (AUC). Models restricted to preoperative demographic information and quantitative imaging features had superior BA (0.60–0.67) and AUC (0.60–0.76) for LF or OS as compared to models based on meningioma grade and extent of resection (BA 0.65, AUC 0.64). Integrated models incorporating all available data provided the most accurate estimates of LF and OS (BA 0.67, AUC 0.76). Radiomic features alone or in combination with other variables showed moderate and marginal predictive value for grade (BA 0.63, AUC 0.72) and LF (BA 0.61, AUC 0.65), respectively. Among radiologic features, meningioma diffusion characteristics significantly strengthened prognostication of grade and LF (RR 25.6, P = 0.001). Recursive partitioning analysis identified tumor size, primary versus recurrent presentation, grade, sphericity, apparent diffusion coefficient, location, extent of resection and T2 signal as the most important features for LF. Models using clinical and quantitative imaging data can accurately predict meningioma outcomes.
Jane Thornton #Olympian #SportsDoc
Authors: Alexandra Ross
Journal: British Journal of Sports Medicine (2018)

Walking into the Bird’s Nest Stadium for the Opening Ceremonies of the 2008 Beijing Olympic Games was an incredible experience, as was singing our national anthem when my pair partner and I won the World Championships. But my most memorable sporting moments date back to when I was learning how to row and train in high school. As a result of learning to row in a fun, supportive environment, I developed lifelong friendships, love the sport now as much as ever, and enjoy giving back in a meaningful way.

I draw inspiration from many people—athletes, patients, friends and family—but especially from those overcoming major challenges and setbacks, whether it is rising above discrimination, health challenges or personal adversity.

The person who refuses to give in and instead chooses to write their own story, who grows through adversity, who is gracious under fire… whenever I encounter that person, he or she becomes a hero in my eyes.

Many good career moves are those I have stumbled upon and tripped over, rather than carefully planned! A common theme for me has been to look beyond the mainstream, to follow my passion, and not be driven by money or ego, but by meaning.

I was in New Zealand in November 2016 for a lectureship in Dunedin followed by the Sports Medicine New Zealand Conference in Auckland. My husband and 1-year-old son travelled with me as we headed up along the coast of the South Island from Dunedin to Auckland when the 7.8 magnitude Kaikoura earthquake hit. We were staying just north of the epicentre and spent most of that night sheltering in …
TMIC-14. AUTO-/PARACRINE SIGNALING OF PI3K/AKT/YKL-40 IN MESENCHYMAL GLIOBLASTOMA PROGRESSION
Authors: Apeng Chen, Vaibhav Sharma, Qianghu Wang, Sameer Agnihotri, Gary Kohanbash, Y Alan Wang, Ian Pollack, Ronald DePinho, Baoli Hu
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM), the most common and deadliest brain tumor with a median survival of 12–15 months, has been characterized by robust angiogenesis, high invasiveness, and universal recurrence. Genomics and transcriptomics studies defined three GBM subtypes (proneuronal, classical, mesenchymal), which are associated with genomic abnormalities, treatment response, and diversity in tumor microenvironment. However, molecular mechanisms of subtype-specific genotype in contribution to tumor phenotype are less understood. We have previously generated a de novo human GBM model by inactivation of p53 and activation of AKT signaling pathways in human neural stem/progenitor cells (hNSCs). Further characterization of this model indicates that the tumors recapitulate GBM’s classical histopathogical features and exhibit a molecular profile resembling the mesenchymal subtype. Comparative transcriptomic analysis revealed that YKL-40/CHI3L1, a secreted glycoprotein, is significantly upregulated during AKT activation induced malignant transformation of hNSCs in vitro and in vivo. Pharmacological inhibition of PI3K/AKT/mTOR signaling pathway results in decreasing YKL-40 mRNA expression and protein secretion level. Mechanistically, motif enrichment analysis and functional validation revealed that YKL-40 is bidirectionally regulated by a gene regulatory network with two transcription factors, BACH2 and CEBPB. Furthermore, YKL-40 significantly activates AKT-S6 and MAPK-ERK kinase signaling pathways, resulting in enhancing tumor cells proliferation, neurosphere and soft-agar colony formation, and tumor progression. In vivo silencing YKL-40 attenuates tumor angiogenesis and prolongs animal survival in the orthotopic xenograft mouse models. Interestingly, knocking down YKL-40 expression decreases microglia/macrophages infiltration in tumor mass. Both in vitro and in vivo validation indicate that PI3K/AKT/YKL-40 mediates tumor-associated microglia/macrophages recruitment and activation during tumor progression. Taken together, these results suggest that auto- and paracrine signaling of PI3K/AKT/YKL-40 affect tumor cells and tumor microenvironment contributing to glioblastoma progression, indicating YKL-40 as a predictive biomarker for evaluation of anti- PI3K/AKT/mTOR therapy, and a potential drug target for the treatment of this devastating disease.
PATH-19. CLINICOPATHOLOGIC FEATURES AND OUTCOMES OF HISTOLOGICALLY CONFIRMED ATYPICAL DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Alexander Diaz, Jason Chiang, Paul Klimo, Frederick Boop, Yuanyuan Han, Yimei Li, Zoltan Patay, Amar Gajjar, Thomas Merchant, Suzanne Baker, Christopher Tinkle
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is predominantly diagnosed clinically, with biopsy often reserved for cases with atypical imaging features and/or symptoms. Outcome data and molecular profiling of DIPG have been limited almost entirely to tumors with typical features. We examined the clinicopathologic characteristics and outcomes of 28 patients with pontine-centered lesions who underwent diagnostic biopsy at our institution from 2003 to 2018 because of atypical MRI findings. The median age at diagnosis was 5.2 years (range, 0.7–17.1), and the median symptom duration pre-diagnosis was 1 month (range, 0–24). Common atypical features included pontine asymmetry, tumor extension into the medulla and cerebellar peduncles, and exophytism. Four patients (14.3%) developed transient neurologic symptoms; one (3.6%) experienced a new, permanent cranial neuropathy; and no biopsy-related deaths occurred. Sixteen of the 28 tumors (57%) were confirmed histologically as DIPGs (WHO grade II–IV gliomas; “atypical DIPG”). Of these 16 cases, H3 K27M status was assessed through immunohistochemistry in 14 (88%) and nine were immunopositive (64.3%). The remainder (“atypical non-DIPGs”) were pilocytic astrocytomas (58.3%), gangliogliomas (8.3%), CNS embryonal tumors, NOS (16.7%), or C19MC-altered embryonal tumors with multilayered rosettes (16.7%). With a median follow-up of 28.6 months (range, 3.0 – 173.2), 2-year overall survival (OS) was 72.4%, 83.3%, and 62.2% for the total cohort, atypical non-DIPGs, and atypical DIPGs, respectively (P=NS for all). However, OS with H3 K27M–mutant atypical DIPG was inferior to that with H3 WT atypical DIPG (P=0.003). Compared to OS in a contemporary typical DIPG cohort (N=100), OS was significantly longer for the total atypical cohort, atypical non-DIPGs, and atypical DIPGs (P<0.001 for all), but not significantly different for H3 K27M–mutant atypical DIPGs. Thus, despite atypical imaging features, most lesions were consistent with DIPG. Biopsy contributed to revised diagnosis and management in a large number of cases. Integrative molecular analyses are ongoing.
Abstract 13886: Heparin Induces the Mobilization of Human Multipotent Circulating Mesoangioblasts From the Heart
Authors: Keisuke Fujitaka, Masayoshi Iwasaki, Yoshihiro Hata, Daisuke Sato, Haengnam Park, Masamichi Koyanagi, Keita Horitani, Miyuki Nakano, Andreas M Zeiher, Stefanie Dimmeler, Ichiro Shiojima
Journal: Circulation (2013)

Rationale: We previously identified circulating mesoangioblasts (cMABs), a subset of mesenchymal stem cells that co-express KDR and Nkx2.5, from the patients undergoing open heart surgery. cMABs ar...
Abstract 18465: The Kinetic Energy of Left Ventricular Ejection Flow During Late Systole Produces Inertia Force of Late Systolic Aortic Flow and Good Left Ventricular Early Diastolic Function
Authors: Junki Yamamoto, Kazuaki Wakami, Shohei Kikuchi, Syunsuke Murai, Hiroshi Fujita, Tomonori Sugiura, Toshihiko Goto, Nobuyuki Ohte
Journal: Circulation (2016)

Background: Inertia force of late systolic aortic flow (IF), which plays a substantial role for the coupling between left ventricular (LV) contraction and relaxation, may depend on the kinetic energy of ejecting flow (KE) during late systole (KE-LS). Good LV contraction generated much greater KE during early systole (KE-ES) and the KE-ES should affect the KE-LS. We investigated whether the KE-ES and -LS obtained using Vector Flow Mapping (VFMTM, Hitachi-Aloka) had any relationships with both IF and LV relaxation parameters invasively obtained. Method: Study subjects were 30 patients who underwent diagnostic cardiac catheterization and echocardiography on the same day. Conventional color Doppler images were acquired in the apical 3-chamber view. KE was obtained using the commercially available software (Hitachi-Aloka) (Figure). We divided the LV ejection time into 3 equal phases, then the KE was computed as a sum of KE values frame by frame basis around ES and LS; The ES was defined as the first one-third ...
INNV-21. AN OVERVIEW OF NIGERIAN NEURO-ONCOLOGY SCHOLARLY OUTPUT
Authors: Adefisayo Adekanmbi, Katherine Peters, Rimas Lukas
Journal: Neuro-Oncology (2018)

Nigeria is the most populous country in Africa and home to the continent's largest economy. In this lower middle income county there is a shortage of optimal neurological/neurosurgical oncology care for a population of 184 million. A systematic review of the literature was performed using Google Scholar, PubMed, and African Journals Online, searching for articles related to neuro-oncology in Nigeria. The following search terms were used: Neuro-oncology, neurooncology, brain tumor, glioma, meningioma, central nervous system tumor, management, practice and Nigeria. Manuscripts were reviewed for relevance and categorized. 63 relevant articles were identified comprising original research in basic science (N= 1), clinical science (N = 59), and reviews (n=3).Retrospective case series were the most common types of publications from amongst these categories. Categorizing according to histology articles focused on meningioma (N=12), pituitary tumors (N=10), glioma (N=7), CNS metastases (N=6), multiple histologic types (N=25) and other types of tumors (N=3). Only 8 pediatric neuro-oncology publications were noted amongst these. Two manuscripts specifically addressed issues on neuro-oncology clinical practice in Nigeria. Twenty-six were published in Nigeria journals, 9 in US journals, and twenty-eight published in other countries. An increase in number of publications over time peaking in 2015 (14 manuscripts) was noted. The most frequent affiliation of authors was University of Ibadan (26), University of Nigeria Teaching Hospital, Enugu (8), and Memfys Hospital for Neurosurgery (6). Two manuscripts were co-authored with American-based authors. There is a small but growing scholarly literature in neuro-oncology from Nigeria. However, there continues to be room for growth in neuro-oncology research output. With its large population of patients much can be learned. While there are logistical impediments to both patient care and research in neuro-oncology in Nigeria, there is promise for favorable advancements.
CBMT-13. UNRAVELLING METABOLISM OF GLIOBLASTOMA USING MASS SPECTROMETRY IMAGING
Authors: Jyotsna Upendra Rao, Katherine Gibson, Gregory Hamm, Alan Wright, Maria Fala, Richard Mair, Richard Goodwin, Kevin Brindle
Journal: Neuro-Oncology (2018)

INTRODUCTION: Glioblastoma Multiforme (GBM) is the most frequent malignant brain tumour in adults. The dismally low survival rates require novel diagnostic and therapeutic approaches. Understanding the tumour metabolic landscape in relation to its microenvironment is paramount. To address this issue, we have used high-resolution Mass Spectrometry Imaging (MSI). A female wistar rat implanted intracranially with C6-GBM cells was infused with [U-13C]glucose (a bolus of 0.4 mg/g body weight followed by infusion with 0.012 mg/g/min at 300 µL/h for 2 h) at 15 days post cell implantation. The presence of tumour at this point was confirmed in a T2-weighted magnetic resonance image. Post-infusion, the rat brain was rapidly excised and fixed by rapid freezing in liquid nitrogen. Coronal cryosections were subjected to desorption electrospray ionization (DESI) MSI. The mass-to-charge (m/z) ratios of 13C-labelled and unlabelled metabolites were compared between different brain regions using unsupervised spatial clustering. Naïve rat brain (not infused with [U-13C]glucose) was used as a control for natural abundance 13C. An increase in circulating blood glucose levels from 8 to 9.5 mmol/L was observed at the end of [U-13C]glucose infusion. Unsupervised clustering of metabolite m/z ratios distinguished different regions of the brain and normal brain from tumour. The profile of metabolite m/z ratios also showed intra-tumoural metabolite heterogeneity with differences between tumour boundary and core regions. These results demonstrate that C6-GBMs are metabolically heterogeneous and different from surrounding brain tissue. MSI can thus help unravel spatial differences in tumour metabolism. Comparison of MSI data to histological staining of brain sections can yield additional information about the relationship between the tumour and its microenvironment.