tbuckley/cabot-search huggingface dataset:
DDRE-02. THERAPEUTIC TARGETING OF BRAIN METASTASIS WITH ERK INHIBITOR LY3214996 USING A NOVEL IN VIVO MODEL OF LUNG-TO-BRAIN METASTASIS
Authors: Mohini Singh, Naema Nayyar, Priscilla Brastianos
Journal: Neuro-Oncology (2020)

Abstract Brain metastases (BM) are the most common neoplasm to affect the adult central nervous system, occurring ten times more frequently than primary brain tumors. BM develop in 40–50% of advanced lung adenocarcinoma (LUAD), but the lack of durable response to chemotherapy, immunotherapy, or targeted therapy results in death within a year of BM diagnosis. Several advances have been made in identifying genetic drivers of primary cancers. For instance, the ERK pathway is critical in oncogenesis, with aberrations linked to driving the progression and metastasis of LUAD. Unfortunately, BM remain poorly understood due to both the difficulty of obtaining a sizable collection of metastatic tissue samples as well as a lack of clinically relevant models. Typical models of BM utilize inoculation routes that are invasive and cannot fully recapitulate the entirety of the metastatic cascade. Here we present a novel murine model of BM through an intrathoracic inoculation method that recapitulates the development of primary lung tumors and brain metastases as seen in patients. Using this method, we evaluated the efficacy of LY3214996, an ERK inhibitor, in targeting BM. Seven days post-inoculation of a patient-derived NSCLC-BM line, mice received LY3214996 P.O. daily for 21 days, and were monitored weekly for metastases with bioluminescent imaging. Upon endpoint lungs and brains were also removed and imaged. In vitro we demonstrated a reduction in cell growth and invasion across multiple cell lines of varying KRAS status (NSCLC and NSCLC-BM) treated with LY3214996. In vivo, we saw a reduction in both lung tumor weight as well as frequency of BM. Further research is necessary to elucidate the dosing and efficacy of LY3214996 in our models in different genetic contexts. Nonetheless, our technique presents a novel preclinical tool to interrogate the metastatic process, allowing validation of genetic drivers as well as therapeutic screening.
EPEN-24. SIOP EPENDYMOMA II: CENTRAL EPENDYMOMA MANAGEMENT ADVISORY GROUP – THE UK EXPERIENCE
Authors: Donald C Macarthur, Conor Mallucci, Ian Kamaly-Asl, John Goodden, Lisa C D Storer, Rebecca J Chapman, J-P Kilday, Martin English, Tim Jaspan, Arpita Chattopadhyay, Rob A Dineen, Shivaram Avula, Stavros Stivaros, Richard Grundy
Journal: Neuro-Oncology (2020)

Abstract Paediatric Ependymoma is the second most common malignant brain tumour of childhood with approximately 50% of cases recurring. It has been described as a “surgical” disease since patients who have undergone a gross total surgical resection (GTR) have a better prognosis than those who have a subtotal resection (STR). Analysis of the UKCCSG/SIOP 1992 04 clinical trial has shown that only 49% of cases had a GTR, with 5-year survival rates for STR of 22–47% and GTR of 67–80%. As part of the SIOP II Ependymoma trial the UK established a panel of experts in the treatment of Ependymoma from Neuro-oncology, Neuro-radiology and Neuro-surgery. Meeting weekly, cases are discussed to provide a consensus on radiological review, ensuring central pathological review, trial stratification and whether further surgery should be advocated on any particular case. Evaluation of the first 68 UK patients has shown a GTR in 47/68 (69%) of patients and STR in 21/68 (31%) of patients. Following discussion at EMAG it was felt that 9/21 (43%) STR patients could be offered early second look surgery. Following this 2nd look surgery the number of cases with a GTR increased to 56/68 (82%). There has been a clear increase in the number of patients for whom a GTR has been achieved following discussion at EMAG and prior to them moving forwards with their oncological treatment. This can only have beneficial effects in decreasing their risk of tumour recurrence or CSF dissemination and also in reducing the target volume for radiotherapy.
Assisted Reproductive Technology Surveillance — United States, 2017
Authors: Saswati Sunderam, Dmitry M. Kissin, Yujia Zhang, Amy Jewett, Sheree L. Boulet, Lee Warner, Charlan D. Kroelinger, Wanda D. Barfield
Journal: MMWR Surveillance Summaries (2020)

Since the first U.S. infant conceived with assisted reproductive technology (ART) was born in 1981, both the use of ART and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Although the majority of infants conceived through ART are singletons, women who undergo ART procedures are more likely than women who conceive naturally to have multiple-birth infants because multiple embryos may be transferred. Multiple births can pose substantial risks for both mothers and infants, including obstetric complications, preterm birth (<37 weeks), and low birthweight (<2,500 g). This report provides state-specific information for the United States (including the District of Columbia and Puerto Rico) on ART procedures performed in 2017 and compares birth outcomes that occurred in 2017 (resulting from ART procedures performed in 2016 and 2017) with outcomes for all infants born in the United States in 2017.
メシル酸イマチニブ(STI571)の局部送達-生体外統合化ナノ粒子による静脈新生内膜肥厚の抑制
Authors: Kimura S, Egashira K, Nakano K, Iwata E, Miyagawa M, Tsujimoto H, Hara K, Kawashima Y, Tominaga R, Sunagawa K
Journal: Circulation (2008)
QOL-25. MICROSTRUCTURAL BRAIN CHANGES ASSOCIATED WITH NEUROCOGNITIVE AND FUNCTIONAL OUTCOMES OF INTRACRANIAL GERM CELL TUMUOR SURVIVORS – A DIFFUSIONAL KURTOSIS IMAGING STUDY
Authors: Wan-Yee Winnie Tso, Sai Kam Hui, Tatia Mei Chun Lee, Anthony Pak Yin Liu, Patrick Ip, Kevin Cheng, Daniel Fong, Dorita Chang, Frederick K W Ho, Ka Man Yip, Dennis Ku, Daniel K L Cheuk, Chung Wing Luk, Ming Kong Shing, L K Leung, Pek Lan Khong, Godfrey Chi Fung Chan
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Childhood intracranial germ cell tumour (iGCT) survivors are prone to radiotherapy-related neurotoxicity which can lead to neurocognitive dysfunction. Diffusion kurtosis imaging (DKI) is a MRI technique that quantifies microstructural changes in the grey and white matter of the brain. This study aims to investigate the associations between MR-DKI metrics, the cognitive and functional outcomes of childhood iGCT survivors. METHOD 20 childhood iGCT survivors who had received cranial radiotherapy were recruited. DKI parameters were determined for iGCT survivors and 18 control subjects. Neurocognitive assessment using the Hong Kong Wechsler Intelligence Scales for Children (HKWISC)/ Wechsler Adult Intelligence Scale – Revised (WAIS-R) and functional assessment using the Lansky/ Karnofsky performance scales were performed for GCT survivors. RESULTS There were significant negative correlation between the IQ scores and the mean diffusivity (MD) in multiple white matter regions of iGCT survivors including: anterior limb of internal capsule, superior fronto-occipital fasciculus, anterior corona radiata, uncinate fasciculus, cingulum and hippocampus. Mean kurtosis (MK) values of the superior fronto-occipital fasciculus were positively correlated with IQ scores. For grey matter, the MD of the olfactory, insula, caudate, heschl gyrus, parahippocampal gyrus, hippocampus, anterior cingulum, frontal inferior operculum, middle and superior temporal gyrus, middle and superior frontal orbital gyri, cuneus and precentral gyrus were negatively correlated with IQ scores. Most of the microstructural changes with associated functional impairment were white matter regions. CONCLUSION Our study identified vulnerable brain regions with significant white and grey matter microstructural changes that were associated with impaired cognitive function or deficits in physical functioning.
STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM
Authors: Stephen Skirboll, Natasha Lucki, Genaro Villa, Naja Vergani, Michael Bollong, Brittney Beyer, Jae Wook Lee, Justin Anglin, Stephan Spangenberg, Emily Chin, Amandeep Sharma, Kevin Johnson, Phillipp Sander, Perry Gordon, Heiko Wurdak, Peter Schultz, Paul Mischel, Luke Lairson
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.
24MO Randomized, multicenter, open-label trial of autologous cytokine-induced killer cell immunotherapy plus chemotherapy for squamous non-small cell lung cancer
Authors: L. Liu, Q. Gao, J. Jiang, J. Zhang, X. Song, J. Cui, Y. Ye, Z. Wang, H. Yao, X. Zhang, X. Hao, R. Xiubao
Journal: Annals of Oncology (2020)
RARE-10. ADAMANTINOMATOUS CRANIOPHARYNGIOMA RESIDES OUTSIDE THE BLOOD BRAIN BARRIER
Authors: Eric Prince, Trinka Vijmasi, Jennifer McWilliams, Astrid Hengartner, Susan Staulcup, Nicholas Foreman, Kimberly Jordan, Kathleen Dorris, Lindsey Hoffman, Todd Hankinson
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Adamantinomatous craniopharyngioma (ACP) is a devastating skull-base tumor believed to derive from epithelial remnants of the primordial craniopharyngeal duct (Rathke’s pouch), which gives rise to the anterior pituitary gland. Genetically engineered mouse models of ACP demonstrate that perturbation of the fetal anterior pituitary can generate tumors analogous to ACP. Clinical and preclinical data indicate that IL-6 blockade may contribute to ACP tumor control, with the most common agent being the humanized monoclonal antibody, tocilizumab. This agent demonstrated poor blood-brain barrier (BBB) penetration in primates. We present findings from two children enrolled on a phase 0 clinical trial (NCT03970226) of a single dose of preoperative intravenous tocilizumab prior to resection of newly diagnosed ACP. METHODS Blood samples were obtained at multiple timepoints. Serum was isolated via ficoll separation. Tumor tissue and cyst fluid were obtained 4–6 hours following the single IV dose of tocilizumab. Tissue was snap-frozen. Tumor was homogenized in RIPA buffer. Free tocilizumab in serum, cyst fluid, and tumor tissue was measured using enzyme-linked immunosorbent assay (ELISA) against a standard curve. RESULTS Both patients in this trial demonstrated clinically relevant levels of tocilizumab (≥ 4µg/mL) in serum, cyst fluid, and tumor tissue, compared to undetectable levels in control samples. CONCLUSION ACP resides outside BBB protection. In addition to demonstrating the feasibility of systemic delivery of tocilizumab, these findings indicate that other large molecules, including those known to have poor BBB penetration, may be systemically delivered as part of an antitumor regimen in the treatment of ACP.
NIMG-52. CHARACTERIZATION OF COGNITIVE FUNCTION IN SURVIVORS OF DIFFUSE GLIOMAS USING MORPHOMETRIC CORRELATION NETWORKS (MCN)
Authors: Chencai Wang, Kathleen Van Dyk, Nicholas Cho, Catalina Raymond, Justin Choi, Noriko Salamon, Whitney Pope, Albert Lai, Timothy Cloughesy, Phioanh Nghiemphu, Benjamin Ellingson
Journal: Neuro-Oncology (2020)

Abstract Advanced multimodality treatments have led to improved survival and quality of life for patients with diffuse gliomas, and widespread functional reorganization has been reported to be associated with improved cognitive function. However, investigation of morphological alterations in patients with diffuse gliomas has been problematic, largely due to the tumor resection cavities. This pilot study has overcome these challenges and aims to characterize the relationship between structural plasticity and cognitive function in survivors of diffuse gliomas. High-resolution T1 weighted images were collected from 24 patients with diffuse gliomas (mean age 44.5 ± 11.5) who had completed their treatment within the previous ten years. Interregional correlations of cortical thickness were computed to establish morphometric correlation networks (MCN) for twelve cognitively impaired and twelve non-impaired glioma patients, as well as correlated with self-reported cognitive impairment. Our findings demonstrated that both cognitively impaired (σ=1.5979) and non-impaired (σ=1.3683) glioma patients have a small world architecture in disrupted morphological networks. Although the left fusiform (p=0.0409), left inferior (p=0.0209), and temporal (p=0.0173) gyri were observed to be thicker in non-impaired patients, the robustness of their morphological network was weak and easily vulnerable to pathological attacks and neurological deterioration. Furthermore, regions such as the superior temporal gyrus (p=0.0126) and rostral middle frontal gyrus (p=0.0148) were not only identified as predominant nodes in the MCN of patients but were also found to have greater gray matter thickness, which is associated with better FACT-cognitive function. Together, these results support our hypothesis that a widespread morphological network is altered in survivors of diffuse gliomas. Predominant regions obtained by topological analysis may lead to reliable imaging biomarkers that help evaluate patients’ cognition and ability to function.
EPID-35. CLINICAL TRIAL ENROLLMENT RATE AMONG ADOLESCENT AND YOUNG ADULTS WITH CENTRAL NERVOUS SYSTEM TUMOR AT DANA-FARBER CANCER INSTITUTE (DFCI)
Authors: Supriya Sarvode, Katherine Warren, David Reardon, Kee Kiat Yeo
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Adolescents and young adults (AYAs; 15–39 yrs.) are a population recognized as facing significant challenges in cancer care and research, characterized by historically poor participation in clinical trials. The clinical trial enrollment rate among AYAs with CNS tumor is unclear. We report the findings from our study evaluating the clinical trial enrollment rate of AYAs with CNS glioma at DFCI, comparing the rates between its affiliated adult and children’s hospitals. METHODS We performed a retrospective cohort study of patients with primary CNS glioma treated at our center between 2008–18. Eligible patients were identified using institutional databases at Boston Children’s Hospital and Brigham and Women’s Hospital. Manual chart review and data abstraction from the electronic medical record were performed to obtain key variables. Clinical trial enrollment rates were reported, followed by univariate and multivariate logistic regression models to identify factors affecting clinical trial enrollment. RESULTS In the adult setting, a total of 608 AYA patients with glioma were identified to meet our inclusion criteria and presented with a median age of 32 years (range:15–39). 92 out of 608 (15%) patients enrolled in a clinical trial during their treatment course. Within this cohort, tumor type was significantly associated with clinical trial enrollment, with higher-grade tumors associated with better enrollment rates (p&amp;lt; 0.001). On the contrary in the pediatric setting, a total of 52 AYA patients were identified from the children’s hospital, with a median age of 17.2 years (range:15–25.4) of whom, 19 out of 52 (36.5%) patients were enrolled on a clinical trial. CONCLUSION Clinical trial enrollment rate remains poor among AYAs with CNS tumors, with tumor type/histology grade associated with enrollment rate. Higher enrollment rates were seen among early AYAs treated at the children’s hospital.
Metabolic impact of persistent organic pollutants on gut microbiota
Authors: Yuan Tian, Wei Gui, Bipin Rimal, Imhoi Koo, Philip B. Smith, Robert G. Nichols, Jingwei Cai, Qing Liu, Andrew D. Patterson
Journal: Gut Microbes (2020)

Emerging evidence supports that exposure to persistent organic pollutants (POPs) can impact the interaction between the gut microbiota and host. Recent efforts have characterized the relationship between gut microbiota and environment pollutants suggesting additional research is needed to understand potential new avenues for toxicity. Here, we systematically examined the direct effects of POPs including 2,3,7,8-tetrachlorodibenzofuran (TCDF), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and polychlorinated biphenyls (PCB-123 and PCB-156) on the microbiota using metatranscriptomics and NMR- and mass spectrometry-based metabolomics combined with flow cytometry and growth rate measurements (OD600). This study demonstrated that (1) POPs directly and rapidly affect isolated cecal bacterial global metabolism that is associated with significant decreases in microbial metabolic activity; (2) significant changes in cecal bacterial gene expression related to tricarboxylic acid (TCA) cycle as well as carbon metabolism, carbon fixation, pyruvate metabolism, and protein export were observed following most POP exposure; (3) six individual bacterial species show variation in lipid metabolism in response to POP exposure; and (4) PCB-153 (non-coplanar)has a greater impact on bacteria than PCB-126 (coplanar) at the metabolic and transcriptional levels. These data provide new insights into the direct role of POPs on gut microbiota and begins to establish possible microbial toxicity endpoints which may help to inform risk assessment.
EPID-34. THE DETRIMENTAL EFFECT OF BIOPSY PRECEDING RESECTION IN SURGICALLY ACCESSIBLE GLIOBLASTOMAS: RESULTS FROM THE NATIONAL CANCER DATABASE
Authors: Ping Zhu, Xianglin Du, Angel Blanco, Leomar Y Ballester, Nitin Tandon, Jay-Jiguang Zhu, Constantinos Hadjipanayis, Mitchel Berger, Yoshua Esquenazi
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES To investigate the impact of biopsy preceding resection compared to upfront resection in glioblastoma overall survival (OS) and post-operative outcomes using the National Cancer Database (NCDB). METHODS A total of 17,334 GBM patients diagnosed between 2010 and 2014 were derived from the NCDB. Patients were categorized into two groups: “upfront resection” versus “biopsy followed by resection”. Primary outcome was OS. Post-operative outcomes including 30-day readmission/mortality, 90-day mortality, and prolonged length of inpatient hospital stay (LOS) were secondary endpoints. Kaplan-Meier methods and accelerated failure time (AFT) models with gamma distribution were applied for survival analysis. Multivariable binary logistic regression models were performed to compare differences in the post-operative outcomes between these groups. RESULTS Patients undergoing “upfront resection” experienced superior survival compared to those undergoing “biopsy followed by resection” (median OS: 12.4 versus 11.1 months, log-rank test: P=0.001). In multivariable AFT models, significant survival benefits were observed among patients undergoing “upfront resection” (time ratio [TR]: 0.83, 95% CI: 0.75–0.93, P=0.001). Patients undergoing upfront GTR had the longest survival compared to upfront STR, GTR following STR, or GTR and STR following an initial biopsy (14.4 vs. 10.3, 13.5, 13.3, and 9.1, months), respectively (TR: 1.00 [Ref.], 0.75, 0.82, 0.88, and 0.67). Recent years of diagnosis, higher income and treatment at academic facilities were significantly associated with the likelihood of undergoing upfront resection after adjusting the covariates. Multivariable logistic regression revealed that 30-day mortality and 90-day mortality were decreased by 73% and 44% for patients undergoing “upfront resection” over “biopsy followed by resection”, respectively (both p &amp;lt; 0.001). CONCLUSIONS Pre-operative biopsies for surgically accessible tumors with characteristic imaging features of Glioblastoma lead to worse survival despite subsequent resection compared to patients undergoing upfront resection.
Global Analysis of Gene Expression Profiles Provides Novel Insights into the Development and Evolution of the Large Crustacean <i>Eriocheir Sinensis</i>
Authors: Jun Wang, Xiaowen Chen, Funan He, Xiao Song, Shu Huang, Wucheng Yue, Yipei Chen, Zhixi Su, Chenghui Wang
Journal: Genomics Proteomics & Bioinformatics (2020)

Chinese mitten crab (Eriocheir sinensis) is an important aquaculture species in Crustacea. Functional analysis, although essential, has been hindered due to the lack of sufficient genomic or transcriptomic resources. In this study, transcriptome sequencing was conducted on 59 samples representing diverse developmental stages (fertilized eggs, zoea, megalopa, three sub-stages of larvae, juvenile crabs, and adult crabs) and different tissues (eyestalk, hepatopancreas, and muscle from juvenile crabs, and eyestalk, hepatopancreas, muscle, heart, stomach, gill, thoracic ganglia, intestine, ovary, and testis from adult crabs) of E. sinensis. A comprehensive reference transcriptome was assembled, including 19,023 protein-coding genes. Hierarchical clustering based on 128 differentially expressed cuticle-related genes revealed two distinct expression patterns during the early larval developmental stages, demonstrating the distinct roles of these genes in "crab-like" cuticle formation during metamorphosis and cuticle calcification after molting. Phylogenetic analysis of 1406 one-to-one orthologous gene families identified from seven arthropod species and Caenorhabditis elegans strongly supported the hypothesis that Malacostraca and Branchiopoda do not form a monophyletic group. Furthermore, Branchiopoda is more phylogenetically closely related to Hexapoda, and the clade of Hexapoda and Branchiopoda and the clade of Malacostraca belong to the Pancrustacea. This study offers a high-quality transcriptome resource for E. sinensis and demonstrates the evolutionary relationships of major arthropod groups. The differentially expressed genes identified in this study facilitate further investigation of the cuticle-related gene expression networks which are likely associated with "crab-like" cuticle formation during metamorphosis and cuticle calcification after molting.