tbuckley/cabot-search huggingface dataset:
EPID-30. PREDICTORS ASSOCIATED WITH LONG-TERM SURVIVORSHIP FOR PATIENTS WITH GLIOBLASTOMA USING THE NATIONAL CANCER DATABASE (NCDB)
Authors: Ping Zhu, Xianglin Du, Yoshua Esquenazi, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES To investigate the long-term survival rates and the related predictors in patients with glioblastoma (GBM) using NCDB. METHODS A total of 51570 GBM patients were derived from the NCDB from 2004 to 2011. Three long-term survival measures were defined as patients who lived for at least 3-year, 5-year, or 10-year after diagnosis, respectively. Multivariable binary logistic regressions were performed to identify predictors in relation to 3-year, 5-year, and 10-year survival rates. The relative importance of each survival predictors was calculated, and random forest method was performed to validate the variable importance and decision tree as well. RESULTS A total of 4782 (9.3%), 1481 (3.9%), and 51 (0.9%) GBM patients survived at least 3-year, 5-year, and 10-years, respectively. Significant predictors related to both 3-year and 5-year survival rates from multivariable logistic regression included tumor resection, recent year of diagnosis, age &amp;lt; 65 years, private insurance, adjuvant therapy, non-whites, female, treatment at facility located in South regions or academic facilities, higher income, and non-comorbidity. Moreover, patients who traveled &amp;gt;50 miles for treatment and received care transition were significantly more likely to survival at least 3 years. However, only five predictors were associated with 10-year survivorship: residence-hospital distance &amp;gt;20 miles, non-whites, age &amp;lt; 65 years, resection, and higher income. Based on the calculations of relative importance and random forest method, the most important five factors to predict long-term survival were age, tumor resection, year of diagnosis, comorbidity, and adjuvant therapy (3-year survival); age, tumor resection, comorbidity, gender, and insurance (5-year survival); and age, race, residence-hospital distance, income, and comorbidity (10-year survival), respectively. CONCLUSIONS This study identifies non-molecular factors predicting long-term survivorship among GBM patients using NCDB dataset. Our findings suggested that 3-year and 5-year survivors share similar determinants, while 10-year survivors could be more different in socio-demographics and clinical features.
DSM-5 Level of Personality Functioning: Refocusing Personality Disorder on What It Means to Be Human
Authors: Carla Sharp, Kiana Wall
Journal: Annual Review of Clinical Psychology (2020)

Level of Personality Functioning (LPF) represents the entry criterion (Criterion A) of the Alternative Model for Personality Disorders (AMPD) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). It is defined as a dimensional general severity criterion common to all personality disorders and conceptually independent of personality types or traits, and it represents maladaptive self (identity and self-direction) and interpersonal (empathy and intimacy) functioning. We review the history, measurement, and significance of LPF. We show that the inclusion of LPF in the AMPD is well justified if it is defined as a general adaptive failure of a subjective intrapsychic system needed to fulfill adult life tasks. If so defined, LPF distinguishes itself from maladaptive traits (Criterion B of the AMPD) and captures the contribution humans make as agentic authors to the interpretation and management of the self. While Criterion B maladaptive traits provide important descriptive nuance to manifestations of personality pathology, maladaptive LPF is conditional to the diagnosis of personality disorder.
Osimertinib plus Ramucirumab: The Best of Both Worlds?
Authors: Edward B. Garon
Journal: Clinical Cancer Research (2021)

Both osimertinib and the combination of erlotinib plus ramucirumab are approved for initial therapy of advanced EGFR mutation-positive non-small cell lung cancer. Osimertinib is also approved in previously treated T790M mutation-positive patients. The accompanying article reports on a study combining osimertinib with ramucirumab.See related article by Yu et al., p. 992.
Update to CDC's Treatment Guidelines for Gonococcal Infection, 2020
Authors: Sancta St. Cyr, Lindley Barbee, Kimberly A. Workowski, Laura H. Bachmann, Cau Pham, Karen Schlanger, Elizabeth Torrone, Hillard Weinstock, Ellen N. Kersh, Phoebe Thorpe
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Sexually transmitted infections (STIs) caused by the bacteria Neisseria gonorrhoeae (gonococcal infections) have increased 63% since 2014 and are a cause of sequelae including pelvic inflammatory disease, ectopic pregnancy, and infertility and can facilitate transmission of human immunodeficiency virus (HIV) (1,2). Effective treatment can prevent complications and transmission, but N. gonorrhoeae's ability to acquire antimicrobial resistance influences treatment recommendations and complicates control (3). In 2010, CDC recommended a single 250 mg intramuscular (IM) dose of ceftriaxone and a single 1 g oral dose of azithromycin for treatment of uncomplicated gonococcal infections of the cervix, urethra, and rectum as a strategy for preventing ceftriaxone resistance and treating possible coinfection with Chlamydia trachomatis (4). Increasing concern for antimicrobial stewardship and the potential impact of dual therapy on commensal organisms and concurrent pathogens (3), in conjunction with the continued low incidence of ceftriaxone resistance and the increased incidence of azithromycin resistance, has led to reevaluation of this recommendation. This report, which updates previous guidelines (5), recommends a single 500 mg IM dose of ceftriaxone for treatment of uncomplicated urogenital, anorectal, and pharyngeal gonorrhea. If chlamydial infection has not been excluded, concurrent treatment with doxycycline (100 mg orally twice a day for 7 days) is recommended. Continuing to monitor for emergence of ceftriaxone resistance through surveillance and health care providers' reporting of treatment failures is essential to ensuring continued efficacy of recommended regimens.
<i>Chi3l1</i> /YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer’s disease pathogenesis
Authors: Brian V. Lananna, Celia A. McKee, Melvin W. King, Jorge L. Del-Aguila, Julie M. Dimitry, Fabiana H. G. Farias, Collin J. Nadarajah, David D. Xiong, Chun Guo, Alexander J. Cammack, Jack A. Elias, Jinsong Zhang, Carlos Cruchaga, Erik S. Musiek
Journal: Science Translational Medicine (2020)

Regulation of glial activation and neuroinflammation are critical factors in the pathogenesis of Alzheimer's disease (AD). YKL-40, a primarily astrocytic protein encoded by the gene Chi3l1, is a widely studied cerebrospinal fluid biomarker that increases with aging and early in AD. However, the function of Chi3l1/YKL-40 in AD is unknown. In a cohort of patients with AD, we observed that a variant in the human CHI3L1 gene, which results in decreased CSF YKL-40 expression, was associated with slower AD progression. At baseline, Chi3l1 deletion in mice had no effect on astrocyte activation while modestly promoting microglial activation. In a mouse APP/PS1 model of AD, Chi3l1 deletion decreased amyloid plaque burden and increased periplaque expression of the microglial lysosomal marker CD68, suggesting that Chi3l1 may suppress glial phagocytic activation and promote amyloid accumulation. Accordingly, Chi3l1 knockdown increased phagocytosis of zymosan particles and of β-amyloid peptide in both astrocytes and microglia in vitro. We further observed that expression of Chi3l1 is regulated by the circadian clock, as deletion of the core clock proteins BMAL1 or CLOCK/NPAS2 strongly suppresses basal Chi3l1 expression, whereas deletion of the negative clock regulators PER1/PER2 increased Chi3l1 expression. Basal Chi3l1 mRNA was nonrhythmic because of a long mRNA half-life in astrocytes. However, inflammatory induction of Chi3l1 was gated by the clock. Our findings reveal Chi3l1/YKL-40 as a modulator of glial phagocytic activation and AD pathogenesis in both mice and humans and suggest that the astrocyte circadian clock regulates inflammatory Chi3l1 induction.
EPID-02. STEREOTACTIC RADIOSURGERY AND CHEMOTHERAPY TREATMENT PATTERNS IN BREAST CANCER BRAIN METASTASES
Authors: Jacqueline Wang, Mustafa Ascha, Carol Kruchko, Bryan Iorgulescu, Jill S Barnholtz-Sloan
Journal: Neuro-Oncology (2020)

Abstract Brain metastases (BM) are typically treated with systemic chemotherapy and stereotactic radiosurgery (SRS). Population-level studies exploring SRS use in different patient populations and its impact on chemotherapy treatment patterns are needed. This study examines data from Surveillance, Epidemiology, and End-Results (SEER) from 2010–2012 and Medicare claims from 2008–2014 to identify the utility of SRS and associated chemotherapy treatment patterns in the breast cancer BM patient population. 25,954 breast cancer patients were identified, of which 6,657 (26%) received SRS. Chi-square and Fisher’s exact tests were used for initial univariate analyses. Univariable logistic regression models were fit for each predictor and multivariable models were selected using LASSO. Compared to patients without SRS, patients who received SRS were older, diagnosed at later disease stages, and less likely to have the Her2-/HR+ subtype. Patients with SRS most commonly received aromatase inhibitors (53.5%), followed by selective estrogen receptor modulators (SERM; 31.7%), taxanes (27.2%), alkylating agents (21.2%), monoclonal antibodies (22.2%), antimetabolite drugs (18.3%), anthracyclines (11.4%), and platinating agents (6.8%). Increased odds of SRS were associated with drug classes including taxanes (aOR: 1.29), monoclonal antibodies (aOR: 1.67), antimetabolites (aOR: 1.77), anthracyclines (aOR: 1.32), and topoisomerase-II inhibitors (aOR: 3.16). Aromatase inhibitors were associated with decreased odds of SRS use (aOR: 0.84). Alkylating agents, platinating agents, and SERM had no such associations. Our findings suggest that use of many chemotherapeutic agents increases with SRS regardless of ability to penetrate the blood-brain-barrier and parallels standard systemic breast cancer treatments. Because large-scale studies on the impact of SRS on breast cancer BM patients are lacking, it is important to identify differences in treatment usage and patterns. Important clinical implications regarding drug usage frequency, adherence to treatment guidelines, and use of different agents across SRS patients may arise by analyzing differences amongst and between populations of patients with and without SRS.
BIOM-58. ASSESSMENT OF ANEUPLOIDY BY REPETITIVE ELEMENT SEQUENCING TO DETECT PEDIATRIC AND ADULT BRAIN CANCERS IN PLASMA
Authors: Christopher Douville, Austin Mattox, Cherie Blair, Chetan Bettegowda
Journal: Neuro-Oncology (2020)

Abstract Central nervous system cancers are the tenth leading cause of death for adults and the leading cause of cancer mortality in children. Non-invasive detection methods are desperately needed for earlier diagnosis and recurrence monitoring. Aneuploidy is common to nearly all cancers and can be detected in circulating tumor DNA (ctDNA) isolated from a variety of biofluids, including plasma. We utilized a sensitive PCR-based assay called Repetitive Element AneupLoidy Sequencing System (RealSeqS) on plasma samples from 90 patients diagnosed with the most common primary brain tumors including pilocytic astrocytoma, Grade II and III astrocytoma, glioblastoma (GBM), oligodendroglioma, ependymoma, and medulloblastoma to detect aneuploidy in ctDNA. RealSeqS employs PCR amplification and sequencing of ~350,000 genome-wide loci to identify chromosomal abnormalities and then aggregate them into a single Genome Aneuploid Score via a supervised machine learning algorithm. RealSeqS identified aneuploidy in 16 of 90 (17.8%) patients, including 20.9% (9/43) of anaplastic astrocytomas and GBMs, 57.1% (4/7) ependymomas, and 18.8% (3/16) pilocytic astrocytomas. Notably, ependymomas have significant chromothripsis and aneuploidy, which was reflected in our plasma analyses. Detection of aneuploidy also correlated with higher mortality rates at the time of last follow-up (p &amp;lt; 0.001). RealSeqS did not detect aneuploidy in the plasma of patients with Grade II astrocytoma, medulloblastoma, or oligodendroglioma. RealSeqS detected focal amplifications of 11q in 16.7% (2/12) and a focal deletion of TERT in 8.3% (1/12) of Grade III astrocytomas, focal deletions of EXT1 (14.3%; 1/7) and focal amplifications of EGFR (14.3%; 1/7) in the plasma of patients with ependymomas, and focal deletions of EXT1 (3.2%, 1/31) and focal amplifications of CDKN2A and CDKN2B in (3.2%; 1/31) GBM. These findings suggest detection of aneuploidy by RealSeqS may be a rapid, cheaper, and more sensitive alternative to low pass whole genome sequencing for the earlier detection of certain CNS neoplasms.
Genomic Characterization of <i>de novo</i> Metastatic Breast Cancer
Authors: Ana C. Garrido-Castro, Liam F. Spurr, Melissa E. Hughes, Yvonne Y. Li, Andrew D. Cherniack, Priti Kumari, Maxwell R. Lloyd, Brittany Bychkovsky, Romualdo Barroso-Sousa, Simona Di Lascio, Esha Jain, Janet Files, Ayesha Mohammed-Abreu, Max Krevalin, Colin MacKichan, William T. Barry, Hao Guo, Daniel Xia, Ethan Cerami, Barrett J. Rollins, Laura E. MacConaill, Neal I. Lindeman, Ian E. Krop, Bruce E. Johnson, Nikhil Wagle, Eric P. Winer, Deborah A. Dillon, Nancy U. Lin
Journal: Clinical Cancer Research (2020)

In contrast to recurrence after initial diagnosis of stage I-III breast cancer [recurrent metastatic breast cancer (rMBC)], de novo metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS).Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC.When comparing primary tumors by subtype, MYB amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, P = 0.0005, q = 0.111). Mutations in KMTD2, SETD2, and PIK3CA were more prevalent, and TP53 and BRCA1 less prevalent, in primary HR+/HER2- tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; P = 0.008, q = 0.107), MYC (79.7 vs. 23.3 months; P = 0.0003, q = 0.011), and cell-cycle (122.7 vs. 54.9 months; P = 0.034, q = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC (P = 0.041).Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments.
Defibrillation Threshold Testing in Implantable Cardioverter-Defibrillators: Might Less Be More Than Enough?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Anne B. Curtis
Journal: Journal of the American College of Cardiology (2008)
Inequalities in Public Water Arsenic Concentrations in Counties and Community Water Systems across the United States, 2006–2011
Authors: Anne E. Nigra, Qixuan Chen, Steven N. Chillrud, Lili Wang, David Harvey, Brian Mailloux, Pam Factor-Litvak, Ana Navas-Acien
Journal: Environmental Health Perspectives (2020)

BACKGROUND: In the United States, nationwide estimates of public drinking water arsenic exposure are not readily available.We used the U.S. Environmental Protection Agency's (EPA) Six-Year Review contaminant occurrence data set to estimate public water arsenic exposure.We compared community water system (CWS) arsenic concentrations during 2006-2008 vs. after 2009-2011, the initial monitoring period for compliance with the U.S. EPA's 10 lg=L arsenic maximum contaminant level (MCL).OBJECTIVE: Our objective was to characterize potential inequalities in CWS arsenic exposure over time and across sociodemographic subgroups.METHODS: We estimated 3-y average arsenic concentrations for 36,406 CWSs (98%) and 2,740 counties (87%) and compared differences in means and quantiles of water arsenic (via quantile regression) between both 3-y periods for U.S. regions and sociodemographic subgroups.We assigned CWSs and counties MCL compliance categories (High if above the MCL; Low if below) for each 3-y period.RESULTS: From 2006-2008 to 2009-2011, mean and 95th percentile CWS arsenic (in micrograms per liter) declined by 10.3% (95% CI: 6.5%, 14.1%) and 11.5% (8.3%, 14.8%) nationwide, by 11.4% (4.7%, 18.1%) and 16.3% (8.1%, 24.5%) for the Southwest, and by 36.8% (7.4%, 66.1%) and 26.5% (12.1%, 40.8%) for New England, respectively.CWSs in the High/High compliance category (not MCL compliant) were more likely in the Southwest (61.1%), served by groundwater (94.7%), serving smaller populations (mean 1,102 persons), and serving Hispanic communities (38.3%).DISCUSSION: Larger absolute declines in CWS arsenic concentrations at higher water arsenic quantiles indicate declines are related to MCL implementation.CWSs reliant on groundwater, serving smaller populations, located in the Southwest, and serving Hispanic communities were more likely to continue exceeding the arsenic MCL, raising environmental justice concerns.These estimates of public drinking water arsenic exposure can enable further surveillance and epidemiologic research, including assessing whether differential declines in water arsenic exposure resulted in differential declines in arsenic-associated disease.
IMMU-27. SINGLE CELL RNA-SEQUENCING IDENTIFIES NOVEL BONE MARROW DERIVED MYELOID CELLS IN GLIOBLASTOMA ASSOCIATED WITH TUMOR AGGRESSION
Authors: Christina Jackson, Christopher Cherry, Sadhana Bom, Hao Zhang, John Choi, Vasan Yegnasubramanian, Michael Lim, Jennifer Elisseeff, Drew Pardoll
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioma associated myeloid cells (GAMs) can be induced to adopt an immunosuppressive phenotype that can lead to inhibition of anti-tumor responses in glioblastoma (GBM). Understanding the composition and phenotypes of GAMs is essential to modulating the myeloid compartment as a therapeutic adjunct to improve anti-tumor immune response. METHODS We performed single-cell RNA-sequencing (sc-RNAseq) of 435,400 myeloid and tumor cells to identify transcriptomic and phenotypic differences in GAMs across glioma grades. We further correlated the heterogeneity of the GAM landscape with tumor cell transcriptomics to investigate interactions between GAMs and tumor cells. RESULTS sc-RNAseq revealed a diverse landscape of myeloid-lineage cells in gliomas with an increase in preponderance of bone marrow derived myeloid cells (BMDMs) with increasing tumor grade. We identified two populations of BMDMs unique to GBMs; Mac-1and Mac-2. Mac-1 demonstrates upregulation of immature myeloid gene signature and altered metabolic pathways. Mac-2 is characterized by expression of scavenger receptor MARCO. Pseudotime and RNA velocity analysis revealed the ability of Mac-1 to transition and differentiate to Mac-2 and other GAM subtypes. We further found that the presence of these two populations of BMDMs are associated with the presence of tumor cells with stem cell and mesenchymal features. Bulk RNA-sequencing data demonstrates that gene signatures of these populations are associated with worse survival in GBM. CONCLUSION We used sc-RNAseq to identify a novel population of immature BMDMs that is associated with higher glioma grades. This population exhibited altered metabolic pathways and stem-like potentials to differentiate into other GAM populations including GAMs with upregulation of immunosuppressive pathways. Our results elucidate unique interactions between BMDMs and GBM tumor cells that potentially drives GBM progression and the more aggressive mesenchymal subtype. Our discovery of these novel BMDMs have implications in new therapeutic targets in improving the efficacy of immune-based therapies in GBM.
Abstract 12920: Identification of SERCA2 as a Novel Effector and Therapeutic Target in Acute Post-Operative Right Ventricular Dysfunction
Authors: Arturo J Cardounel, Edgar Aranda-Michel, Rishab Humar, Walter Navid, Arman Kilic, Joon Lee, Thomas G Gleason, Ibrahim Sultan
Journal: Circulation (2019)

Introduction: Acute right ventricular (RV) dysfunction after cardiac surgery can be seen in up to 20 % of patients post-operatively and is a significant cause of morbidity and mortality with an in-...
Neuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study
Authors: Camilla E Lindan, Kshitij Mankad, Dipak Ram, Larry K Kociolek, V Michelle Silvera, Nathalie Boddaert, Stavros Michael Stivaros, Susan Palasis, Sameen Akhtar, Douglas Alden, Suraj Amonkar, Pascale Aouad, Mélodie Aubart, Jose Alejandro Bacalla, Alcino A Barbosa, Romain Basmaci, Laureline Berteloot, Thomas Blauwblomme, Gilles Brun, Olivia Carney, Judith Chareyre, Gérard Chéron, Pablo Picasso De Araujo Coimbra, Volodia Dangouloff-Ros, Felice D'Arco, Rob Dineen, Loic De-Pontual, Isabelle Desguerre, Wissam Elfallal, D. Gareth Evans, Suely Fazio Ferraciolli, Nadine Girard, Fabrício Guimarães Gonçalves, Ivan Gonzalez, P. Ellen Grant, David Grévent, Carolina Valduga de Alencastro Guimaraes, Jane Hassell, Fabiana C.C. Hirata, Ian Kamaly-Asl, Jeffrey Jacob, Kandise Jackson, Blaise V. Jones, Robin Joseph, Ah Young Jung, Amna Kashgari, John-Paul Kilday, Alyssa Kirsch, Manoelle Kossorotoff, Anant Krishnan, Shilpa Kulkarni, Marianne Leruez-Vill, Fabrice Lesage, Raphaël Levy, Yi Li, Carol Cavalcante de Vasconcelos Lima, Lokesh Lingappa, Ulrike Löbel, Roberto Lopez-Alberola, Leandro Tavares Lucato, Daniela Duarte Moreira, Jonathan G. Murnick, Sarah Nahmani, Shubra Pagariya, Julija Pavaine, Bryan Philbrook, Ana Cláudia Piovesan, Kelsey E. Poisson, Nihaal Reddy, Phil Riley, Andrea Romsauerova, Charlies-Joris Roux, Carlos Rugilo, Gaurav Saigal, Gabriel Lucca de Oliveira Salvador, David Seidenwurm, Isabelle Sermet-Gaudelus, Jai Sidpra, Sniya Valsa Sudhakar, María Sol Toronchik, Gilbert Vézina
Journal: The Lancet Child & Adolescent Health (2020)
In acute soft tissue injuries, NSAIDs do not differ from acetaminophen for pain reduction
Authors: Jonathan Kirschner, Benton Hunter
Journal: Annals of Internal Medicine (2020)

Jones P, Lamdin R, Dalziel SR. Oral non-steroidal anti-inflammatory drugs versus other oral analgesic agents for acute soft tissue injury. Cochrane Database Syst Rev. 2020;8:CD007789. 32797734.