tbuckley/cabot-search huggingface dataset:
NCOG-65. MR-GUIDED LASER INTERSTITIAL THERMAL THERAPY FOR BRAIN TUMORS IN GERIATRIC PATIENTS
Authors: Elizabeth Ginalis, Shabbar Danish
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION There is a paucity of studies assessing the use of magnetic resonance-guided laser interstitial thermal therapy (LITT) in the elderly population. METHODS Geriatric patients (≥65 years) treated with LITT for intracranial tumors at a single institution from January 2011 to November 2019 were retrospectively identified. We grouped patients into two cohorts: 65-74 years (group 1) and 75 years or older (group 2). Baseline characteristics, operative parameters, postoperative course, and morbidity were recorded. RESULTS There were 55 patients who underwent 64 distinct LITT procedures. The majority of tumors (62.5%) treated were recurrent brain metastasis/radiation necrosis. The median hospital length of stay was 1 day, with no significant difference between age groups. Hospital stay was significantly longer in patients who presented with a neurological symptom and in those who experienced a postoperative complication. The majority of patients (68.3%) were discharged to their preoperative accommodation. Rate of discharge to home was not significantly different between age groups. Those discharged to rehabilitation facilities were more likely to have presented with a neurological symptom. Nine patients (14.1%) were found to have acute neurological complications, with nearly all patients showing complete or partial recovery at follow-up. The 30-day postoperative mortality rate was 1.6% (n = 1). The complication and 30-day postoperative mortality rate were not significantly different between age groups. CONCLUSIONS LITT can be considered as a minimally invasive and safe neurosurgical procedure for treatment of intracranial tumors in geriatric patients. Careful preoperative preparation and postoperative care is essential as LITT is not without risk. Appropriate patient selection for cranial surgery is essential as neurosurgeons treat an increasing number of elderly patients, but advanced age alone should not exclude patients from LITT.
2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
Authors: Catherine M. Otto, Rick A. Nishimura, Robert O. Bonow, Blase A. Carabello, John P. Erwin, Federico Gentile, Hani Jneid, Eric V. Krieger, Michael Mack, Christopher McLeod, Patrick T. O’Gara, Vera H. Rigolin, Thoralf M. Sundt, Annemarie Thompson, Christopher Toly
Journal: Circulation (2020)
Incorporation of a Biocompatible Nanozyme in Cellular Antioxidant Enzyme Cascade Reverses Huntington's Like Disorder in Preclinical Model
Authors: Aniruddha Adhikari, Susmita Mondal, Monojit Das, Pritam Biswas, Uttam Pal, Soumendra Darbar, Siddhartha Sankar Bhattacharya, Debasish Pal, Tanusri Saha‐Dasgupta, Anjan Kumar Das, Asim Kumar Mallick, Samir Kumar Pal
Journal: Advanced Healthcare Materials (2020)

Abstract The potentiality of nano‐enzymes in therapeutic use has directed contemporary research to develop a substitute for natural enzymes, which are suffering from several disadvantages including low stability, high cost, and difficulty in storage. However, inherent toxicity, inefficiency in the physiological milieu, and incompatibility to function in cellular enzyme networks limit the therapeutic use of nanozymes in living systems. Here, it is shown that citrate functionalized manganese‐based biocompatible nanoscale material (C‐Mn 3 O 4 NP) efficiently mimics glutathione peroxidase (GPx) enzyme in the physiological milieu and easily incorporates into the cellular multienzyme cascade for H 2 O 2 scavenging. A detailed computational study reveals the mechanism of the nanozyme action. The in vivo therapeutic efficacy of C‐Mn 3 O 4 nanozyme is further established in a preclinical animal model of Huntington's disease (HD), a prevalent progressive neurodegenerative disorder, which has no effective medication to date. Management of HD in preclinical animal trial using a biocompatible (non‐toxic) nanozyme as a part of the metabolic network may uncover a new paradigm in nanozyme based therapeutic strategy.
MBRS-02. BET BROMODOMAIN PROTEIN-KINASE INHIBITOR COMBINATIONS FOR THE TREATMENT OF MEDULLOBLASTOMA
Authors: Nagi Ayad, Robert Suter, David Robbins, Martine Roussel
Journal: Neuro-Oncology (2020)

Abstract Recent sequencing studies have implicated many epigenetic regulators in medulloblastoma. The epigenetic reader protein Brd4 has been implicated in various cancers including medulloblastoma. Brd4 controls expression of the medulloblastoma essential genes MYC in G3 medulloblastomas, which have poor prognosis as well as GLI1 and GLI2 levels in Sonic hedgehog (SHH) driven medulloblastomas, which have intermediate prognosis. Highly selective Brd4 inhibitors have been developed that reduce MYC, GLI1 and GLI2 levels. These inhibitors have gone into clinical trials for multiple cancer indications including medulloblastoma. However, resistance is common for Brd4 inhibitors warranting combination therapies for improved clinical outcome. We have developed a computational pipeline termed SynergySeq that predicts patient specific combinations of Brd4 inhibitors along with kinase inhibitors. We demonstrate that Brd4-kinase inhibitors robustly reduce proliferation of Shh and MYC driven medulloblastoma cells. Improved efficacy is related to dampening the adaptive kinome reprogramming response that occurs after Brd4 inhibition. Our findings suggest that SynergySeq can be utilized to inform patient selection for clinical trials utilizing Brd4 inhibitors in medulloblastoma and other brain tumors.
Epidemiologic Trends in Fatal and Nonfatal Firearm Injuries in the US, 2009-2017
Authors: Elinore J. Kaufman, Douglas J. Wiebe, Ruiying Aria Xiong, Christopher N. Morrison, Mark J. Seamon, M. Kit Delgado
Journal: JAMA Internal Medicine (2020)

Firearm injury research in the US has focused on fatal injuries. The incidence and epidemiologic factors associated with nonfatal firearm injuries are less understood.To evaluate estimates of incidence and trends over time of fatal and nonfatal firearm injuries.A cross-sectional, ecologic study was conducted using data throughout the US from 2009 to 2017. Data on fatal injuries from the Centers for Disease Control and Prevention were combined with national data on emergency department visits for nonfatal firearm injury from the Nationwide Emergency Department (ED) sample. Data analysis was conducted from August 2019 to September 2020.Firearm injuries identified with International Classification of Diseases external cause of injury codes and categorized by intent of injury, age group, and urban-rural location.Incidence, case fatality rate, and trends over time of firearm injury according to intent, age group, and urban-rural location.From 2009 to 2017, there was a mean of 85 694 ED visits for nonfatal firearm injury and 34 538 deaths each year. An annual mean of 26 445 deaths (76.6%) occurred outside of the hospital. Assault was the most common overall mechanism (38.9%), followed by unintentional injuries (36.9%) and intentional self-harm (19.6%). Self-harm, which accounted for 21 128 deaths (61.2%), had the highest case fatality rate (89.4%; 95% CI, 88.5%-90.4%), followed by assault (25.9%; 95% CI, 23.7%-28.6%) and legal intervention (23.4%; 95% CI, 21.6%-25.5%). Unintentional injuries were the most common nonfatal injuries (43 729 [51.0%]) and had the lowest case fatality rate (1.2%; 95% CI, 1.1%-1.3%). Self-harm deaths, 87.8% of which occurred outside the hospital, increased in all age groups in both rural and urban areas during the study period and were most common among people aged 55 years and older. The rate of fatal assault injuries was higher in urban than in rural areas (16.6 vs 9.0 per 100 000 per year) and highest among people aged 15 to 34 years (38.6 per 100 000 per year). Rates of unintentional injury were higher in rural than in urban areas (18.5 per 100 000 vs 12.4 per 100 000).In this cross-sectional study, suicide appears to be the most common cause of firearm injury death in the US, and most people who die from suicide never reach the hospital. These findings suggest that assaults and unintentional injuries account for most nonfatal and overall firearm injuries and for most of the injuries that are treated in hospitals.
EPID-17. THE RELATIONSHIP OF HORMONE EXPOSURE IN BREAST CANCER AND SUBSEQUENT RISK OF HIGH GRADE GLIOMAS
Authors: Carlos Lopez-Garcia, Victor Lopez-Rivera, Antonio Dono, Leomar Y Ballester, Yoshua Esquenazi
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Women have a lower incidence of high grade gliomas (HGGs), which is thought to be related to sex differences and hormone exposure. The association between hormone dependent tumors in women and HGGs remains poorly investigated. METHODS The Surveillance, Epidemiology, and End Results (SEER) database of 18 Registries (2000–2017) was used to assess age-adjusted incidence rates and temporal trends of breast cancer (BC) and HGG. Female BC patients 18 years of age or older and with ductal or lobular BC were then assessed for the risk of subsequent HGG, calculated as the standardized incidence ratio (SIR). RESULTS A total of 976,134 patients diagnosed with BC between 2000–2017 were identified. The temporal trend of BC and HGG incidence rates remained comparable throughout the study, with a higher incidence of BC and lower incidence of HGGs in females. Female BC patients had a 22% lower risk of developing a HGG (SIR 0.78 [0.69–0.87], p&amp;lt; 0.05) compared to general population. HGG risk by age groups in BC females was significant, with a lower risk found in pre-menopausal women (Ages 18–50, SIR 0.66 [0.45–0.94] vs Ages 50+ SIR 0.79 [0.70–0.89], p&amp;lt; 0.05 for both). Among HGG tumors, a decreased risk of developing glioblastoma (SIR 0.83 [0.75–0.93], p&amp;lt; 0.05) and anaplastic astrocytoma (SIR 0.58 [0.35–90, p&amp;lt; 0.05), was found, but not for anaplastic oligodendrogliomas. CONCLUSIONS The findings of our study allude to the protective effect of hormone exposure in the development of HGGs, as shown by the lower risk in female patients with BC compared to the general population.
Abstract 10629: Maternal Obesity and Gestational Diabetes Affect Child Body Composition but Are Not Related With Offspring Left Ventricle Mass 6 Years Postpartum
Authors: Linda Litwin, Johnny K Sundholm, Kristiina Rönö, Saila B Koivusalo, Johan G Eriksson, Taisto Sarkola
Journal: Circulation (2018)

Introduction: Increasing prevalence of maternal obesity and gestational diabetes (GDM) is associated with offspring early weight gain and affects long-term cardiovascular risk. Fetal programming ha...
TMOD-16. A NOVEL ADENOVIRAL-PERMISSIVE, IMMUNOCOMPETENT HAMSTER GLIOMA MODEL TO EVALUATE ONCOLYTIC ADENOVIRAL THERAPY
Authors: Lynette Phillips, Joy Gumin, Shoudong Li, Marc Daou, Daniel Ledbetter, Anwar Hossain, Brittany Parker Kerrigan, Candelaria Gomez-Manzano, Juan Fueyo, Frederick Lang
Journal: Neuro-Oncology (2020)

Abstract Oncolytic adenoviruses, including Delta-24-RGD, target tumors by direct tumor cell oncolysis and by activation of an anti-tumor immune response. Due to the species selectivity of oncolytic adenoviruses, there is currently no single preclinical animal model of glioma that supports viral replication, tumor oncolysis, and virus-mediated immune responses. To address this gap, we took advantage of the Syrian hamster to develop the first glioma model that is both adenovirus replication-permissive and immunocompetent. Hamster glioma stem-like cells (GSCs), transformed by forced expression of hTERT, SV40 large T antigen, and h-RasV12, reproducibly form intracranial tumors in hamsters. In vitro, electron microscopy and cytopathic effect assays demonstrated that hamster GSCs supported viral replication and were susceptible to Delta-24-RGD-mediated cell death. In vivo, hamster GSCs consistently developed into highly proliferative tumors resembling high-grade gliomas. Following intratumoral delivery of Delta-24-RGD, immunohistochemistry for viral proteins demonstrated viral infectivity and replication in hamster gliomas. Flow cytometry revealed increased T cell infiltration in Delta-24-RGD-infected tumors. Delta-24-RGD treatment of tumor-bearing hamsters led to significantly increased survival compared with hamsters treated with PBS. Using this model, we evaluated the effects of corticosteroid-mediated immunosuppression on Delta-24-RGD efficacy. Dexamethasone treatment significantly decreased peripheral blood lymphocytes, decreased tumor-infiltrating lymphocytes, and suppressed the levels of serum anti-adenovirus antibodies. Dexamethasone reduced the number of long-term survivors and decreased the median survival (50 days for Delta-24-RGD + dexamethasone vs undetermined for Delta-24-RGD alone). In summary, we have developed the first adenovirus-permissive, immunocompetent hamster glioma model, addressing a critical need for a model in which to study the role of direct oncolysis in driving immune mediated viral clearance versus driving an antiglioma immune response. Understanding these mechanisms is critical to optimizing the success of oncolytic adenoviral therapy in the clinic.
DDEL-10. A NANOPARTICLE PLATFORM FOR INTRATHECAL DELIVERY OF THE HISTONE DEACETYLASE INHIBITOR (HDACi) PANOBINOSTAT IN METASTATIC OR RECURRENT MEDULLOBLASTOMA
Authors: Sauradip Chaudhuri, Afroz S Mohammad, Wenqui Zhang, Cassandra Baker, Colton W Broughton, Martha J Fowler, Sarah E Stabenfeldt, Robert J Wechsler-Reya, David I Sandberg, William F Elmquist, Rachael W Sirianni
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Panobinostat is a histone deacetylase inhibitor (HDACi) that is a clinical candidate for treatment of pediatric medulloblastoma and diffuse intrinsic pontine glioma. Panobinostat is poorly water-soluble and experiences a number of barriers to effective delivery. Here, we developed a novel drug delivery system consisting of β-cyclodextrin-poly(β-amino ester). These cyclodextrin-networks (CDNs) self-assemble into nanoparticles encapsulating a high quantity of HDACi for slow release. We sought to test the hypothesis that panobinostat-loaded CDNs would demonstrate a differentiated pharmacokinetic profile compared to free panobinostat in mice after direct administration to cerebrospinal fluid. METHODS CDNs were synthesized via Michael addition and engineered to encapsulate a library of HDACi drugs. Nanoparticles were characterized for size, surface charge, loading, controlled release, and stability. CDNs or fluorescent surrogate nanoparticles were administered to the cisterna magna of mice. Tissues were collected for LC-MS/MS (pharmacokinetics [PK]: 1, 4, 8, 24, and 48 hrs) or microscopy (localization: 2, 6, 24, and 48 hrs, 1 and 3 wks). RESULTS Intravital and confocal microscopy demonstrate that nanoparticles distribute rapidly in subarachnoid space and can localize with metastases, persisting for &amp;gt; 3 weeks. Nanoparticle panobinostat is released over weeks and is better tolerated than free drug. CDN-panobinostat delivery tended to be higher in the cerebellum and lower in the spinal cord at both early and late time points compared to freely administered drug. CONCLUSIONS We present a nanoparticle platform for HDACi delivery with a differentiated PK profile in the CSF compared to free drug. Additional PK and therapeutic studies are ongoing.
CTNI-26. ACCELERATOR-BASED BNCT IN RESCUE TREATMENT OF PATIENTS WITH RECURRENT GBM: A MULTICENTER PHASE II STUDY
Authors: Shin-Ichi Miyatake, Shinji Kawabata, Hiromi Goto, Yoshitaka Narita, Minoru Suzuki, Katsumi Hirose, Yoshihiro Takai, Koji Ono, Takanori Ohnishi, Hiroki Tanaka, Takahiro Kato
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Boron neutron capture therapy (BNCT) is tumor-selective particle radiation and theoretically efficacious especially for tumors with infiltrative nature, such as glioblastoma (GBM). The aim of this study is to assess safety and efficacy of accelerator-based BNCT (AB-BNCT) using cyclotron-based neutron generator, BNCT30, and 10B-boronophenylalanine (borofalan(10B)) agent, SPM-011, in patients with recurrent malignant gliomas, chiefly GBM. METHODS The multi-institutional open-label, phase II clinical trial for recurrent 27 cases of malignant gliomas (MG) (24 cases were GBM) was conducted with above AB-BNCT system, using 500mg/kg of SPM-011 (study code, JG002). The patients were enrolled from February 2016 to June 2018. The inclusion criteria are bevacizumab-naïve MG, recurrent after standard treatment composed of XRT and chemotherapy with TMZ. Neutron-irradiation time were determined not to exceed to 8.5 Gy-Eq for scalp dose. Primary endpoint was 1-year survival rate and secondary ones were median overall survival (mOS), median progression free survival (mPFS). The results were compared to previous Japanese domestic bevacizumab trial for recurrent GBM (JO22506) which had the similar inclusion criteria with JG002. RESULTS 1-year survival rate and mOS of recurrent GBM cases in JG002 was 79.2% (95% CI:57.0–90.8) and 18.7 months (95% CI:12.9–23.4) respectively, while those of JO22506 was 34.5% (90% CI:20.0–49.0) and 10.5 months (95% CI:8.2–12.4), respectively. Median PFS of JG002 and JO22506 were 0.9 and 3.3 months, respectively. Most important adverse event in JG002 was brain edema. Brain edema in 21 out of 27 cases was treated with bevacizumab after progress disease. CONCLUSIONS AB-BNCT demonstrated acceptable safety and prolonged survival for recurrent MG chiefly GBM. AB-BNCT might produce brain edema somewhat after the treatment, which might be the unavoidable adverse event of re-irradiation for recurrent MG, however that seemed to be controlled well with bevacizumab.
Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development
Authors: George F. Koob
Journal: Pharmacological Reviews (2020)

Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and γ-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development. <h3>Significance Statement</h3> The focus of this review is on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the drug addiction cycle and a driving force for negative reinforcement in addiction. Medications and behavioral therapies that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis would be promising new targets for medication development.
MBRS-60. THE ACTIONABLE GENOMIC LANDSCAPE OF RELAPSED MEDULLOBLASTOMA IS DEFINED BY MAINTENANCE AND ACQUISITION OF DRIVER EVENTS
Authors: Stacey Richardson, Rebecca M Hill, Christopher Kui, Janet C Lindsey, Yura Grabovska, Edward C Schwalbe, Debbie Hicks, Daniel Williamson, Stephen Crosier, Abjhit Joshi, Stephen B Wharton, Jordan Hansford, Barry Pizer, Maria Vinci, Angela Mastronuzzi, Andrea Carai, Anthony Michalski, Thomas S Jacques, Simon Bailey, Steven C Clifford
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma relapse (rMB) occurs in 30–40% of patients and is almost universally fatal. Understanding the genomic landscape of rMB, and its relationship to disease characteristics at diagnosis, will be essential to underpin the development of improved therapeutic strategies, delivered at both diagnosis and relapse. Utilising NGS and Illumina DNA methylation arrays, we interrogated the molecular landscape of &amp;gt;100 rMBs, alongside matched diagnostic samples (n&amp;gt;80), encompassing molecular subgroup, novel subtypes, copy number (CNV) and mutational variants. Molecular subgroup and novel subtypes were stable over disease-course. The majority of genomic aberrations were also maintained (total arm-level CNVs at relapse, 60% maintained/40% acquired; deleterious/driver mutations, 75% maintained/25% acquired). Importantly, however, the landscape of alterations differed markedly at relapse, through both selective maintenance and acquisition of specific gene and pathway aberrations. For instance, we observed significant enrichment of subgroup-specific events at relapse, including focal CDK6/CDK14 amplifications (4/26 (15%) of MBGroup4) and CDKN2A/CDKN2B deletions (3/48 (6%) of MBSHH). In contrast, mutations in DNA damage response pathways were commonly enriched across all molecular subgroups, most significantly in MBSHH (~40% of rMBSHH; TP53, 9/36 (25%); ATM, 5/36 (14%)). Driver events in rMB are characterised by both selective maintenance and acquisition across disease-course, and together combine to define its actionable genetic landscape. Evaluation of their clinical and biological significance will be essential to establish their potential (i) as biomarkers to direct disease management and (ii) as a basis for therapeutic strategies targeted against medulloblastoma relapse.
Diagnosis and Management of Monoclonal Gammopathy and Smoldering Multiple Myeloma
Authors: Timothy M. Schmidt, Natalie S. Callander
Journal: Journal of the National Comprehensive Cancer Network (2020)

The presence of monoclonal proteins is common, with a prevalence in the United States around 5% that increases with age. Although most patients are asymptomatic, most cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma. In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to myeloma. This review summarizes the current diagnosis treatment guidelines for MGUS and SMM and highlights recent advances that underscore a shifting paradigm in the evaluation and management of plasma cell precursor conditions.