tbuckley/cabot-search huggingface dataset:
SURG-40. SURGICAL RESECTIONS IN BROCA’S AREA DO NOT LEAD TO BROCA’S APHASIA
Authors: John Andrews, Nathan Cahn, Benjamin Speidel, Valerie Lu, Mitchel Berger, Edward Chang
Journal: Neuro-Oncology (2020)

Abstract Brodmann’s areas 44/45 of the inferior frontal gyrus (IFG), are the seat of Broca’s area. The Western Aphasia Battery is a commonly used language battery that diagnoses aphasias based on fluency, comprehension, naming and repetition. Broca’s aphasia is defined as low fluency (0-4/10), retained comprehension (4-10/10), and variable deficits in repetition (0-7.9/10) and naming (0-8/10). The purpose of this study was to find anatomic areas associated with Broca’s aphasia. Patients who underwent resective brain surgery in the dominant hemisphere were evaluated with standardized language batteries pre-op, POD 2, and 1-month post-op. The resection cavities were outlined to construct 3D-volumes of interest. These were aligned using an affine transformation to MNI brain space. A voxel-based lesion-symptom mapping (VLSM) algorithm determined areas associated with Broca’s aphasia when incorporated into a resection. Post-op MRIs were reviewed blindly and percent involvement of pars orbitalis, triangularis and opercularis was recorded. 287 patients had pre-op and POD 2 language evaluations and 178 had 1 month post-op language evaluation. 82/287 patients had IFG involvement in resections. Only 5/82 IFG resections led to Broca’s aphasia. 11/16 patients with Broca’s aphasia at POD 2 had no involvement of IFG in resection. 35% of IFG resections were associated with non-specific dysnomia and 36% were normal. By one-month, 76% of patients had normal speech. 80% of patients with Broca’s aphasia at POD 2 improved to normal speech at 1-month, with 20% improved to non-specific dysnomia. The most highly correlated (P&amp;lt; 0.005) anatomic areas with Broca’s aphasia were juxta-sylvian pre- and post-central gyrus extending to supramarginal gyrus. While Broca’s area resections were rarely associated with Broca’s aphasia, juxta-sylvian pre- and post-central gyri extending to the supramarginal gyrus were statistically associated with Broca’s type aphasia when resected. These results have implications for planning resective brain surgery in these presumed eloquent brain areas.
Neutrophil recruitment and leukocyte response following focused ultrasound and microbubble mediated blood-brain barrier treatments
Authors: Charissa Poon, Carly Pellow, Kullervo Hynynen
Journal: Theranostics (2020)

Rationale: Delivery of therapeutic agents to the brain is limited by the presence of the blood-brain barrier (BBB). An emerging strategy to temporarily and locally increase the permeability of the BBB is the use of transcranial focused ultrasound (FUS) and systematically injected microbubbles (MBs). FUS+MB BBB treatments cause an acute inflammatory response, marked by a transient upregulation of pro-inflammatory genes; however, the cellular immune response remains unknown. Methods: FUS+MB BBB treatments were monitored in real-time using two-photon fluorescence microscopy and transgenic EGFP Wistar rats, which harbour several fluorescent cell types. Leukocyte identification and counts were confirmed using magnetic resonance imaging-guided FUS+MB BBB treatments. Participation of leukocytes in reducing β-amyloid pathology following repeated FUS+MB BBB treatments was investigated in the TgCRND8 mouse model of Alzheimer's disease. Results: Intravascular leukocyte activity indicative of acute inflammation were identified, including transendothelial migration, formation of cell aggregates, and cell masses capable of perturbing blood flow. Leukocyte responses were only observed after the onset of sonication. Neutrophils were identified to be a key participating leukocyte. Significantly more neutrophils were detected in the sonicated hemisphere compared to the contralateral hemisphere, and to untreated controls. Three to five biweekly FUS+MB BBB treatments did not induce significantly more neutrophil recruitment, nor neutrophil phagocytosis of β-amyloid plaques, in TgCRND8 mice compared to untreated controls. Conclusions: This study provides evidence that the cellular aspect of the peripheral immune response triggered by FUS+MB BBB treatments begins immediately after sonication, and emphasizes the importance for further investigations to be conducted to understand leukocyte dynamics and cerebral blood flow responses to FUS+MB BBB treatments.
RARE-02. POLYAMINE PATHWAY INHIBITION IS A POTENT NOVEL THERAPEUTIC STRATEGY AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Aaminah Khan, Laura Gamble, Dannielle Upton, Denise Yu, Ruby Pandher, Chelsea Mayoh, Mark R Burns, Murray D Norris, Michelle Haber, Maria Tsoli, David S Ziegler
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive paediatric brainstem tumour, with a median survival of less than 1 year. Polyamines are intracellular polycations that control important aspects of cell growth and are often upregulated in cancer. Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1) which is a key driver of polyamine synthesis. We investigated the efficacy of polyamine pathway inhibitors as a therapeutic strategy against DIPG. We found that there were high over-expression levels of polyamine synthetic enzymes from DIPG primary patient samples and neurosphere cultures. Using alamar blue cytotoxicity and soft-agar clonogenic assays, we found that DFMO inhibited the proliferation of DIPG neurospheres. However, DIPG cells compensated for DFMO inhibition by increasing expression of the polyamine transporter SLC3A2 and subsequently uptake of polyamines. Addition of polyamine transporter inhibitor AMXT 1501 to DFMO led to synergistic inhibition of DIPG proliferation in vitro. Consistent with the in vitro results, the combination of DFMO and AMXT 1501 significantly prolonged the survival of mice bearing 3 different DIPG orthografts with at least 2/3 of the animals surviving up to 160 days. Addition of irradiation further improved the survival of mice treated with DFMO and AMXT 1501. Differential expression analysis showed that the polyamine transporter, SLC3A2, was significantly overexpressed in DIPG and other paediatric brain tumours including high grade gliomas compared with normal brain tissue. Our results suggest that DIPG tumours are exquisitely sensitive to polyamine inhibitors, and that dual blockade of polyamine synthesis and transport is a promising novel therapeutic strategy. AMXT 1501 is currently in clinical development, and following completion of an adult Phase 1 trial, a clinical trial of AMXT 1501 + DFMO for DIPG patients is planned through the CONNECT consortium.
Impact of Myocardial Scar on Prognostic Implication of Secondary Mitral Regurgitation in Heart Failure
Authors: Bhupendar Tayal, Dany Debs, Faisal Nabi, Maan Malahfji, Stephen H. Little, Michael Reardon, William Zoghbi, Neal Kleiman, Dipan J. Shah
Journal: JACC. Cardiovascular imaging (2020)
Autophagy protects tumors from T cell–mediated cytotoxicity via inhibition of TNFα-induced apoptosis
Authors: Tara M. Young, Claudia Reyes, Elizabeth Pasnikowski, Carla Castanaro, Chung Wong, Corinne E. Decker, Joyce Chiu, Hang Song, Yi Wei, Yu Bai, Brian Zambrowicz, Gavin Thurston, Christopher Daly
Journal: Science Immunology (2020)

Autophagy reduces tumor cell sensitivity to T cell killing; thus, inhibiting autophagy may improve T cell–engaging therapies.
RADT-04. RESECTION CAVITY FAILURE OF MELANOMA BRAIN METASTASES WHEN TREATED WITH SYSTEMIC THERAPY, WITH OR WITHOUT FOCAL RADIOTHERAPY
Authors: Matthew S Susko, Harish N Vasudevan, Lijun Ma, Jean Nakamura, David Raleigh, Lauren Boreta, Shannon Fogh, Philip Theodosopoulos, Michael McDermott, Katy Tsai, Penny Sneed, Steve Braunstein
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES Brain metastases are a common sequelae of advanced melanoma, and can lead to significant morbidity and mortality. Systemic therapy, inclusive of BRAF/MEK inhibitors and immunotherapy, are increasingly being utilized for metastatic melanoma brain metastases. This study sought to evaluate the clinical outcomes of resected melanoma brain metastases treated with systemic therapy, with or without focal radiotherapy. METHODS Patients at a single institution who underwent resection of a melanoma brain metastasis were retrospectively identified and reviewed. Patients were required to have received immunotherapy or BRAF/MEK inhibitors in the 3-month perioperative time period. This cohort was then analyzed by receipt of focal radiotherapy, including SRS and brachytherapy, for resection cavity failure, distant CNS progression, and adverse radiation effect, using the Kaplan Meier method. RESULTS From 2011-2020, 43 resections for melanoma brain metastases were performed, of which 29 patients and 37 resection cavities met criteria for analysis. Median MRI follow up was 15 months (IQR: 6-38). Twenty-two (59%) lesions were treated with focal radiotherapy and systemic therapy, and 15 (41%) were treated with systemic therapy alone. 12-month freedom from local recurrence was 64.8% (95% CI: 42.1-99.8%) for systemic therapy alone, and 93.3% (95% CI: 81.5-100%) for focal radiotherapy with systemic therapy (p=0.01). 12-month CNS progression free survival was 35.7% (95% CI: 17.7-72.1%) for systemic therapy alone, and 31.8% (95% CI: 17.3-58.7%) for focal radiotherapy (p=0.51). UVA demonstrated focal radiotherapy (HR: 0.10; 95% CI: 0.01-0.85; p=0.04) was the only significant factor associated with reduction of risk for surgical cavity recurrence. CONCLUSIONS Use of focal radiotherapy with systemic therapy for resected melanoma brain metastases significantly reduced surgical cavity recurrence compared to systemic therapy alone. Focal radiotherapy did not delay initiation of systemic therapy and should be the preferred treatment option for optimal local control of the surgical cavity in melanoma brain metastases.
DIPG-78. REVERTANCE OF THE H3K27M MUTATION RESCUES CHROMATIN MARKS NECESSARY FOR ONCOGENESIS IN DIFFUSE MIDLINE GLIOMA
Authors: Cody Nesvick, Charles Day, Liang Zhang, Edward Hinchcliffe, David Daniels
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline glioma (DMG) is a lethal brain tumor that typically occurs in children. Numerous studies have demonstrated the central role of the H3K27M mutation and secondary loss of H3K27 trimethylation (H3K27me3) in DMG tumorigenesis. Understanding how the H3K27M mutation alters the epigenetic landscape of the cell is necessary for revealing molecular targets that are critical to tumorigenesis. To investigate the epigenetic effects of H3K27M mutation in DMG, we developed revertant DMG cell lines with the mutant methionine residue reverted to wildtype (i.e., M27K). Revertant cells were analyzed for epigenetic changes and phenotypic differences in vitro and in vivo. H3M27K DMG cells grew in culture but displayed diminished proliferative capacity. H3M27K cells demonstrated total loss of H3K27M expression and restored trimethylation of H3K27 and H3K4. Furthermore, consistent with the hypothesis that the H3K27M mutation impacts H3 phosphorylation via expression of Aurora Kinase during mitosis, H3M27K cells demonstrated reduced expression of both Aurora Kinase A and phosphorylation of H3 serine residues 10 and 28. In line with the critical role of H3S10 phosphorylation in chromatin segregation, H3M27K cells also demonstrated restored chromosome segregation compared to H3K27M cells. In vivo data will be discussed. Revertance of the H3K27M mutation reduces tumorigenesis in DMG tumors. Isogenic H3M27K cells display reversal of key epigenetic changes associated with oncogenesis in DMG. The revertant H3M27K DMG model is a useful tool to investigate the downstream epigenetic reprogramming specific to H3K27M mutation in these tumors.
75P Efficacy and updated safety results from pivotal phase II trial 201 of naxitamab (Hu3F8): A humanized GD2-targeted immunotherapy for the treatment of refractory/relapsed (R/R) high-risk (HR) neuroblastoma (NB)
Authors: J. Mora, G.C. Chan, D.A. Morgenstern, K. Nysom, M. Bear, L. Worsaae Dalby, S. Lisby, B.H. Kushner
Journal: Annals of Oncology (2020)
Polymeric Nitric Oxide Delivery Nanoplatforms for Treating Cancer, Cardiovascular Diseases, and Infection
Authors: Guorui Jin, Zhiyuan Gao, Yangjing Liu, Jing Zhao, Hanlin Ou, Feng Xu, Dan Ding
Journal: Advanced Healthcare Materials (2020)

The shortened Abstract is as follows: Therapeutic gas nitric oxide (NO) has demonstrated the unique advances in biomedical applications due to its prominent role in regulating physiological/pathophysiological activities in terms of vasodilation, angiogenesis, chemosensitizing effect, and bactericidal effect. However, it is challenging to deliver NO, due to its short half-life (<5 s) and short diffusion distances (20-160 µm). To address these, various polymeric NO delivery nanoplatforms (PNODNPs) have been developed for cancer therapy, antimicrobial and cardiovascular therapeutics, because of the important advantages of polymeric delivery nanoplatforms in terms of controlled release of therapeutics and the extremely versatile nature. This reviews highlights the recent significant advances made in PNODNPs for NO storing and targeting delivery. The ideal and unique criteria that are required for PNODNPs for treating cancer, cardiovascular diseases and infection, respectively, are summarized. Hopefully, effective storage and targeted delivery of NO in a controlled manner using PNODNPs could pave the way for NO-sensitized synergistic therapy in clinical practice for treating the leading death-causing diseases.
Transaminase Elevation As a Marker of Liver GVHD Is Associated with Poor Survival Among Allogeneic Stem Cell Transplant Recipients
Authors: Dipenkumar Modi, Wei Chen, Hyejeong Jang, Abhinav Deol, Lois Ayash, Asif Alavi, Divaya Bhutani, Voravit Ratanatharathorn, Joseph P. Uberti
Journal: Blood (2017)
Assessing the Role of Rare Genetic Variation in Patients With Heart Failure
Authors: Gundula Povysil, Olympe Chazara, Keren J. Carss, Sri V. V. Deevi, Quanli Wang, Javier Armisen, Dirk S. Paul, Christopher B. Granger, John Kjekshus, Vimla Aggarwal, Carolina Haefliger, David B. Goldstein
Journal: JAMA Cardiology (2020)

Sequencing studies have identified causal genetic variants for distinct subtypes of heart failure (HF) such as hypertrophic or dilated cardiomyopathy. However, the role of rare, high-impact variants in HF, for which ischemic heart disease is the leading cause, has not been systematically investigated.To assess the contribution of rare variants to all-cause HF with and without reduced left ventricular ejection fraction.This was a retrospective analysis of clinical trials and a prospective epidemiological resource (UK Biobank). Whole-exome sequencing of patients with HF was conducted from the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) and Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) clinical trials. Data were collected from March 1999 to May 2003 for the CHARM studies and September 2003 to July 2007 for the CORONA study. Using a gene-based collapsing approach, the proportion of patients with HF and controls carrying rare and presumed deleterious variants was compared. The burden of pathogenic variants in known cardiomyopathy genes was also investigated to assess the diagnostic yield. Exome sequencing data were generated between January 2018 and October 2018, and analysis began October 2018 and ended April 2020.Odds ratios and P values for genes enriched for rare and presumed deleterious variants in either patients with HF or controls and diagnostic yield of pathogenic variants in known cardiomyopathy genes.This study included 5942 patients with HF and 13 156 controls. The mean (SD) age was 68.9 (9.9) years and 4213 (70.9%) were male. A significant enrichment of protein-truncating variants in the TTN gene (P = 3.35 × 10-13; odds ratio, 2.54; 95% CI, 1.96-3.31) that was further increased after restriction to variants in exons constitutively expressed in the heart (odds ratio, 4.52; 95% CI, 3.10-6.68). Validation using UK Biobank data showed a similar enrichment (odds ratio, 4.97; 95% CI, 3.94-6.19 after restriction). In the clinical trials, 201 of 5916 patients with HF (3.4%) had a pathogenic or likely pathogenic cardiomyopathy variant implicating 21 different genes. Notably, 121 of 201 individuals (60.2%) had ischemic heart disease as the clinically identified etiology for the HF. Individuals with HF and preserved ejection fraction had only a slightly lower yield than individuals with midrange or reduced ejection fraction (20 of 767 [2.6%] vs 15 of 392 [3.8%] vs 166 of 4757 [3.5%]).An increased burden of diagnostic mendelian cardiomyopathy variants in a broad group of patients with HF of mostly ischemic etiology compared with controls was observed. This work provides further evidence that mendelian genetic conditions may represent an important subset of complex late-onset diseases such as HF, irrespective of the clinical presentation.
The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine — United States, December 2020
Authors: Sara E. Oliver, Julia W. Gargano, Mona Marin, Megan Wallace, Kathryn G. Curran, Mary Chamberland, Nancy McClung, Doug Campos-Outcalt, Rebecca L. Morgan, Sarah Mbaeyi, José R. Romero, H. Keipp Talbot, Grace M. Lee, Beth P. Bell, Kathleen Dooling
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

This report describes the interim recommendation made by the Advisory Committee on Immunization Practices on December 12, 2020, for use of the Pfizer-BioNTech COVID-19 vaccine in persons aged ≥16 years.
<i>QuickStats</i>: Age-Adjusted Lung Cancer Death* Rates,† by State — National Vital Statistics System, United States, 2018
Authors: Sibeso Joyner
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Rate signi cantly higher than U.S. rate Rate not signi cantly di erent from U.S. rate Rate signi cantly lower than U.S. rate DC Abbreviation: DC = District of Columbia.* As underlying cause of death, lung cancer deaths are identified with International Classification of Diseases, Tenth Revision codes C33 and C34.† Deaths per 100,000 population are age-adjusted to the 2000 U.S. standard population, for a U.S. rate of 34.8.In 2018, the age-adjusted lung cancer death rate in the United States was 34.8 per 100,000.Twenty-one states had a higher lung cancer death rate than the national rate, 15 states and DC had lower death rates, and 14 states had rates that were not statistically different from the national rate.Most states with higher death rates were in the Midwest or Southeast.The five states with the highest age-adjusted lung cancer death rates were Kentucky (53.5),West Virginia (50.8),Mississippi (49.6), Arkansas (47.4), and Oklahoma (46.8).The five jurisdictions with the lowest lung cancer death rates were Utah (16.4),New Mexico (22.5),Colorado (23.0), DC (24.6), and California (25.0).
NIMG-14. MACHINE LEARNING-BASED EVALUATION OF STATIC AND DYNAMIC FET-PET FOR THE DETECTION OF PSEUDOPROGRESSION IN PATIENTS WITH IDH-WILDTYPE GLIOBLASTOMA
Authors: Sied Kebir, Teresa Schmidt, Matthias Weber, Lazaros Lazaridis, Norbert Galldiks, Karl-Josef Langen, Christoph Kleinschnitz, Elke Hattingen, Ulrich Herrlinger, Philipp Lohmann, Martin Glas
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pseudoprogression (PSP) detection in glioblastoma has important clinical implications and remains a challenging task. With the significant advances provided by machine learning (ML) in health care, we investigated the potential of ML in improving the performance of PET using O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) for differentiation of tumor progression from PSP in IDH-wildtype glioblastoma. METHODS We retrospectively evaluated the PET data of patients with newly diagnosed IDH-wildtype glioblastoma following chemoradiation. All patients presented imaging findings suspected of PSP/TP on contrast-enhanced MRI. For further diagnostic evaluation, patients underwent subsequently an additional dynamic FET-PET scan. The modified Response Assessment in Neuro-Oncology (RANO) criteria served to diagnose PSP. To develop a robust ML model, we trained a Linear Discriminant Analysis (LDA)-based classifier using FET-PET derived features on a training cohort and validated the results on a separate test cohort. The results of the ML model were compared with a conventional FET-PET analysis using the receiver-operating-characteristic (ROC) curve. RESULTS Of the 44 patients included in this study, 14 patients were diagnosed with PSP. The mean (TBRmean) and maximum tumor-to-brain ratios (TBRmax) were significantly higher in the TP group as compared to the PSP group (p=0.010 and p=0.047, respectively). The area under the ROC curve (AUC) for TBRmax and TBRmean was 0.68 and 0.74, respectively. Using the LDA-based algorithm, the AUC (0.93) was significantly higher than the AUC for TBRmax. CONCLUSIONS This study shows that in IDH-wildtype glioblastoma, ML-based PSP detection leads to better diagnostic performance compared to conventional ROC analysis.
DDEL-09. HIGH DOSE MTX110 (SOLUBLE PANOBINOSTAT) SAFELY ADMINISTERED INTO THE FOURTH VENTRICLE IN A NON-HUMAN PRIMATE MODEL
Authors: Rachael W Sirianni, Natasha Kharas, Bangning Yu, Christopher F Janssen, Amanda Trimble, Leomar Y Ballester, Rajan Patel, Afroz S Mohammad, William F Elmquist, David I Sandberg
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE This study tested the safety and pharmacokinetics of short-term and long-term administration of MTX110 (soluble panobinostat; Midatech Pharma, UK) into the fourth ventricle of non-human primates. METHODS Four rhesus macaque monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In Group I (n=2), catheters were externalized and lumbar drain catheters were placed simultaneously to assess cerebrospinal fluid (CSF) distribution after short-term infusions. MTX110 (0.5 ml of 300 μM panobinostat solution) was infused into the fourth ventricle daily for five consecutive days. Serial CSF and serum panobinostat levels were measured. In Group II (n=2), fourth ventricle catheters were connected to a subcutaneously-placed port for subsequent long-term infusions. Four cycles of MTX110, each consisting of 5 daily infusions (0.5 ml of 300 μM panobinostat solution), were administered over 8 weeks. Animals underwent detailed neurological evaluations, MRI scans, and post-mortem histological analysis. RESULTS Neurological assessments, MRI, and histology confirmed catheter placement and an absence of neurotoxicity. Panobinostat was undetectable in serum collected two and four hours after infusions in all samples in both groups. In Group I, mean peak panobinostat level in fourth ventricle CSF (6242 ng/ml) was significantly higher than in lumbar CSF (9 ng/ml; p &amp;lt; 0.0001). In Group II, mean peak CSF panobinostat level (11,042 ng/ml) was significantly higher than mean trough CSF level (33 ng/ml; p&amp;lt;0.0001). CONCLUSION MTX110 can be safely delivered via 4th ventricle at supra-therapeutic doses. These results provide data for a pilot clinical trial in patients with recurrent medulloblastoma.