tbuckley/cabot-search huggingface dataset:
Mobilization of pre-existing polyclonal T cells specific to neoantigens but not self-antigens during treatment of a patient with melanoma with bempegaldesleukin and nivolumab
Authors: Joshua R Veatch, Naina Singhi, Brenda Jesernig, Kelly G Paulson, Jonathan Zalevsky, Ernesto Iacucci, Scott S Tykodi, Stanley R Riddell
Journal: Journal for ImmunoTherapy of Cancer (2020)

T cells that recognize self-antigens and mutated neoantigens are thought to mediate antitumor activity of immune checkpoint blockade (ICB) in melanoma. Few studies have analyzed self and neoantigen-specific T cell responses in patients responding to ICB. Here, we report a patient with metastatic melanoma who had a durable clinical response after treatment with the programmed cell death protein 1 inhibitor, nivolumab, combined with the first-in-class CD122-preferential interleukin-2 pathway agonist, bempegaldesleukin (BEMPEG, NKTR-214). We used a combination of antigen-specific T cell expansion and measurement of interferon-γ secretion to identify multiple CD4 + and CD8 + T cell clones specific for neoantigens, lineage-specific antigens and cancer testis antigens in blood and tumor from this patient prior to and after therapy. Polyclonal CD4 + and CD8 + T cells specific to multiple neoantigens but not self-antigens were highly enriched in pretreatment tumor compared with peripheral blood. Neoantigen, but not self-antigen-specific T cell clones expanded in frequency in the blood during successful treatment. There was evidence of dramatic immune infiltration into the tumor on treatment, and a modest increase in the relative frequency of intratumoral neoantigen-specific T cells. These observations suggest that diverse CD8 + and CD4 + T cell clones specific for neoantigens present in tumor before treatment had a greater role in immune tumor rejection as compared with self-antigen-specific T cells in this patient. Trial registration number: NCT02983045 .
DIPG-49. BRAINSTEM AND PONTINE VOLUMETRIC ANALYSIS AS A SURROGATE MEASURE OF LOCAL DISEASE CONTROL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Evan D Bander, Morgan E Freret, Eva Wembacher-Schroeder, Suzanne L Wolden, Mark M Souweidane
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Response-assessment in pediatric neuro-oncology (RAPNO) criteria designed to describe treatment outcomes are poorly implemented in diffuse intrinsic pontine glioma (DIPG), due to inter-observer variability in measurement of tumor volume, lack of tumor enhancement, and undefined relationships between radiographic parameters and survival. Given these issues, this study assessed whether anatomically defined brainstem and pontine volumes can serve as surrogate measures of local disease burden and response to therapy in DIPG. METHODS Thirty-two consecutive patients with newly diagnosed DIPG were treated with standard definitive radiation therapy (RT) between 2010 and 2016 at a single institution. MRI brain scans throughout treatment course were analyzed using iPlan® Flow software (Brainlab AG, Munich, Germany). Semi-automated 3D measurements of the brainstem and pons were calculated using a built-in knowledge-based segmentation approach and manually adjusted. RESULTS Mean age at diagnosis was 6.5+/-0.5 years (range 2–12 years). Median follow up time was 317 days. Average brainstem volume at diagnosis (Vdiag) was 52.7+/-2.1mL with subsequent decrease at first post-RT MRI to 41.4+/-2.0mL (p &amp;lt; 0.0001). By time of last follow up, brainstem volume increased to 51.9+/-3.3, no longer significantly different as compared to Vdiag (p=0.61). The same relationships were found for pontine volume. CONCLUSIONS Volumetric changes in the brainstem and pons occur in response to treatment and correlate with local disease burden and response to therapy. This surrogate may be a useful standardized measure in ongoing and future trials involving localized delivery of therapeutics in DIPG that require evaluation of local-regional disease control in addition to survival.
Audio Interview: SARS-CoV-2 Vaccination and Vulnerable Populations
Authors: Eric J. Rubin, Lindsey R. Baden, Joshua A. Barocas, Stephen Morrissey
Journal: New England Journal of Medicine (2020)

SARS-CoV-2 Vaccination and Vulnerable Populations In this audio interview conducted on December 9, 2020, the editors are joined by Dr. Joshua Barocas, an infectious disease specialist at Boston Med...
Overexpression of the Multidrug Resistance Protein-4 Transporter in Patients Undergoing Coronary Artery Bypass Graft Surgery: A Cause of Aspirin Resistance?⁎⁎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: John W. Eikelboom, Graeme J. Hankey
Journal: Journal of the American College of Cardiology (2011)
Frailty is highly prevalent in specific cardiovascular diseases and females, but significantly worsens prognosis in all affected patients: A systematic review
Authors: Nastasia Marinus, Carlo Vigorito, Francesco Giallauria, Laura Haenen, Thomas Jansegers, Paul Dendale, Peter Feys, Raf Meesen, Annick Timmermans, Joke Spildooren, Dominique Hansen
Journal: Ageing Research Reviews (2020)
CTNI-68. EFFICACY OF TTFIELDS IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM) – SUB-GROUP ANALYSIS OF THE EF-14 TRIAL
Authors: Zvi Ram, Chae-Yong Kim, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment that utilizes low intensity alternating electric fields delivered non-invasively to the tumor using a portable medical device. In the EF-14 phase 3 study leading to FDA approval, TTFields significantly extended survival in newly diagnosed GBM when added to maintenance temozolomide (TMZ). Elderly GBM patients usually have worse prognosis and often receive only partial treatment for the disease. This sub-group analysis examined the effects of TTFields in the elderly population (≥65 years of age) enrolled in the EF-14 study. METHODS All 134 elderly patients (≥65 years of age) from the EF-14’s intent-to-treat population were included in the analysis, Overall survival (OS) and progression-free survival (PFS), as well as adverse event frequency and severity were compared between the TMZ/TTFields arm and the TMZ alone arm. RESULTS The median age was 69 (range: 65–83), median KPS was 90%, and 69% were male. Median PFS from randomization was 6.5 months versus 3.9 months in the TMZ/TTFields versus TMZ alone arms, respectively (hazard ratio [HR], 0.47 [95%CI 0.30, 0.74] P&amp;lt; 0.0236). Median OS was 17.4 months versus 13.7 months in the TMZ/TTFields versus TMZ alone arm, respectively (HR 0.51 [CI 0.33, 0.77] P&amp;lt; 0.020). Serious adverse events (SAEs) were reported in 39% of patients treated with TMZ/TTFields and in 33% of patients treated with TMZ alone. None of the SAEs were considered related to TTFields but attributed to TMZ or to the underlying disease. Grades 1–2 skin AEs related to TTFields were observed in 51% of patients. CONCLUSION Consistent with the overall outcome of the EF-14 study, elderly patients treated with TMZ/TTFields showed significantly better OS compared to patients on TMZ alone, and without increase in grade III or IV toxicity.
TBIO-11. DEEP LEARNING-BASED SINGLE-CELL RNA SEQUENCING DIFFERENTIATION IDENTIFIES SIMPLE AND COMPLEX TRANSCRIPTIONAL NETWORKS FOR SUBPOPULATION CLASSIFICATION
Authors: Eric Prince, Todd Hankinson
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Genomic assays capable of cellular resolution (i.e. scRNA-seq) are becoming ubiquitous in biomedical research. Machine learning, and the subtype known as Deep Learning, have broad application within scRNA-seq analytics. However, methods to facilitate the classification of cell populations are lacking. We present the novel computational framework HD Spot, which generates interpretable and robust Deep Learning classifiers that enable unbiased interrogation of linear and non-linear genomic signatures. METHODS HD Spot is written in python and relies on Google’s TensorFlow2 deep learning framework. Four datasets of immune cells were obtained from the publicly available Seurat repository, generated using the 10X chromium platform. Data preprocessing used standard Seurat methodology. HD Spot generated optimized classifiers via a custom platform. Network interpretability was achieved using Shapley values. Ontology analysis was performed using Metascape. RESULTS HD Spot identified meaningful ontologic signatures across all tested datasets. In the binary case of control versus IFN-B stimulated CD4+ T cells, gene ontologies reflected Th0 and Th2 T cell populations, congruent with T cell activation. In the 9-class case of PBMCs, HD Spot identified meaningful gene networks characteristic of the ground-truth populations using raw feature counts alone. When feature counts are processed into expression values, HD Spot demonstrates increased specificity of top genes and respective ontologies between subpopulations. CONCLUSION This work introduces a broadly applicable computational tool for the advanced bioinformatician to decipher complex cellular heterogeneity (e.g., tumors) in an unbiased way. Additionally, HD Spot lowers the barrier for novice bioinformaticists to derive actionable insights from their data.
HGG-17. HIGH-GRADE GLIOMA IN VERY YOUNG CHILDREN; A SINGLE-CENTER 11-YEAR-EXPERIENCE
Authors: Moatasem El-ayadi, Omar Shawky, Eman Naguib, Eslam Maher, Amal Abdelaziz, Soha Ahmed, Amal Refaat, André O von Bueren, Hala Taha, Shahenda El-naggar, Mohamed El-beltagy
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Data about high-grade glioma (HGG) in very young children (≤3 years old at diagnosis) is scarce. METHODS 180 pediatric HGG patients were treated at the Children Cancer Hospital - Egypt (CCHE-57357) between July 2007 and June 2018, with 17 patients aged ≤3 years at diagnosis. Medical records were retrospectively reviewed for clinical, radiological and histopathological data, treatment received and survival outcome. RESULTS Median age was 29.2 months (range: 2.4 – 35.8 months; males = 9). Most frequent pathological diagnosis was Glioblastoma, WHO grade-IV (n = 11, 64.7%) and one patient had H3-mutant diffuse midline glioma. All patients underwent surgery (gross-total resection, n = 6, 35.3%; subtotal-resection, n = 5, 29.4%; biopsy, n = 6, 35.3%). One patient (age = 7 months) progressed and died before starting adjuvant therapy. All patients ≤1 year of age (n = 5) received adjuvant chemotherapy (CT) only, older children (n = 11) received adjuvant radiotherapy (RT) (total dose range: 54 – 60 Gy) and CT (CCG-945 protocol). The 1-year overall survival (OS) rate was 47.1%; and event-free survival (EFS) rate was 35.3%. EFS differed between those who received RT and those who did not (1-year EFS 54.5% and 0% respectively, p = 0.001). Compared to older children, anatomical distribution of tumors was significantly different with non-midline locations being the commonest in patients ≤3 years old (88.2% vs 46.4%, p=0.01). CONCLUSIONS HGG in very young children arise predominantly in non-midline locations and usually lack the H3-mutation. RT seems crucial in the management of pHGG regardless of age subgroup.
Neutrophils Fuel Effective Immune Responses through Gluconeogenesis and Glycogenesis
Authors: Pranvera Sadiku, Joseph A. Willson, Eilise M. Ryan, David Sammut, Patricia Coelho, Emily R. Watts, Robert Grecian, Jason M. Young, Martin Bewley, Simone Arienti, Ananda S. Mirchandani, Manuel A. Sanchez Garcia, Tyler Morrison, Ailing Zhang, Leila Reyes, Tobias Griessler, Privjyot Jheeta, Gordon G. Paterson, Christopher J. Graham, John P. Thomson, Kenneth Baillie, A.A. Roger Thompson, Jessie-May Morgan, Abel Acosta-Sanchez, Veronica M. Dardé, Jordi Duran, Joan J. Guinovart, Gio Rodriguez-Blanco, Alex Von Kriegsheim, Richard R. Meehan, Massimiliano Mazzone, David H. Dockrell, Bart Ghesquiere, Peter Carmeliet, Moira K.B. Whyte, Sarah R. Walmsley
Journal: Cell Metabolism (2020)

Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.
Electronic Health Record Use by Sex Among Physicians in an Academic Health Care System
Authors: Sarah D. Tait, Sachiko M. Oshima, Yi Ren, Alexander E. Fenn, Mina Boazak, Eugenia McPeek Hinz, E. Shelley Hwang
Journal: JAMA Internal Medicine (2020)

high-dose colchicine in the treatment of acute gout. 4 Consistent with the recommendations of the European League Against Rheumatism, low-dose colchicine was found to be equally effective as high-dose drug in the reduction of gouty pain; the rate of gastrointestinal adverse events with lowdose colchicine was one-third that observed with high-dose colchicine.In response to these study findings, the FDA approved Colcrys, which, consequently, became the first colchicine product to ever be approved for the treatment of acute gout.Considering that the Waxman-Hatch Act (https://www.govinfo.gov/content/pkg/STATUTE-98/pdf/STATUTE-98-Pg1585.pdf)resulted in market exclusivity for a newly approved drug, URL Pharma received this benefit.In addition to a period of exclusivity, the manufacturer was able to remove all generic competitors from the market.Upon FDA approval, the manufacturer increased the price of colchicine from what had previously been only a few cents to $5 a tablet.A second colchicine brand-name product (Mitigare) was approved in 2015 at the very conclusion of the 4-year Colcrys monopoly.An additional point considering the study findings 1 is the fact that the potential uses for colchicine currently extend beyond acute gout.The increase in potential indications will likely result in even more demand for this drug.As the authors noted, 1 colchicine has been found to have value in the treatment of pericarditis, as well as prevention of additional cardiovascular complications after myocardial infarction.Currently, the Montreal Heart Institute (NCT04322682) 5 is studying colchicine in the treatment of COVID-19 infection.Early results as of October 2020 suggest that early in-hospital initiation of low-dose colchicine treatment within 3 days of myocardial infarction significantly reduces the risk of future ischemic cardiovascular events.Notably, all the colchicine products used for these indications have been trade products; there have been no approved independent colchicine generics marketed after the approval of Colcrys.Wouters et al 6 estimated the investment required to bring a new medicine to market.The median capitalized research and development investment was estimated to be between $985.3 and $1335.9 million.Such investments inevitably require an appropriate return on investment, which usually translates into a high selling price of the drug.However, such investment and its resultant cost should be associated with potential worth to society.The ideal investment would be a new molecular entity that provides an objective, meaningful improvement in public health.Colchicine does not fit this example.Only a fraction of an investment was required for Colcrys, a product that has provided no increased value and an unnecessary, long-term cost burden to the health care system.The current study findings 1 illustrate that we can never allow such an egregious case to take place again.
Abstract P521: Dairy Consumption and Risk of Cardiovascular Disease and Mortality in the Million Veteran Program
Authors: Omar Al-Ramady, Laura Tarko, Petra Schubert, David R Gagnon, Kelly Cho, John M Gaziano, Luc DJOUSSE
Journal: Circulation (2020)

Background: Dietary habits are a major determinant of cardiovascular disease (CVD) and mortality risk. However, data on the role of dairy intake on the risk of CVD and death has been inconsistent. Objective: The primary objective is to assess whether total consumption of dairy products is associated with a lower risk of CVD and/or total mortality among US Veterans. Methods: In a prospective cohort study of US Veterans from the Million Veteran Program (MVP), dairy intake was collected through a self-reported food frequency questionnaire at baseline. Incidence of composite CVD (including MI, stroke, and cardiovascular death) and total mortality were measured via electronic health records and the National Death Index database. Cox Proportional hazard models were used to compute the multivariable adjusted hazard ratio of CVD and total mortality. Results: A total of 188,833 Veterans were studied with a mean age of 63.3 ± 12.3 years. After a mean follow-up of 3.2 years for CVD and 3.3 years for total mortality, 9,898 cases of CVD and 6,826 deaths occurred. Median dairy consumption was 1.2 servings/day. In a multivariable Cox regression adjusted for age, gender, race, body mass index (BMI), smoking, alcohol use, exercise, diet quality, diabetes mellitus, and level of education; hazard ratios (95% CI) for CVD were 1.00 (0.89-1.14) for dairy intake of 1-2 servings/week, 1.05 (0.92-1.20) for 2-3 servings/week, 1.01 (0.90-1.12) for 3-5 servings/week, 0.97 (0.87-1.08) for 5-7 servings/week, 0.96 (0.87-1.05) for 1-2 servings/day, 1.02 (0.91-1.13) for 2-3 servings/day, 1.02 (0.90-1.15) for 3-4 servings/day, and 1.11 (0.98-1.26) for 4+ servings/day as compared to &lt;1 serving/week. For total mortality, the hazard ratios across consecutive categories of dairy intake were 0.85 (0.73-0.99), 0.83 (0.70-0.99), 0.87 (0.76-0.99), 0.84 (0.74-0.96), 0.94 (0.84-1.06), 1.10 (0.97-1.25), 1.12 (1.04-1.39), and 1.36 (1.18-1.58). Conclusion: Dairy intake was not associated with composite CVD. However, there was suggestive evidence for J-shaped relation of dairy intake with total mortality.
Phylogenetic Analysis of SARS-CoV-2 Data Is Difficult
Authors: Benoit Morel, Pierre Barbera, Lucas Czech, Ben Bettisworth, Lukas Hübner, Sarah Lutteropp, Dora Serdari, Evangelia-Georgia Kostaki, Ioannis Mamais, Alexey M Kozlov, Pavlos Pavlidis, Dimitrios Paraskevis, Alexandros Stamatakis
Journal: Molecular Biology and Evolution (2020)

Numerous studies covering some aspects of SARS-CoV-2 data analyses are being published on a daily basis, including a regularly updated phylogeny on nextstrain.org. Here, we review the difficulties of inferring reliable phylogenies by example of a data snapshot comprising a quality-filtered subset of 8,736 out of all 16,453 virus sequences available on May 5, 2020 from gisaid.org. We find that it is difficult to infer a reliable phylogeny on these data due to the large number of sequences in conjunction with the low number of mutations. We further find that rooting the inferred phylogeny with some degree of confidence either via the bat and pangolin outgroups or by applying novel computational methods on the ingroup phylogeny does not appear to be credible. Finally, an automatic classification of the current sequences into subclasses using the mPTP tool for molecular species delimitation is also, as might be expected, not possible, as the sequences are too closely related. We conclude that, although the application of phylogenetic methods to disentangle the evolution and spread of COVID-19 provides some insight, results of phylogenetic analyses, in particular those conducted under the default settings of current phylogenetic inference tools, as well as downstream analyses on the inferred phylogenies, should be considered and interpreted with extreme caution.
GCT-67. CENTRAL NERVOUS SYSTEM GERMINOMA IN TWO CAUCASIAN AMERICAN SIBLINGS WITH AUTISM SPECTRUM DISORDER
Authors: Stephanie Toll, Hamza Gorsi
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Central nervous system germ cell tumors (CNS-GCT) account for approximately 5% of all pediatric brain tumors. These tumors are pathologically heterogeneous, but have recurrent somatic mutations in KIT and rare germline variants in a Japanese cohort. Chromosomal abnormalities, specifically Klinefelter Syndrome, are associated with increased tumor development and familial cases have been reported, but no germline tumor syndromes are known. We describe a pair of siblings, both with autism spectrum disorder (ASD) that developed CNS-GCT, which previously has not been described outside of Japan. CASES: We report two siblings with ASD who developed CNS germinomas within two months of each other. The older brother, with basal ganglia and hypothalamic tumors, underwent surgical resection followed by treatment per ACNS0232 with chemotherapy and whole-ventricular irradiation (WVI). The younger sibling, with a midbrain tumor, also received ACNS0232, but due to poor response required additional chemotherapy and WVI. Both siblings are without evidence of disease 7 years after end of therapy. Genetic testing, including chromosomal microarray, karyotyping, and whole genome sequencing did not elucidate any variant identified as causative at that time. CONCLUSIONS CNS-GCT are rare tumors, diverse in both histopathologic diagnosis and clinical outcomes. Currently there are known somatic alterations and germline chromosomal disorders associated with increased tumor development, but no known inheritable causes. Despite this, familial CNS-GCT have been reported in patients of Japanese descent. The description of two Caucasian American siblings with ASD and CNS-GCT is novel, refuting that familial CNS-GCT are limited to the Japanese population.
BIOM-31. PROGNOSTIC VALUE OF MGMT METHYLATION IN IDH MUTANT GLIOMAS
Authors: Keng Lam, Blaine Eldred, Bryan Kevan, Matthew Ji, Jerry Lou, Sean Pianka, William Yong, Linda Liau, Phioanh Nghiemphu, Timothy Cloughesy, Richard Green, Albert Lai
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Patients with isocitrate dehydrogenase (IDH) mutant gliomas have been associated with longer survival time than those with IDH wildtype. Previous studies have also shown the predictive value of O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for glioblastoma. However, little is known in the prognostic value of MGMT methylation status for IDH mutant gliomas. METHODS We retrospectively identified IDH mutant gliomas patients from University of California Los Angeles and Kaiser Permanente Los Angeles that had been tested for MGMT methylation status. We performed Kaplan-Meier and Cox regression analyses of overall survival (OS) to compare the MGMT methylated versus MGMT unmethylated patients. RESULTS We identified a total of 375 IDH mutant gliomas with MGMT testing. Subgroups include 52 glioblastoma, 191 astrocytoma, and 132 oligodendroglioma. The median OS for all MGMT methylated patients was 20.0 years and for unmethylated patients 14.3 years (log-rank P=0.008). Cox regression analysis also confirmed patients with MGMT methylated to have better survival than those with MGMT unmethylated (hazard ratio of 0.47, P= 0.005). During subgroup analysis, MGMT methylated glioblastoma patients have a median OS of 13.7 years compared to MGMT unmethylated patients 3.2 years (log-rank P=0.004) with a hazard ratio of 0.14 (P=0.005). However, we see no difference yet for astrocytoma (hazard ratio of 1.09, P= 0.81) and oligodendrogliomas (hazard ratio of 0.36, P= 0.193), possibly as a result of immature survival data. CONCLUSIONS MGMT promoter methylation is associated with better outcomes in IDH mutant glioblastoma patients. Progression free survival will be analyzed to determine predictive benefit of MGMT methylation for other glioma subtypes.