tbuckley/cabot-search huggingface dataset:
SWK-11. ASSESSMENT OF THE INDIRECT COSTS ASSOCIATED WITH PROTON THERAPY TREATMENT FOR ALBERTA PATIENTS REFERRED OUT OF COUNTRY
Authors: Karina Black, Jackie Middleton, Sunita Ghosh, David Eisenstat, Samor Patel
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Proton therapy for benign and malignant tumors has dosimetric and clinical advantages over photon therapy. Patients in Alberta, Canada are referred to the United States for proton treatment. The Alberta Heath Care Insurance Plan (AHCIP) pays for the proton treatment and the cost of flights to and from the United States (direct costs). This study aimed to determine the out-of-pocket expenses incurred by patients or their families (indirect costs). METHODS Invitation letters linked to an electronic survey were mailed to patients treated with protons between 2008 and 2018. Expenses for flights for other family members, accommodations, transportation, food, passports, insurance, and opportunity costs including lost wages and productivity were measured. RESULTS Fifty-nine invitation letters were mailed. Seventeen surveys were completed (28.8% response rate). One paper survey was mailed at participant request. Nine respondents were from parent/guardian, 8 from patients. All patients were accompanied to the US by a family member/friend. Considerable variability in costs and reimbursements were reported. Many of the accompanying family/friends had to miss work; only 3 patients themselves reported missed work. Time away from work varied, and varied as to whether it was paid or unpaid time off. CONCLUSIONS Respondents incurred indirect monetary and opportunity costs which were not covered by AHCIP when traveling out of country for proton therapy. Prospective studies could help provide current data minimizing recall bias. These data may be helpful for administrators in assessing the societal cost of out-of-country referral of patients for proton therapy.
LGG-14. MULTI-OMIC ANALYSIS OF MAPK ACTIVATION IN PEDIATRIC PILOCYTIC ASTROCYTOMA
Authors: Romain Sigaud, Florian Selt, Thomas Hielscher, Nina Overbeck, Diren Usta, Marc Remke, Daniel Picard, Stephan M Pfister, David T W Jones, Tilman Brummer, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2020)

Abstract Pilocytic astrocytomas (PA) are low-grade gliomas (pLGG) and are the most frequent childhood brain tumors. They are characterized by oncogene-induced senescence (OIS) initiated and sustained by senescence-associated secretory phenotype (SASP) factors. OIS and SASP in PA are thought to be driven by aberrations of the mitogen-activated protein kinase (MAPK) pathway (e.g. KIAA1549:BRAF fusion, BRAFV600E mutation, for the most common MAPK alterations occuring in PA), leading to its sustained activation. The MAPK pathway cascade is activated in a sequential manner: 1) ERK activation, which phosphorylates downstream partners in both cytoplasm and nucleus. 2) ERK-mediated induction of immediate early genes encoding transcription factors. 3) Induction of MAPK target genes expression. 4) Activation of downstream pathways. Our aim is to unravel the molecular partners involved at each level of the sustained MAPK pathway activation in pLGG with different genetic backgrounds (KIAA1549:BRAF fusion and BRAFV600E mutation), and leading to the induction of OIS and SASP factors expression. pLGG cell lines DKFZ-BT66 (KIAA1549:BRAF) and BT-40 (BRAFV600E) were treated with the MEK inhibitor trametinib at key time points, and gene expression profile analysis was performed, allowing transcriptome analysis at each step of the MAPK cascade. This will be combined with a whole proteomic and phospho-proteomic analysis. Combination of the transcriptome and proteome data layers will allow the identification of a) downstream targetable partners activated by the MAPK pathway involved in PA senescence, b) new putative targets that might bring benefit in combination with MAPK inhibitors.
Proteomic analysis reveals ginsenoside Rb1 attenuates myocardial ischemia/reperfusion injury through inhibiting ROS production from mitochondrial complex I
Authors: Lujing Jiang, Xiaojian Yin, Ya-Hui Chen, Yan Chen, Wei Jiang, Hao Zheng, Feng-Qing Huang, Baolin Liu, Wei Zhou, Lian-Wen Qi, Jia Li
Journal: Theranostics (2020)

Rationale: Reactive oxygen species (ROS) burst from mitochondrial complex I is considered the critical cause of ischemia/reperfusion (I/R) injury. Ginsenoside Rb1 has been reported to protect the heart against I/R injury; however, the underlying mechanism remains unclear. This work aimed to investigate if ginsenoside Rb1 attenuates cardiac I/R injury by inhibiting ROS production from mitochondrial complex I. Methods: In in vivo experiments, mice were given ginsenoside Rb1 and then subjected to I/R injury. Mitochondrial ROS levels in the heart were determined using the mitochondrial-targeted probe MitoB. Mitochondrial proteins were used for TMT-based quantitative proteomic analysis. In in vitro experiments, adult mouse cardiomyocytes were pretreated with ginsenoside Rb1 and then subjected to hypoxia and reoxygenation insult. Mitochondrial ROS, NADH dehydrogenase activity, and conformational changes of mitochondrial complex I were analyzed. Results: Ginsenoside Rb1 decreased mitochondrial ROS production, reduced myocardial infarct size, preserved cardiac function, and limited cardiac fibrosis. Proteomic analysis showed that subunits of NADH dehydrogenase in mitochondrial complex I might be the effector proteins regulated by ginsenoside Rb1. Ginsenoside Rb1 inhibited complex I- but not complex II- or IV-dependent O2 consumption and enzyme activity. The inhibitory effects of ginsenoside Rb1 on mitochondrial I-dependent respiration and reperfusion-induced ROS production were rescued by bypassing complex I using yeast NADH dehydrogenase. Molecular docking and surface plasmon resonance experiments indicated that ginsenoside Rb1 reduced NADH dehydrogenase activity, probably via binding to the ND3 subunit to trap mitochondrial complex I in a deactive form upon reperfusion. Conclusion: Inhibition of mitochondrial complex I-mediated ROS burst elucidated the probable underlying mechanism of ginsenoside Rb1 in alleviating cardiac I/R injury.
MBRS-46. CHARTING NEOPLASTIC AND IMMUNE CELL HETEROGENEITY IN HUMAN AND GEM MODELS OF MEDULLOBLASTOMA USING scRNAseq
Authors: Andrew Donson, Kent Riemondy, Sujatha Venkataraman, Ahmed Gilani, Bridget Sanford, Andrea Griesinger, Vladimir Amani, Todd Hankinson, Michael Handler, Jay Hesselberth, Timothy Gershon, Robert Wechsler-Reya, Nicholas Foreman, Rajeev Vibhakar
Journal: Neuro-Oncology (2020)

Abstract We explored cellular heterogeneity in medulloblastoma using single-cell RNA sequencing (scRNAseq), immunohistochemistry and deconvolution of bulk transcriptomic data. Over 45,000 cells from 31 patients from all main subgroups of medulloblastoma (2 WNT, 10 SHH, 9 GP3, 11 GP4 and 1 GP3/4) were clustered using Harmony alignment to identify conserved subpopulations. Each subgroup contained subpopulations exhibiting mitotic, undifferentiated and neuronal differentiated transcript profiles, corroborating other recent medulloblastoma scRNAseq studies. The magnitude of our present study builds on the findings of existing studies, providing further characterization of conserved neoplastic subpopulations, including identification of a photoreceptor-differentiated subpopulation that was predominantly, but not exclusively, found in GP3 medulloblastoma. Deconvolution of MAGIC transcriptomic cohort data showed that neoplastic subpopulations are associated with major and minor subgroup subdivisions, for example, photoreceptor subpopulation cells are more abundant in GP3-alpha. In both GP3 and GP4, higher proportions of undifferentiated subpopulations is associated with shorter survival and conversely, differentiated subpopulation is associated with longer survival. This scRNAseq dataset also afforded unique insights into the immune landscape of medulloblastoma, and revealed an M2-polarized myeloid subpopulation that was restricted to SHH medulloblastoma. Additionally, we performed scRNAseq on 16,000 cells from genetically engineered mouse (GEM) models of GP3 and SHH medulloblastoma. These models showed a level of fidelity with corresponding human subgroup-specific neoplastic and immune subpopulations. Collectively, our findings advance our understanding of the neoplastic and immune landscape of the main medulloblastoma subgroups in both humans and GEM models.
Covid-19: Guidance is still lacking on how ethnic minorities can protect themselves better, say MPs
Authors: Shaun Griffin
Journal: BMJ (2020)

Pre-existing inequalities in health, employment, housing, and access to Universal Credit created a “perfect storm” of factors that have exacerbated the effects of coronavirus on minority ethnic communities, an influential committee of MPs has said.

To tackle these inequalities the House of Commons Women and Equalities Committee has made 18 recommendations, which its chair, Caroline Nokes, says will help to “rebuild society in an equal, fairer way.” Most urgent is the need for culturally competent guidance, says the committee’s report into the effects of the covid pandemic on people from ethnic minority communities.1

Despite concerns having been raised since the beginning of the pandemic that advice and guidance had not been targeted to different communities2 this is still happening, says the report. It is not sufficient to simply translate guidance into other languages without an understanding …
18F-Fluoromisonidazole PET in Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease Presenting With Tumefactive Demyelinating Lesion
Authors: Katsuya Mitamura, Takashi Norikane, Tadayuki Takata, Yuka Yamamoto, Yoshihiro Nishiyama
Journal: Clinical Nuclear Medicine (2020)

Abstract Tumefactive demyelinating lesions have been appreciated as part of the clinical and radiological spectrum of myelin oligodendrocyte glycoprotein antibody–associated disease. A 63-year-old woman was followed up for myelin oligodendrocyte glycoprotein antibody–associated disease. Two years later, she presented with right facial paralysis. T2-weighted MRI scan demonstrated a high-signal-intensity area with edematous change in the right frontal lobe, and partial enhancement was shown on contrast-enhanced T1-weighted image. This contrast-enhanced area showed increased 18 F-fluoromisonidazole uptake.
QOLP-22. POSTTRAUMATIC GROWTH IN NEURO-ONCOLOGY
Authors: Laurel Kovalchick, Kelcie Willis, Julia Brechbiel, Autumn Lanoye, Mariya Husain, Farah Aslanzadeh, Sarah Braun, Kyra Parker, Ashlee Loughan
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Posttraumatic Growth (PTG) refers to the positive psychological change following a trauma and may include a heightened appreciation for life, greater value in meaningful relationships, and/ or spiritual development. A brain cancer diagnosis may be experienced as a traumatic event given the high risk of tumor progression, lack of curative treatments, and ultimately unexpected disheartening prognosis; however, there is limited research on PTG in neuro-oncology. The aim of this study was to determine the profile of PTG in patients diagnosed with primary brain tumors (PBTs). METHODS Patients with PBTs (N = 53, Mage = 48.17, 52.8% male) completed the Post Traumatic Growth Inventory (PTGI) during routine neuro-oncology clinic visits. Descriptive statistics and frequencies for the five factors of the PTGI and PTGI total were calculated. RESULTS PTG was evident across all domains with the most growth reported in appreciation for life and the least growth in new possibilities. Most patients endorsed low levels of growth across the five factors; 29-49% of patients endorse moderate-to-high severity in at least one PTG domain. Lastly, the average total score (M = 46.10) of this sample met the established cutoff for moderate-to-high PTG (&amp;gt; 46). CONCLUSIONS The results suggest that patients with PBTs may perceive positive psychological growth following the traumatic event of a brain tumor diagnosis. Specifically, patients may experience a greater appreciation for life but relatively less growth in new possibilities, perhaps due to the poor prognosis of many PBTs. In non-CNS cancer populations, patients with higher PTG reported better quality of life and lower distress. Further research to expand our knowledge of PTG and the associated factors, including the demographic, medical, and psychological correlates, will better equip providers to promote positive change in PBT patients.
Abstract P561: Fall in the Proportion of Atherothrombotic Stroke in the Last Decade. Success of Current Medical Treatment?
Authors: julieta S rosales, Matias Alet, Virginia Pujol Lereis, Sebastian F Ameriso
Journal: Circulation (2020)

Background and Purpose: Etiologic subtypes of ischemic strokes are influenced by the vascular risk factors profile of patients. Strict management of hypertension and dyslipidemia may have an impact on the prevalence of atherosclerosis. We evaluated changes in the proportion of different ischemic stroke etiologies during the last 22 years. Methods: We studied patients with acute ischemic strokes admitted to a single institution between 1997 and 2018. Demographics, VRF, treatments prior to admission and TOAST subtypes of ischemic strokes were assessed. These variables were compared between 2 periods: 1997-2007 (P1) and 2008-2018 (P2). Results: There were 2747 patients (64% men, aged 66.6 ±14.9 years), 920 subjects in P1 and 1827 in P2. Age and gender distribution did not change over time. Proportion of large artery atherothrombotic strokes decreased from 29% in P1 to 14% in P2 (p &lt;0.0001) and small vessel strokes from 15% in P1 to 11% in P2 (p &lt;0.05). Cardioembolic and undetermined strokes increased from 17 to 25% (p &lt;0.0001) and from 30% to 41% (p &lt;0.0001), respectively. Detection of atrial fibrillation increased from 10% to 19% (p&lt;0.00001). Use of medication prior to stroke increased for aspirin from 27% in P1 to 45% in P2 (p &lt;0.0001), for antihypertensive drugs from 26% to 62% (p &lt;0.0001), for statins from 14% to 42% (p &lt;0.0001) and for anticoagulants from 4% to 9% (p&lt;0.0001). Conclusion: The proportion of strokes associated to large and small vessel atherosclerosis is declining with a substantial increase in the proportion of cardioembolic and undetermined strokes. Higher rates of use of preventive medications and higher prevalence and/or better screening for atrial fibrillation could explain, at least in part, these findings.
Abstract 1466: SIRT1 Overexpression Modulates Cardiac Metabolic Genes Expression and Induces Dilated Cardiomyopathy
Authors: Tsuneaki Kawashima, Yasutaka Inuzuka, Takao Kato, Yodo Tamaki, Shinichiro Niizuma, Yoshitaka Iwanaga, Toru Kita, Tetsuo Shioi
Journal: Circulation (2008)

SIRT1, a mammalian homolog of yeast Sir2, is an NAD+-dependent protein deacetylase. SIRT1 regulates lifespan in model organisms, and is also important in glucose and fatty acid metabolism. To exami...
Functional Block in the Posterior Left Atrium: Another Piece in the Puzzle of Atrial Fibrillation Initiation⁎⁎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: Edward P. Gerstenfeld
Journal: Journal of the American College of Cardiology (2008)
Toxicological analysis of George’s marvellous medicine: literature review
Authors: Graham Johnson, Patrick Davies
Journal: BMJ (2020)

Abstract Objective To analyse the therapeutic effects and toxicity of the eponymous concoction described in Roald Dahl’s book George’s Marvellous Medicine . Design Literature review. Setting Two literature loving households in England. Participants George Kranky and grandma Kranky. Main outcome measures Clinical and toxic effects of the individual ingredients checked against those listed in ToxBase, the National Poisons Information Service’s poisons database. Results The medicine contained 34 ingredients. The most common toxic effect identified on ToxBase was nausea and vomiting (16 ingredients, 47%). Potentially life threatening effects were associated with 13 (38%) ingredients, including depression of the central nervous system, kidney injury, convulsions, cardiac toxicity, and mucosal erosion. The effects described in the book were accurate initially but then diverted from the most likely clinical outcome (death). Conclusions Although Dahl ought to be applauded for his initial accuracy about the toxicology of the ingredients in George’s marvellous medicine, the overall effect would be fatal catastrophic physiological collapse. Scientific exploration and experimentation should be encouraged in children, although any medicinal ingredients need to be checked for potential toxicity before being administered—to grandmas or anyone else.
IMG-10. MRI-BASED RADIOMIC PROGNOSTIC MARKERS OF DIFFUSE MIDLINE GLIOMA
Authors: Lydia Tam, Michelle Han, Jason Wright, Sebastien Toescu, Andrew Campion, Katie Shpanskaya, Kshitij Mankad, Chang Ho, Robert Lober, Samuel Cheshier, Darren Hargrave, Tom Jacques, Kristian Aquilina, Michelle Monje, Gerald Grant, Sarah Mattonen, Nick Vitanza, Kristen Yeom
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diffuse midline gliomas (DMG) are lethal pediatric brain tumors with dismal prognoses. Presently, MRI is the mainstay of disease diagnosis and surveillance. We aimed to identify prognostic image-based radiomics markers of DMG and compare its performance to clinical variables at presentation. METHODS 104 treatment-naïve DMG MRIs from five centers were used (median age=6.5yrs; 18 males, median OS=11mos). We isolated tumor volumes of T1-post-contrast (T1gad) and T2-weighted (T2) MRI for PyRadiomics high-dimensional feature extraction. 900 features were extracted on each image, including first order statistics, 2D/3D Shape, Gray Level Co-occurrence Matrix, Gray Level Run Length Matrix, Gray Level Size Zone Matrix, Neighboring Gray tone Difference Matrix, and Gray Level Dependence Matrix, as defined by Imaging Biomarker Standardization Initiative. Overall survival (OS) served as outcome. 10-fold cross-validation of LASSO Cox regression was used to predict OS. We analyzed model performance using clinical variable (age at diagnosis and sex) only, radiomics only, and radiomics plus clinical variable. Concordance metric was used to assess the Cox model. RESULTS Nine radiomic features were selected from T1gad (2 texture wavelet) and T2 (5 first-order features (1 original, 4 wavelet), 2 texture features (1 wavelet, 1 log-sigma). This model demonstrated significantly higher performance than a clinical model alone (C: 0.68 vs 0.59, p&amp;lt;0.001). Adding clinical features to radiomic features slightly improved prediction, but was not significant (C=0.70, p=0.06). CONCLUSION Our pilot study shows a potential role for MRI-based radiomics and machine learning for DMG risk stratification and as image-based biomarkers for clinical therapy trials.
BIOM-27. PREDICTIVE EVALUATION OF QUANTITATIVE SPATIAL PROFILING OF THE TUMOR MICROENVIRONMENT BY MULTIPLEX IMMUNOFLUORESCENCE IN RECURRENT GLIOBLASTOMA TREATED WITH PD-1 INHIBITORS
Authors: David Cieremans, Ju Young Kim, Ariana Valencia, Justin Mercado Santos, Jennifer Bordeaux, Thai Tran, Christine Vaupel, Naveen Dakappagari, Shabnam Tangri, Fabio Iwamoto
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND PD-1 inhibitors have shown limited efficacy in glioblastoma (GBM) due to microenvironment immunosuppression and low tumor mutational burden. In GBM, PD-L1 expression is not a predictive marker for response to PD-1 or PD-L1 inhibitors. Multiplex immunostaining panel technology allows for detailed analyses of tumor microenvironment cells and their interaction. METHODS Pre-treatment tumor tissue was collected retrospectively from 27 patients in our neurooncology database at Columbia University Irving Medical Center with primary glioblastoma who were diagnosed within the past three years, had surgery here, and were either treated with SOC therapy (n= 8) or PD-1 inhibitors at recurrence (n= 19). Multiplex immunofluorescence was done for 1) CD11b/IDO1/HLADR/GFAP, 2) PD1/PD-L1/GFAP, and 3) CD4/CD8/CD25/FoxP3/Ki67/GFAP. RESULTS Multiplex immunofluorescence panels did not show any correlation with outcomes in patients treated with SOC therapy (non-immunotherapy). Among the 19 patients treated with PD-1 inhibitors, those with more HLA-DR positive cells had worse outcomes (p= 0.02). PD-L1 expression on tumor cells was not predictive of outcomes. There was a correlation trend between PD-1/PD-L1 interaction score (p= 0.08), which measures density of PD-1-positive cells in proximity to PD-L1-positive cells, and outcomes. PTEN loss was correlated with higher Ki67 expression in both tumor cells (p= 0.05) and non-tumors cells (p= 0.03); however, this relationship was not found when looking at Ki67 in CD4+ cells, CD8+ cells, or CD4+CD8+ cells combined. This assay allowed us to evaluate tumor- associated macrophages, myeloid-derived suppressor cells, CD8+ lymphocytes, and CD4+ T regulatory cells; however, none of these were significant predictive markers for outcome. CONCLUSION Quantitative spatial profiling by multiplex immunofluorescence is feasible in FFPE glioblastoma tissue. More refined and extensive quantitative and spatial microenvironment analyses may allow for the development of biomarkers for immunotherapy in GBM.