tbuckley/cabot-search huggingface dataset:
Abstract P450: Radon is Associated With Clonal Hematopoiesis of Indeterminate Potential in the Women’s Health Initiative
Authors: Kurtis M Anthony, Joann E Manson, Siddhartha Jaiswal, Pradeep Natarajan, Pinkal Desai, Kathleen M Hayden, Alexander G Bick, Cara L Carty, Jason M Collins, Shelly-ann Love, James Stewart, Gary Schwartz, Alex Reiner, Eric A Whitsel
Journal: Circulation (2020)

Background: Clonal hematopoiesis of indeterminate potential (CHIP) occurs when there is expansion of leukocyte clones in the blood due to mutations in hematopoietic stem cells. CHIP is associated with a high risk of hematologic malignancy and increased risk of cardiovascular disease (CVD). Although the environmental risk factors for CHIP remain poorly understood, radon is a ubiquitous mutagen and may deliver non-negligible doses of α-radiation to bone marrow that trigger CHIP development. Methods: We conducted a cross-sectional study of 10,495 postmenopausal women without hematologic malignancy from the Women’s Health Initiative clinical trials and observational study (mean age: 69 years; 82% white; 9% African American; 4% Hispanic/Latina; 3% Asian). Using blood from the 1993-1998 screening visit or a subsequent annual visit, and whole genome sequence data from the Trans-Omics for Precision Medicine project, we identified CHIP using the GATK Mu TECT2 somatic variant caller, a pre-specified list of leukemogenic driver mutations in 74 genes, and a threshold variant allele fraction &gt; 0.02. We linked geocoded participant addresses at the time of blood draw to county-level, indoor, screening radon concentrations that were predicted by the Environmental Protection Agency (EPA) in 1993 using data on indoor radon, geology, aerial radioactivity, soil parameters, and foundation types. Radon exposure was classified as follows: Zone 3 (&lt; 2 pCi/L), Zone 2 (2-4 pCi/L), and Zone 1 (&gt; 4 pCi/L), the level at which EPA recommends remediation. We estimated the radon-related risk of CHIP as an odds ratio (OR, 95% CI) using logistic regression with and without adjustment for study design, participant sampling, age, race/ethnicity, smoking, and other sociodemographic / behavioral covariates. Results: We identified CHIP in 887 (8.5% of) participants. 3106 (29.6%), 3982 (37.9%), and 3407 (32.5%) had Zone 3, 2, and 1 radon exposures. The corresponding percentage of participants with CHIP across zones was 7.6%, 8.6%, and 9.1%. Relative to participants in Zone 3, those in Zones 2 and 1 had a higher adjusted risk of CHIP: OR (95% CI) = 1.13 (0.95, 1.35) and 1.24 (1.03, 1.48). Conclusion: Risk of CHIP was positively associated with indoor radon concentrations in this cross-sectional study of post-menopausal women. Longitudinal study of temporally integrated, in-home radon exposures, incident CHIP, and CVD would help confirm this novel radon-CHIP association and place it in context.
TMOD-25. IN VIVO MODEL OF TREATMENT-RESISTANT GLIOBLASTOMA HIGHLIGHTS SEX DIFFERENCES IN SURVIVAL
Authors: Mona Al-Gizawiy, Robert Wujek, Melissa Prah, Salvatore Molino, Christopher Chitambar, Kathleen Schmainda
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Sex differences independent from acute hormone action are evident in the incidence and tumorigenesis of several cancers, including glioblastoma (GBM). Malignant brain tumors with mesenchymal, proneural, and neural GBM subtypes occur twice as frequently in males than in females, implying a molecular basis for the sex disparities observed. Accordingly, response to therapy and overall survival, may also differ between male and female GBM patients. Further elucidation of these differences would benefit from a robust preclinical testing system, such as the one described here. METHODS Adult (U87-MG) GBM cells were exposed to a total radiation dose of 10 Gy, effecting an epithelial to mesenchymal transition. The resultant irradiated U87-10Gy cells were tested for cell viability and allowed to reach confluence prior to stereotactic implantation into the right striatum of male and female athymic rats. In vivo advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics™ Software (IQ-AI, Ltd.). RESULTS Tumor take was 90% in males and 60% in females, indicating an ‘incidence’ ratio of 1.5. Overall survival was significantly higher in females (median = 48, range = 40-72 days) than in males (median = 28, range = 27-30 days) (p = 0.024). Immunohistochemical and imaging analyses are pending and will be discussed. CONCLUSION The outcomes noted in this pilot study mirror incidence and survival outcomes noted in GBM patients undergoing standard care. Our model of treatment-resistant glioma provides a robust testing system to study underlying sex differences in GBM biology and treatment response in parallel analyses of male and female data.
CTIM-19. MOLECULAR AND GENETIC DETERMINANTS OF RESPONSE TO PD-1 BLOCKADE IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Robert Prins, Mildred Galvez, Meelad Amouzgar, Katie Campbell, Daniel Wells, Nicholas Bayless, Richard Everson, Timothy Cloughesy
Journal: Neuro-Oncology (2020)

Abstract Despite immune checkpoint inhibitors having success in several other tumor types, many glioblastoma (GBM) patients fail to respond or maintain a sustained response. Work published by our group (Cloughesy et al, 2019) demonstrated that relative to adjuvant programmed cell death-1 (PD-1) blockade, neoadjuvant treatment doubled the median overall survival (OS) for recurrent GBM patients and resulted in an enhanced interferon-γ signature. This suggests that anti-PD-1 given in the neoadjuvant setting may improve outcomes for recurrent GBM patients. The challenge remains in identifying the molecular and genetic signatures associated with response to immune checkpoint blockade. To address this, we analyzed the tumor sample and clinical response data from the patients treated in this clinical trial (n=31). We stratified patients as stable disease (SD) versus progressive disease (PD) based on their response assessment in neuro-oncology criteria (RANO) scores from cycle 2 of treatment post-surgery. Among the SD patients, 77.8% received neoadjuvant treatment while 22.2% received adjuvant therapy. In this group, a median OS was not reached. Among the PD patients, 40.9% received neoadjuvant treatment and 59.1% received adjuvant therapy, with a median OS of 257 days. Next, we analyzed factors that impact response to immunotherapy, which includes somatic mutational burden and interferon-γ pathway induction. We calculated somatic mutational variants, copy number variants (CNVs), and differential gene expression from the bulk tumor exome and RNA-sequencing data. The total mutation counts were similar between groups and no association was identified with increased mutational burden. In addition, total CNV stability was similar between groups. However, when looking at genes involved in the JAK/STAT signaling pathway, there were notably more copy number losses of JAK2 in the PD group when compared to the SD group (85.0% versus 66.7%). These findings merit further exploration as the JAK/STAT pathway has been implicated in response to immune checkpoint blockade.
INNV-01. NEUROLOGIC IMPROVEMENT WITH CORTICOSTEROIDS PRIOR TO SURGERY IS PREDICTIVE OF DURABLE POST-OPERATIVE IMPROVEMENT IN MOTOR DEFICITS DUE TO BRAIN METASTASES
Authors: Stephen Bowden, Barry Cheaney, Nasser Yaghi, Daniel Munger, Christian Lopez Ramos, Emma Richie, Matthew Wood, Ahmed Raslan, Justin Cetas, Aclan Dogan, Seunggu Han
Journal: Neuro-Oncology (2020)

Abstract Corticosteroids reduce vasogenic cerebral edema and are thought to improve related neurologic deficits or symptoms of increased intracranial pressure. Brain metastases are typically associated with a large amount of edema and, consequently, come with a disproportionate degree of mass effect that may cause such deficits. There remains no standard approach to pre-operative corticosteroid therapy, nor is it understood what clinical characteristics are associated with a neurologic response to pre-operative steroids. We examined characteristics of steroid responders versus non-responders and, further, evaluated whether a response to preoperative steroids is predictive of durable improvement in neurologic function. Patients with pathology-proven brain metastases who underwent open surgical resection between 2009 and 2019 were identified from departmental records. Charts were reviewed to identify patients with motor dysfunction who received corticosteroids prior to surgery. Multiple patient and clinical characteristics were extracted and compared using student t-, chi-square, and Fisher’s exact tests. 90 patients exhibited pre-operative motor deficits, 69 of whom received corticosteroids prior to surgery (dose 2 – 112 mg; median 25 mg). 34 patients neurologic function improved prior to surgery, whereas 35 patients had no demonstrable improvement. All 34 patients (100%) whose motor function improved pre-operatively with steroids had sustained improvement at follow-up, whereas 27 of 35 (77%) patients who did not improve pre-operatively were better at follow-up (p = 0.005). All other clinical characteristics were similar between responders and non-responders. All motor deficits related to brain metastases that responded to steroids prior to surgery demonstrated durable improvement at follow-up, suggesting such an improvement portends a favorable long-term functional outcome. Conversely, a failure to improve with steroid therapy confers a more guarded prognosis.
Differential Diagnosis for Electrocardiography Challenge
Authors: Chakrapani Mahabala, Sushmita R. S. Upadhya, Ashraf Malik
Journal: JAMA Internal Medicine (2020)

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DDRE-24. ACQUIRED RESISTANCE TO TARGETED INHIBITORS IN EGFR-DRIVEN GLIOBLASTOMA: IDENTIFICATION OF DUAL KINASE TARGETS
Authors: Abigail Shelton, Erin Smithberger, Madison Butler, Allie Stamper, Ryan Bash, Steven Angus, Mike East, Gary Johnson, Michael Berens, Frank Furnari, C Ryan Miller
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is a devastating primary brain tumor with 5-year survival &amp;lt; 5%. CDKN2A deletion (~60%) and EGFR amplification (55–60%) mutations frequently co-occur in these tumors. EGFR is an attractive therapeutic target due to its mutational frequency and availability of multiple brain-penetrant tyrosine kinase inhibitors (TKI). Several EGFR TKI have failed clinically, due in part to acquired resistance. To mechanistically examine this type of resistance, we used genetically engineered mouse astrocytes harboring Cdkn2a deletion and EGFRvIII, a common (35%) activating mutation. Resistant cells were generated via chronic exposure to gefitinib or erlotinib, either in vitro or in vivo. Resistance to these first-generation EGFR TKI conferred cross resistance (up to 36-fold ΔIC50) to a panel of second- and third-generation TKI relative to sensitive parental lines. Moreover, integrated RNA sequencing (RNA-seq) and chemical proteomics (multiplexed inhibitor beads and mass spectrometry (MIB-MS)) showed that the kinase transcriptome and proteome were rewired in resistant cells: 113 of ~300 detected kinases were differentially expressed (p&amp;lt; 0.05). We then used these techniques to examine acute (≤ 48 h) kinome changes in both sensitive and resistant cells upon treatment with a CNS-penetrant, second-generation EGFR TKI, afatinib. Whereas exposure of treatment-naïve, sensitive cells to afatinib significantly rewired the kinome (120 differentially expressed kinases), the response of resistant cells to drug re-challenge was significantly blunted (13 differentially expressed kinases). A subset of expressed kinases (35 of 263) dynamically responded to afatinib in both sensitive and resistant cells. Overall, upregulated kinases include those implicated in the biology of gliomas (Bmx, Fgfr2) and of other cancers (Pdgfrb, Mapk3/4, Ddr1/2, Pdk2). These kinases thus represent putative druggable targets for dual inhibition therapy. Integrated kinome profiling using MIB-MS and RNA-seq in GBM models with defined mutational profiles provides a powerful framework to identify novel therapeutic targets that could significantly alter current treatment paradigms.
The Babinski sign in Renaissance paintings—a reappraisal of the toe phenomenon in representations of the Christ Child: observational analysis
Authors: François Sellal, Laurent Tatu
Journal: BMJ (2020)

Abstract Objective To investigate systematically the presence of the Babinski sign in paintings of the Christ Child by the greatest painters of the Renaissance. Design Observational analysis. Setting Large collection of paintings depicting the Christ Child from Flemish, Rhenish, and Italian schools between 1400 and 1550 CE, searched using published catalogues and Google. Study sample 302 Renaissance paintings (by 19 painters) depicting the Christ Child. Main outcome measure Babinski sign, defined as a hallux extension with an amplitude greater than 30°. The presence of foot sole stimulation was also noted. Results An unquestionable upgoing toe was apparent in 90 (30%) of the 302 paintings. The Babinski sign was present in more than 60% of Christ Child paintings by Rogier van der Weyden, Hans Memling, Martin Schongauer, and Matthias Grünewald. A bilateral Babinski sign was observed in three paintings. Stimulation of the sole was noted in 48/90 (53%) paintings and was always present in paintings by Andrea del Verrocchio, Leonardo da Vinci, and Giorgione. No association existed between the presence of the Babinski sign and the period during which the painter was active. Conclusions Four main factors were noted in relation to the representation of the Babinski sign in paintings of the Christ Child: the physiological toe phenomenon in infants, the representation of the nudity of the Christ by painters during the 15th century to demonstrate the incarnation, Renaissance painters’ need for precise observation of anatomy, and the desire of some Rhenish and Flemish painters to depict very realistic details. Italian Renaissance painters, whether Mannerist or not, tended to idealise the beauty of human body, and they often did not reproduce the Babinski sign.
HGG-01. ENTRECTINIB IN RECURRENT OR REFRACTORY SOLID TUMORS INCLUDING PRIMARY CNS TUMORS: UPDATED DATA IN CHILDREN AND ADOLESCENTS
Authors: Giles Robinson, Ami Desai, Ellen Basu, Jennifer Foster, Karen Gauvain, Amit Sabnis, Suzanne Shusterman, Margaret Macy, Luke Mease, Janet Yoon, Thomas Cash, Mohamed Abdelbaki, Kellie Nazemi, Christine Pratilas, Brian Weiss, Saibah Chohan, Alison Cardenas, Katherine Hutchinson, Guillaume Bergthold, Amar Gajjar
Journal: Neuro-Oncology (2020)

Abstract STARTRK-NG (phase 1/2) is evaluating entrectinib, a CNS-penetrant oral, TRK/ROS1/ALK tyrosine kinase inhibitor, in patients &amp;lt;21 years with recurrent/refractory solid tumors, including primary CNS tumors. After determining the recommended dose, 550mg/m2/day, in all-comers, expansion cohorts with gene-fusion-positive CNS/solid tumors (NTRK1/2/3, ROS1) are being enrolled. As of 5Nov2019 (data cut-off), 39 patients (4.9m–20y; median 7y) have been evaluated for response, classified as complete (CR) or partial response (PR), stable (SD) or progressive disease (PD) using RANO (CNS), RECIST (solid tumors), or Curie score (neuroblastoma). Responses in patients with fusion-positive tumors were Investigator-assessed (BICR assessments are ongoing) and occurred at doses ≥400mg/m2. Best responses in fusion-positive CNS tumors (n=14) were: 4 CR (GKAP1-NTRK2, ETV6-NTRK3 [n=2], EML1-NTRK2); 5 PR (KANK1-NTRK2, GOPC-ROS1, ETV6-NTRK3, TPR-NTRK1, EEF1G-ROS1); 3 SD (BCR-NTRK2, ARHGEF2-NTRK1, KIF21B-NTRK1); 2 PD (PARP6-NTRK3, EML4-ALK); and in fusion-positive solid tumors (n=8) were: 3 CR (ETV6-NTRK3 [n=2], DCTN1-ALK); 5 PR (EML4-NTRK3, TFG-ROS1 [n=3], KIF5B-ALK). Responses (Investigator-assessed) in non-fusion tumors (n=17) were: 1 CR (ALK F1174L mutation), 3 SD, 10 PD, 3 no data/unevaluable. The objective response rate (CR+PR/total) in patients with fusion-positive tumors was 77% (17/22) versus 6% (1/17) in those with non-fusion tumors. All 39 patients experienced ≥1 adverse event (AE); the most frequent AEs included weight gain and anemia (both 48.7%); increased ALT, increased AST, cough and pyrexia (all 46.2%); increased creatinine and vomiting (both 43.6%); and bone fractures (n=10, in 9 patients). Entrectinib has produced striking, rapid, and durable responses in solid tumors with target gene fusions, especially high-grade CNS neoplasms.
ATRT-10. ATYPICAL TERATOID/RHABDOID TUMOR OF THE PINEAL REGION IN A PEDIATRIC PATIENT
Authors: Carlos Almeida, Bruna Minniti Mançano, Marcus Matsushita, Stephanie Previdelli, Marina Lopes Lamim, Fabio Costa Faustino, Fernanda Magalhaes Souza, Lucas Dias Lourenço
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumor (ATRT) is a malignant neoplasm of the central nervous system and corresponds to 1.5% of all intracranial tumors. Mainly affects children under three years of age and shows aggressive behavior (most pediatric patients succumb to their disease within a year after the initial diagnosis, despite the treatment performed). Its place of occurrence in children is preferably in the posterior fossa, and it is rare to appear in other regions. There are only seven patients with ATRT reported on literature; all of them are adults. We present the case of a pediatric patient with a tumor in the pineal region diagnosed as ATRT. CASE REPORT: Three-year-old female patient admitted with occipital headache, vomiting, and seizure. Magnetic resonance imaging (MRI) showed obstructive hydrocephalus secondary to a solid-cystic lesion located at the pineal region that was 3.0 x 3.0 x 3.5 cm in size. Spine MRI did not reveal leptomeningeal spreading. We performed an occipital transtentorial approach to achieve the best safe resection possible, and a ventriculoperitoneal shunt. Histological examination revealed ATRT. The patient received adjuvant treatment with radiotherapy and chemotherapy according to the “Head Start” protocol. One year after the surgery, MRI did not identify any remaining lesion. CONCLUSION ATRT is an aggressive and rare neoplasm whose clinical picture depends on the location of the tumor; however, it must be considered in the differential diagnosis of tumors of the pineal region in the pediatric population.
EXTH-58. ONCOSCILLATORS: INDUCTION OF THE MITOCHONDRIAL PERMEABILITY TRANSITION IN CANCER CELLS
Authors: Martyn Sharpe, David Baskin, Santosh Helekar
Journal: Neuro-Oncology (2020)

Abstract Magnetic fields in the mT range influence spin state pairing in redox-active radical pairs generating spin-forbidden quantum states which are kinetically inert. Studies examining the effects of static magnetic fields on mitochondrial electron transfer kinetics have demonstrated only modest effects. When neodymium super-magnets are securely attached to and precision-balanced on the shafts of electronically-controlled motors it is possible to generate rotating magnetic fields of desirable strengths and frequencies. Unlike a static magnetic field or an alternating field in a static electromagnetic coil, oscillating magnetic field (OMF) produced by rotating lines of force of a spinning permanent magnet can dynamically couple the electron spins of radical pairs within proteins whose orientations are ‘fixed’. The frequencies of rotation of magnets can also be tuned to appropriate electron cycling resonances within the proteins. Using OMF of appropriate field strength, frequency and on/off acceleration/deceleration profiles we can completely arrest electron transport in isolated respiring rat liver mitochondria. Parallel to this inhibition of electron flux, we also independently observe an increase in superoxide and hydrogen peroxide. Under certain OMF exposure regimes, we observe membrane permeability transition in these mitochondria when using succinate as substrate, and show that the mitochondrial membrane permeability transition effect can be blocked by bongkrekic acid. We have examined the effect of OMF on oxygen consumption in cultured primary cancer cells with a rotating magnet (oncoscillator) that is an integral component of a new anti-cancer Oncomagnetic device. We observe three main effects in addition to the inhibition of respiratory flux in cancer cells – damage to the respiratory complex, uncoupling and generation of superoxide/hydrogen peroxide. OMF generated by oncoscillators can induce mitochondrial permeability transition in primary cultured malignant meningioma, diffuse intrinsic pontine glioma and GBM cells. Parallel experiments with normal human astrocytes show only minor changes in cellular/mitochondrial function under these conditions.