tbuckley/cabot-search huggingface dataset:
NIMG-49. VALIDATION OF SIMULTANEOUS PH- AND O2-WEIGHTED MOLECULAR MRI USING 18F-FDG PET, IMMUNOHISTOCHEMISTRY, AND BIOENERGETICS
Authors: Akifumi Hagiwara, Jingwen Yao, Catalina Raymond, Danielle Morrow, Sergey Mareninov, Saewon Chun, David Nathanson, William Yong, Johannes Czernin, Ajit Divakaruni, Richard Everson, Kunal Patel, Noriko Salamon, Whitney Pope, Phioanh Nghiemphu, Linda Liau, Timothy Cloughesy, Benjamin Ellingson
Journal: Neuro-Oncology (2020)

Abstract This study aimed to investigate the potential of a novel MRI metric related to aerobic glycolysis in patients with diffuse gliomas. All subjects (Study I–III; 7, 26, and 11 subjects, respectively) were scanned on 3-T systems and underwent pH-weighted amine chemical exchange saturation transfer spin-and-gradient-echo echoplanar imaging (CEST-SAGE-EPI) or CEST-EPI, and perfusion imaging. Relative oxygen extraction fraction (rOEF) was calculated by dividing hypoxia-sensitive R2’ by normalized relative cerebral blood volume (nrCBV); a novel metric that characterizes glycolytic status (aerobic glycolytic index, AGI) was calculated by dividing amine CEST contrast by rOEF. Patients in Study I were additionally scanned by 18F-fluorodeoxyglucose (FDG)-PET. Stereotactic image-guided biopsies were performed on patients in Study II and III, and samples were analyzed by immunohistochemistry (IHC) and extracellular flux bioenergetic analysis, respectively. Pairwise correlation between MR metrics and standardized uptake value of 18F-FDG, IHC metrics, or indices of cellular metabolism was calculated using Spearman’s correlation analysis. In Study I, AGI showed very strong significant correlation with 18F-FDG uptake in glioma (correlation coefficient ρ = 0.86, P =0.014). In Study II, AGI was significantly correlated with glucose transporter 3 (ρ = 0.71; P = 0.0041) and hexokinase 2 (ρ = 0.73; P = 0.0029) in IDH wild-type glioma, while it was significantly correlated with monocarboxylate transporter 1 (ρ = 0.59; P = 0.0094) in IDH mutant glioma. This result may reflect the different glycolytic statuses of these gliomas; specifically, the rate-limiting steps in glycolysis. In Study III, a strong significant correlation with cellular AGI derived from the bioenergetic analysis was found for AGI derived from MRI (ρ = 0.79, P = .036). In conclusion, AGI derived from MRI was correlated with FDG, IHC measurements, and cellular AGI. Future studies investigating the clinical utility of AGI in prediction and evaluation of treatment effects are warranted.
NCMP-19. SIDE EFFECTS FROM CHEMOTHERAPY VERSUS SYMPTOMS FROM COVID-19 INFECTION
Authors: Senxi Du, Maya Hrachova, Xiao-Tang Kong
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Adverse effects from chemotherapy such as high dose methotrexate (HD-MTX) are seen during and after chemotherapy. During this coronavirus disease 2019 (COVID-19) pandemic period, COVID-19 infection symptoms following chemotherapy due to immune compromise could mimic chemotherapy associated side effects. Differentiation on time is needed for correct management. CASE REPORT A 50-year old male with clinical history of ocular lymphoma underwent HD-MTX therapy. Before admission, his routine COVID-19 test was negative. After receiving HD-MTX, he developed fatigue, nausea and vomiting. The symptoms resolved before discharge. Next day after discharge, he developed diarrhea, fatigue, subjective fever and feeling cold. His temperature was normal. His symptoms have been persistent for 4-5 days and have resolved gradually and spontaneously. Family members have had no symptoms. The patient denies COVID-19 contact history. The above symptoms were considered adverse effects from chemotherapy. The patient did not seek medical attention. Prior to admission for next cycle of HD-MTX, COVID-19 test was found positive. Chemotherapy was on hold. The patient started home quarantine. The patient has been doing well and practiced COVID-19 infection precaution at home. DISCUSSION The fatigue, nausea and vomiting during HD-MTX treatment are adverse effects from chemotherapy while the diarrhea, fatigue, subjective fever and chills developed after discharge are symptoms of COVID-19 infection. Our case highlights the importance of keeping in mind and differentiating between side effects from chemotherapy and symptoms of COVID-19 viral infection in cancer patients who receive chemotherapy.
EPCT-05. A PHASE I TRIAL OF THE CDK 4/6 INHIBITOR PALBOCICLIB IN PEDIATRIC PATIENTS WITH PROGRESSIVE OR REFRACTORY CNS TUMORS: A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY
Authors: David Van Mater, Sridharan Gururangan, Sarah Leary, Oren Becher, Joanna Phillips, Jie Huang, Olivia Campagne, Tina Poussaint, Stewart Goldman, Patricia Baxter, Girish Dhall, Giles Robinson, Mariko DeWire-Schottmiller, Eugene Hwang, Clinton Stewart, Arzu Onar-Thomas, Ira Dunkel, Maryam Fouladi
Journal: Neuro-Oncology (2020)

Abstract PBTC-042 was a phase I trial of palbociclib to determine the maximum tolerated dose (MTD) and describe toxicities in children. Palbociclib is an oral, selective cyclin dependent kinase 4/6 inhibitor. METHODS: A rolling-6 design was utilized. Eligible patients were children ≥4 and ≤21 years-old with a progressive/refractory CNS tumor with intact retinoblastoma protein, measurable disease, and ability to swallow capsules. Pharmacokinetic studies were performed during the first course. Here, we report on the heavily pretreated stratum, which included patients who received &amp;gt;4 prior treatment regimens (either chemotherapy or biologic agent), and/or craniospinal irradiation, and/or myeloablative chemotherapy plus stem cell rescue. Palbociclib was initiated at 50 mg/m2/day for 21 consecutive days of a 28-day course. This was one dosage level below the MTD for the less heavily pretreated stratum (75 mg/m2). RESULTS: Fourteen eligible patients were enrolled (median age 12.8 years; male 79%). Eleven patients (79%) had either ependymoma or medulloblastoma. Four eligible and evaluable patients were enrolled at 50 mg/m2 with no DLTs. This prompted a dosage increase to 75 mg/m2. Ten eligible subjects were enrolled and 7 were evaluable for DLT assessment. One of 7 evaluable patients experienced a DLT (grade 3 thrombocytopenia). This established 75 mg/m2 as the MTD for more heavily pretreated patients. Mean ± SD palbociclib apparent oral clearance was 34.6 ± 18.4 L/h/m2. CONCLUSION: The MTD for palbociclib on a 3 week on/1 week off schedule in children with brain tumors is 75 mg/m2 and does not appear to be influenced by the degree of prior therapy.
<i>ERCC1</i>mutations impede DNA damage repair and cause liver and kidney dysfunction in patients
Authors: Katja Apelt, Susan M. White, Hyun Suk Kim, Jung-Eun Yeo, Angela Kragten, Annelotte P. Wondergem, Martin A. Rooimans, Román González-Prieto, Wouter W. Wiegant, Sebastian Lunke, Daniel Flanagan, Sarah Pantaleo, Catherine Quinlan, Winita Hardikar, Haico van Attikum, Alfred C.O. Vertegaal, Brian T. Wilson, Rob M.F. Wolthuis, Orlando D. Schärer, Martijn S. Luijsterburg
Journal: The Journal of Experimental Medicine (2020)

ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER), interstrand cross-link (ICL) repair, and DNA double-strand break (DSB) repair. Only two patients with bi-allelic ERCC1 mutations have been reported, both of whom had features of Cockayne syndrome and died in infancy. Here, we describe two siblings with bi-allelic ERCC1 mutations in their teenage years. Genomic sequencing identified a deletion and a missense variant (R156W) within ERCC1 that disrupts a salt bridge below the XPA-binding pocket. Patient-derived fibroblasts and knock-in epithelial cells carrying the R156W substitution show dramatically reduced protein levels of ERCC1 and XPF. Moreover, mutant ERCC1 weakly interacts with NER and ICL repair proteins, resulting in diminished recruitment to DNA damage. Consequently, patient cells show strongly reduced NER activity and increased chromosome breakage induced by DNA cross-linkers, while DSB repair was relatively normal. We report a new case of ERCC1 deficiency that severely affects NER and considerably impacts ICL repair, which together result in a unique phenotype combining short stature, photosensitivity, and progressive liver and kidney dysfunction.
Association Between Achieving Inpatient Glycemic Control and Clinical Outcomes in Hospitalized Patients With COVID-19: A Multicenter, Retrospective Hospital-Based Analysis
Authors: David C. Klonoff, Jordan C. Messler, Guillermo E. Umpierrez, Limin Peng, Robby Booth, Jennifer Crowe, Valerie Garrett, Raymie McFarland, Francisco J. Pasquel
Journal: Diabetes Care (2020)

Diabetes and hyperglycemia are important risk factors for poor outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19). We hypothesized that achieving glycemic control soon after admission, in both intensive care unit (ICU) and non-ICU settings, could affect outcomes in patients with COVID-19.
NCOG-03. FACTORS ASSOCIATED WITH ADJACENT LEVEL TUMOR PROGRESSION IN PATIENTS RECEIVING SEPARATION SURGERY FOLLOWED BY SPINE STEREOTACTIC RADIOSURGERY FOR METASTATIC EPIDURAL SPINAL CORD COMPRESSION
Authors: Vikram Chakravarthy, Hammad Khan, Shaarada Srivatsa, Konrad Knusel, Todd Emch, Ajit Krishnaney
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Separation surgery followed by spine stereotactic radiosurgery (SSRS) has been shown to achieve favorable rates of local tumor control and patient-reported outcomes in patients with metastatic epidural spinal cord compression (MESCC). If left untreated, MESCC causes severe pain, progressive neurological impairment, and eventual paraplegia with a median survival of 3-6 months. The present study aimed to identify factors associated with adjacent level progression and examine its impact on overall survival (OS) in this population. METHODS This study included 39 patients who received separation surgery followed by SSRS for MESCC. Preoperative, postoperative, and post-SSRS MRIs were used to measure amount of epidural disease, amount of local bone marrow involvement, and adjacent level epidural (AEP) and osseous (AOP) progression. Factors associated with AEP and AOP were examined using the log-rank test and cox proportional hazards modeling. RESULTS Median OS in our cohort was 14.7 mo (2.07-96.3). AEP and AOP were observed in 4/39 (10.3%) and 16/39 (41.0%) patients at a mean of 6.1±5.4 mo and 5.3±5.3 mo post-SSRS, respectively. AEP (7.52 vs. 17.1 mo, p = 0.014) and AOP (13.0 vs. 17.1 mo, p = 0.047) were each significantly associated with decreased OS. Factors associated with AEP included primary tumor histology, low-dose hypofractionated SSRS, increased time from surgery to SSRS, and greater amount of local epidural disease preoperatively (p &amp;lt; 0.05). Factors associated with AOP included greater amount of local bone marrow infiltration by tumor pre- and postoperatively and greater amount of local epidural disease postoperatively (p &amp;lt; 0.05). Primary tumor histology and increased time from surgery to SSRS were associated with AOP by trend (p &amp;lt; 0.10). CONCLUSION This study identifies factors associated with adjacent level progression and shows that AEP and AOP are associated with shorter OS in patients receiving separation surgery followed by SSRS for MESCC.
Abstract 13513: Impact of Geriatric Nutritional Risk Index on Heart Failure Re-Hospitalization in Patients With Heart Failure With Preserved Ejection Fraction Compared With Hfmref and Hfref
Authors: Shintaro Mori, Takashi Morinaga, Akihiro Isotani
Journal: Circulation (2019)

Introduction: It has been shown that malnutrition is a risk factor for the development of heart failure and risk factors for the occurrence of an event after the onset of heart failure. However, it...
2P Lung immune prognostic index (LIPI) can identify the fast-progressor to immune checkpoints inhibitors (ICI) in microsatellite instability (MSI) or mismatch repair deficient (dMMR) tumours
Authors: E. Auclin, P. Vuagnat, C. Smolenschi, J. Taieb, J. Adeva Alfonso, L. Nebot, M. Garcia de Herreros, R. Vidal Tocino, F. Longo, Y. El Dakdouki, P. Martin Romano, E. Castanon Alvarez, R. Garcia-Carbonero, L. Gaba Garcia, T. Sauri Nadal, H. Oliveres, B. Besse, C. Massard, L. Mezquita, A. Hollebecque
Journal: Annals of Oncology (2020)
CTIM-23. A PHASE 1 TRIAL OF D2C7-IT IN COMBINATION WITH ATEZOLIZUMAB IN RECURRENT WHO GRADE IV MALIGNANT GLIOMA (MG)
Authors: Annick Desjardins, Dina Randazzo, Vidya Chandramohan, Katherine Peters, Margaret Johnson, Daniel Landi, Mustafa Khasraw, Stevie Threatt, Chevelle Bullock, James Herndon, Eric Lipp, John Sampson, Allan Friedman, Henry Friedman, David Ashley, Darell Bigner
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR-wt and mutant-specific (EGFRvIII) monoclonal antibody fragment and a genetically engineered form of the pseudomonas exotoxin. When injected directly into the tumor mass by convection enhanced delivery (CED), in addition to direct tumor cell killing, immunotoxins induce secondary immune responses by the activation of CD4+ and CD8+ T-cells. We completed a phase 1 dose escalation study of D2C7-IT injected by CED into recurrent WHO grade III-IV MG and identified the phase 2 dose (6,920 ng/mL). Three patients remain in partial response more than 58, 38, and 32 months after a single D2C7-IT intratumoral infusion. As optimal induction of anti-tumor immune responses by immunotoxins is impeded by potent MG-mediated immunosuppression, we are assessing the toxicity of the combination of D2C7-IT with atezolizumab in patients with recurrent WHO grade IV MG. METHODS Eligibility includes adult patients with recurrence of a solitary supratentorial WHO grade IV MG; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS &amp;gt;70%. Patient receives an intratumoral infusion of D2C7-IT and initiates two weeks later atezolizumab at 1200mg, followed by atezolizumab every 3 weeks for up to 2 years. Two cohorts of 3 patients are initially accrued to assess the toxicity of the combination. Assuming accrual continues after the initial two cohorts of 3 patients, an additional 12 patients will be accrued to the study. RESULT The first enrolled patient experienced a grade 3 DLT (grade III ALT elevation) after the first infusion of atezolizumab, but showed a more extensive immunotherapeutic effect by imaging than observed with patients on the D2C7-IT monotherapy trial. Enrollment is ongoing. CONCLUSION D2C7-IT monotherapy has shown prolonged survival and disease control in some patients. We are now evaluating the combination of D2C7-IT with checkpoint inhibition.
PATH-29. HIGH FREQUENCY OF CLINICALLY-RELEVANT TUMOR VARIANTS DETECTED BY MOLECULAR TESTING OF HIGH-RISK PEDIATRIC CNS TUMORS – PRELIMINARY FINDINGS FROM THE TEXAS KidsCanSeq STUDY
Authors: Frank Y Lin, Ross Mangum, Jacquelyn Reuther, Samara L Potter, Dolores H López-Terrada, Adekunle M Adesina, Carrie A Mohila, Guillermo Aldave, Murali M Chintagumpala, Donna M Muzny, Juan Carlos Bernini, Jonathan Gill, Timothy Griffin, Gail Tomlinson, Kelly Vallance, Kevin E Fisher, Angshumoy Roy, Sharon E Plon, D Williams Parsons
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND DNA and RNA-based tumor sequencing tests have the potential to guide the clinical management of children with CNS tumors. However, data describing the utility of these tests are limited. METHODS Children with high-risk or recurrent CNS tumors are included in the diverse cohort of patients enrolling in the KidsCanSeq study from six Texas sites. DNA and RNA from FFPE tumor is subjected to targeted sequencing using a 124-gene mutation panel and an 81-gene fusion panel. Tumor capture transcriptome sequencing, exome sequencing, and copy number array (as well as germline panel and exome testing) are also performed. Tumor variants are classified using AMP/ASCO/CAP consensus guidelines. RESULTS A total of 74 children with high-risk/recurrent CNS tumors enrolled as of 1/28/20. Targeted tumor DNA and RNA panel testing was completed for 57 patients with varied diagnoses. At least one tumor variant with strong or potential clinical significance was identified in 43 of 57 (75%) tumors, with therapeutic significance in 20 of 57 (35%) tumors. The 38 therapeutically-relevant variants most frequently affected MAPK signaling (BRAF x9, EGFR x3, FGFR2, FGFR3, KRAS, NF1, NTRK2) and the AKT/mTOR pathway (PIK3CA x3, PTEN x2, mTOR, TSC1, PIK3R1). Most had not been detected by prior targeted diagnostic testing (27/38, 71%). CONCLUSION Integrated DNA and RNA-based panel testing identified variants with potential to impact clinical decision-making in a majority of children with high-risk/recurrent CNS tumors. The comparative yield of panel testing vs. exome/transcriptome/array will be evaluated in the KidsCanSeq study cohort.
“Sensing Danger”
Authors: Andrew N. Carley, E. Douglas Lewandowski
Journal: Circulation (2020)

athological stress on the heart, as occurs during chronic pressure overload, resulting from either hypertension in humans or aortic constriction in animal models, induces a well-known but incompletely understood hypertrophic response.From the simplest of perspectives, cardiac hypertrophy is a suitable adaptation to increased afterload, and previous investigators have theorized that left ventricular hypertrophy (LVH) is a direct response to an increase in wall stress. 1 Under physiological conditions such as pregnancy or exercise training, the growth of the heart is an adaptive response facilitating the ultimate goal of delivering adequate blood flow to the peripheral organs. 2 In the case of pathological increases in afterload, the progression of concentric hypertrophy ultimately culminates in contractile dysfunction and overt failure. 3Blocking or attenuating LVH in response to chronic pressure overload improves cardiac function and attenuates the progression toward failure, even in the absence of reduced afterload. 3,4mong several components of cardiac decompensation, mitochondrial dysfunction is a primary contributor to the pathogenesis of heart failure, and abnormal mitochondrial function, as a consequence of deficient mitophagy and mitochondrial quality control, can itself induce cardiomyopathy. 5Disruption of ATP production by mitochondria in failing hearts as a result of multiple mechanisms, too numerous to address here, leads to adverse metabolic remodeling and has led to the general characterization as an energy-deprived system. 6However, disruption of the network of metabolic pathways linked to oxidative ATP synthesis by the mitochondria has greater implications beyond reduced energy supply for the heart as a result of the consequential production of metabolic intermediates that serve as physiological effectors involved in intracellular signaling and deleterious chemical agents. 7Thus, mitochondria play an active role, at multiple levels, in the pathogenesis of decompensatory cardiac hypertrophy in the development of heart failure.One newly identified role for mitochondria in the development of heart failure is induction of a proinflammatory response mediated by a novel function of the MAVS (mitochondrial antiviral-signaling protein), as reported by Lin et al 8 in this issue of Circulation.Inflammation is a well-reported and deleterious response to pathological stress involving not only the heart but also peripheral organs during the progression to heart failure. 9,10Mitochondria are already known to be a source of proinflammatory signaling leading to increased mitochondrial oxidative stress, and sterile inflammation is a significant factor in the pathogenesis of heart failure. 11Mitochondria contribute to sterile inflammation through release of reactive oxygen species and the release of damage-associated molecular patterns such as mitochondrial DNA, cardiolipin, and N-formyl peptides.Similar to the pathogenassociated molecular patterns, these damage-associated molecular patterns can
Mortality and adverse events of special interest with intravenous belimumab for adults with active, autoantibody-positive systemic lupus erythematosus (BASE): a multicentre, double-blind, randomised, placebo-controlled, phase 4 trial
Authors: Saira Z Sheikh, Morton A Scheinberg, James Cheng-Chung Wei, Dana Tegzova, William Stohl, Ricardo Acayaba de Toledo, Tamara Mucenic, Mauricio R Abello Banfi, Kathleen Maksimowicz-McKinnon, Carlos Abud-Mendoza, Sandra Navarra, Mercedes Garcia, Ignacio Garcia-De La Torre, Josep Ordi Ros, Roger A Levy, Damon L Bass, Jorge Ross Terrés, Raj Punwaney, Julia Harris, Alireza Nami, Amy Pierce, Kevin S Thorneloe, Beulah Ji, David A Roth
Journal: The Lancet Rheumatology (2020)
BIOM-24. IDENTIFYING VULNERABILITY SIGNATURES THROUGH MACHINE LEARNING IN AN UMBRELLA TRIAL FOR GLIOBLASTOMA
Authors: Matthew Lee, Nanyun Tang, Manmeet Ahluwalia, Ekokobe Fonkem, Karen Fink, Harshil Dhruv, Michael Berens, Sen Peng
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma is characterized by intra- and inter-tumoral heterogeneity. An umbrella trial tests multiple treatment arms depending on corresponding biomarker signatures. A contingency of an umbrella trial is a suite of preferably orthogonal molecular biomarkers to classify patients into the likely-most-beneficial arm. Assigning thresholds of molecular signatures to classify a patient as a “most-likely responder” for one specific treatment arm is a crucial task. Gene Set Variation Analysis (GSVA) of specimens from a GBM clinical trial of methoxyamine associated differential enrichment in DNA repair pathways activities with patient response. The 44 DNA-repair related pathways confound confident “high” enrichment of responder, as well as obscuring to what degree each feature contributes to the likelihood of a patient’s response. Here, we utilized semi-supervised machine learning, Entropy-Regularized Logistic Regression (ERLR) to predict classification. By first training all available data using semi-supervised algorithms we transformed unclassified TCGA GBM samples with highest certainty of predicted response into a self-labeled dataset. In this case, we developed the predictive model which has a larger sample size and potential better performance. Our umbrella trial design currently includes three treatment arms for GBM patients: arsenic trioxide, methoxyamine, and pevonedistat. Each treatment arm manifests its own signature developed by the above (or similar) machine learning pipeline based on selected gene mutation status and whole transcriptome data. By expansion to three, independent treatment arms within a single umbrella trial, a “mock” stratification of TCGA GBM patients binned 56% of all cases into a “high likelihood of response“ arm. Predicted vulnerability using genomic data from preclinical PDX models placed 4 out of 6 models into a “high likelihood of response” regimen. Our utilization of multiple vulnerability signatures in an umbrella trial demonstrates how a precision medicine model can support an efficient clinical trial for heterogeneous diseases such as GBM.
Tropomyosin and Dilated Cardiomyopathy: Revenge of the Actinomyosin “Gatekeeper”**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Jil C. Tardiff
Journal: Journal of the American College of Cardiology (2010)
SURG-07. CEREBELLAR PEDUNCLE TUMORS IN PEDIATRIC NEUROSURGERY: FEW CITATIONS FOR BEING RARE OR FOR LACK OF AWARENESS
Authors: Felipe Hada Sanders, Hamilton Matushita
Journal: Neuro-Oncology (2020)

Abstract We present a case-series of 6 pediatric patients, with a follow-up for a minimum of 1 year, with a diagnostic, therapeutic and prognostic description. This type of disease was first mentioned by Professor Tomita in 1986, in a case-series with 4 patients, with few citations in literature, no other case series cited at the literatures. and in our oncology center of excellence it is an entity that draws attention for diverging from intrinsic tumors of the cerebellum, fourth ventricle and trunk. In this way, we created an algorithm approaching these patients and would like to present this associated to honouring the esteemed professor in neurosurgery.