tbuckley/cabot-search huggingface dataset:
CBMT-35. METABOLIC REWIRING BY ONC201/TIC10 AND 2-DEOXYGLUCOSE HAS SYNERGISTIC ANTI-GLIOBLASTOMA ACTIVITY
Authors: Maximilian Pruss, Annika Dwucet, Michal Hlavac, Richard Kast, Mike-Andrew Westhoff, Rainer Wirtz, Marc-Eric Halatsch, Markus Siegelin, Georg Karpel-Massler
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Metabolic dysregulation is a common feature of cancers such as primary brain malignancies. In this work we examined whether a rewiring of the metabolome by a multi-targeting approach would induce enhanced anti-neoplastic activity in glioblastoma. METHODS Preclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS (OCR) and glycolysis (ECAR). Expression of respiratory chain complexes was analysed by Western blotting. Biological effects on tumor formation were tested in patient-derived model systems on the chorion allantoic membrane (CAM). Protein array analyses were performed to determine effects on phospho protein kinase expression. RESULTS Treatment with ONC201/TIC10 leads to impaired mitochondrial respiration and a dose-dependent increase of glycolysis. ONC201/TIC10 combined with 2-Deoxyglucose, induces a state of energy deprivation characterized by a significant decrease in ATP levels. On the molecular level, pAMPK α1 was significantly up-regulated while a hypo-phosphorylation signature was noted including mTOR signaling, src family kinases and receptor tyrosine kinases such as EGFR and PDGFR-β. As a result, synergistic anti-proliferative and anti-migratory effects were observed among established and primary cultured glioblastoma cells. In addition, tumor formation on the CAM was significantly impaired following the combination treatment. CONCLUSIONS Simultaneous treatment with ONC201/TIC10 and 2-Deoxyglucose causes a reprogramming of the metabolic circuitry and results in a synergistic anti-glioblastoma activity. Since both agents were tested in clinical trials with good tolerability, and they both penetrate the blood-brain barrier, further clinical evaluation of this therapeutic strategy seems promising.
Prognostic Significance of IKZF1, PAX5, and CDKN2A Deletions in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Hyper-CVAD/MA with Dasatinib or Ponatinib
Authors: Yuya Sasaki, Nicholas J. Short, Hagop M. Kantarjian, Rebecca Garris, Nitin Jain, Koji Sasaki, Farhad Ravandi, Marina Y Konopleva, Michael E. Rytting, Guillermo Garcia-Manero, Latasha Little, Curtis Gumbs, Li Zhao, P. Andrew Futreal, Feng Wang, Koichi Takahashi, Elias Jabbour
Journal: Blood (2019)
Therapeutic Stratification of PTEN-MYC Axis Appears to be Promising for Molecular Targeted Therapies in Refractory and Relapsed T-Cell Acute Lymphoblastic Leukemia
Authors: Heinz Ahlert, Sanil Bhatia, Marc Remke, Melf Sönnichsen, Niklas Dienstbier, Ute Fischer, Julia Hauer, Arndt Borkhardt
Journal: Blood (2019)
Comparative Efficacy and Safety of Bortezomib, Thalidomide, and Dexamethasone (VTd) without and with Daratumumab (D-VTd) from Cassiopeia Versus Vtd from Pethema/GEM in Patients with Newly Diagnosed Multiple Myeloma Using Propensity Score Matching (PSM)
Authors: Philippe Moreau, Cyrille Hulin, Sonja Zweegman, Yannan Hu, Bart Heeg, Mahmoud Hashim, Carla de Boer, Veronique Vanquickelberghe, Tobias Kampfenkel, Annette Lam, Sarah Cote, Pieter Sonneveld
Journal: Blood (2019)
GENE-22. GENOME-WIDE METHYLATION PROFILING OF GLIOBLASTOMA EXTRACELLULAR VESICLE DNA ALLOWS TUMOR CLASSIFICATION
Authors: Franz Ricklefs, Cecile Maire, Katharina Kolbe, Mareike Holz, Manfred Westphal, Ulrich Schüller, Katrin Lamszus
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Genome-wide methylation profiling has recently been developed into a tool that allows subtype tumor classification in central nervous system (CNS) tumors. Extracellular vesicles (EVs) are released by CNS tumor cells and contain high molecular weight tumor DNA, rendering EVs a potential biomarker source to identify tumor subgroups, stratify patients and monitor therapy by liquid biopsy. We investigated whether the DNA in glioma-derived EVs reflects genome-wide tumor methylation profiles and allows tumor subtype classification. METHODS DNA was isolated from EVs secreted by cultured glioma stem-like cells (GSC) as well as from the cells of origin and from the original tumor samples (n=3 patients). EVs were classified by nanoparticle analysis (NTA), immunoblotting, imaging flow cytometry (IFCM), multiplex EV assays and electron microscopy. Genome-wide DNA methylation profiling was performed using an 850k Illumina EPIC array and results were classified according to the DKFZ brain tumor classifier. RESULTS The size range of GSC-derived EVs was 120–150 nm, as measured by NTA. The majority of secreted EVs exhibited high expression of common EV markers (i.e. CD9, CD63 and CD81), as characterized by IFCM and multiplex EV assays. Genome-wide methylation profiling of GSC-derived EVs correctly identified the methylation class of the original tumor, including information on the IDH mutation status and subclass classification (RTK1, RTK2). In addition, copy number alterations and the MGMT metyhlation status matched the pattern of the parental GSCs and original tumor samples. CONCLUSION EV DNA faithfully reflects the tumor methylation class as well as the MGMT methylation status and copy number variations present in the parental cells and the original tumor. Methylation profiling of circulating tumor EV DNA could become a useful tool to detect and classify CNS tumors.
Heterogeneity in influenza seasonality and vaccine effectiveness in Australia, Chile, New Zealand and South Africa: early estimates of the 2019 influenza season
Authors: Sheena G Sullivan, Carmen S Arriola, Judy Bocacao, Pamela Burgos, Patricia Bustos, Kylie S Carville, Allen C Cheng, Monique BM Chilver, Cheryl Cohen, Yi-Mo Deng, Nathalie El Omeiri, Rodrigo A Fasce, Orienka Hellferscee, Q Sue Huang, Cecilia Gonzalez, Lauren Jelley, Vivian KY Leung, Liza Lopez, Johanna M McAnerney, Andrea McNeill, Maria F Olivares, Heidi Peck, Viviana Sotomayor, Stefano Tempia, Natalia Vergara, Anne von Gottberg, Sibongile Walaza, Timothy Wood
Journal: Eurosurveillance (2019)

We compared 2019 influenza seasonality and vaccine effectiveness (VE) in four southern hemisphere countries: Australia, Chile, New Zealand and South Africa. Influenza seasons differed in timing, duration, intensity and predominant circulating viruses. VE estimates were also heterogeneous, with all-ages point estimates ranging from 7–70% (I 2 : 33%) for A(H1N1)pdm09, 4–57% (I 2 : 49%) for A(H3N2) and 29–66% (I 2 : 0%) for B. Caution should be applied when attempting to use southern hemisphere data to predict the northern hemisphere influenza season.
Imerge: A Phase 3 Study to Evaluate Imetelstat in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment
Authors: Uwe Platzbecker, Pierre Fenaux, David P. Steensma, Koen Van Eygen, Azra Raza, Ulrich Germing, Patricia Font, Maria Diez-Campelo, Sylvain Thepot, Edo Vellenga, Mrinal M. Patnaik, Jun Ho Jang, Laurie Sherman, Souria Dougherty, Libo Sun, Fei Huang, Ying Wan, Aleksandra Rizo, Tymara Berry, Faye Feller, Valeria Santini
Journal: Blood (2020)
Outcomes in Aggressive B-Cell Non-Hodgkin Lymphomas with Anti-CD19 CAR T-Cell (CTL019) Products Not Meeting Commercial Release Specifications
Authors: Elise A. Chong, James N. Gerson, Daniel J. Landsburg, Sunita Dwivedy Nasta, Jakub Svoboda, David L. Porter, Karen Dengel, Don L. Siegel, Joan Gilmore, Stefan K. Barta, Bruce L Levine, Carl H June, Stephen J. Schuster
Journal: Blood (2019)
Evaluation of Efficacy and Safety of Front-Line Regimens for the Treatment of Transplant Ineligible Patients with Multiple Myeloma: A Network Meta-Analysis of Phase 2/3 Randomized Controlled Trials
Authors: Smith Giri, Madan R Aryal, Han Yu, Alyssa Grimshaw, Ranjan Pathak, Scott F. Huntington, Binod Dhakal
Journal: Blood (2019)
SCIDOT-46. MicroRNA NANOCELL THERAPY FOR GLIOBLASTOMA
Authors: Muhammad Babar Khan, Rosamaria Ruggieri, Nhan Tran, Jann Sarkaria, Jennifer MacDiarmid, Himanshu Brahmbhatt, John Boockvar, Marc Symons
Journal: Neuro-Oncology (2019)

Abstract Therapeutic resistance stemming from inter and intra-tumoral heterogeneity is a significant impediment towards development of effective therapeutics for glioblastoma. We hypothesized that microRNAs can potentially counteract resistance emanating from such heterogeneity as they simultaneously modulate the expression of multiple proteins. We identified microRNA-34a as a unique microRNA which modulates multiple oncoproteins in GBM using two different in silico approaches. We investigated the therapeutic effects of microRNA-34a in three primary patient-derived xenografts (PDX) representing classical (GBM6), proneural (GBM118) and mesenchymal (GBM118) subtypes; four established cell lines (T98G, U251, A172, LN229) and two cell lines with acquired resistance to temozolomide (A172-TR, LN229-TR) in vitro. Glioblastoma cell cultures showed variable responses to temozolomide but microRNA-34a inhibited proliferation in all cell cultures. Furthermore, microRNA-34a also sensitized all tested cell lines to temozolomide (combination index &lt; 0.8, p=.03) and radiation treatment (dose enhancement factor 1.7–2.2, p=0.02). Mechanistically, microRNA 34a down-regulates at least six distinct therapeutic resistance proteins. Importantly, these resistance proteins are expressed in distinct spatial niches and are prognostic for patient survival based on our analysis of the cancer genome atlas (TCGA) data. For in vivo delivery of microRNA-34a, we utilized nanocells which are derived from genetically modified bacteria, loaded with microRNA-34a and tagged with a bispecific antibody targeting EGFR. Nanocells were injected intravenously while temozolomide was administered by oral gavage in an orthotopic PDX model. We confirmed delivery of microRNA-34a to tumor by observing down-regulation of cMet and phosphorylated Akt in treated mice. Importantly, microRNA-34a nanocells resulted in significant reduction in tumor growth (p=0.021), increased survival (p&lt;0.001) with microRNA-34a monotherapy and synergy in combination with temozolomide in vivo. Taken together, our results suggest that delivery of miR-34a may be a powerful new adjuvant for the treatment of glioblastoma in combination with temozolomide that can mitigate both inter- and intra-tumor heterogeneity.
Targeted FGFR Inhibition Results in Hematologic and Cytogenetic Remission in a Myeloid Neoplasm Driven By a Novel PCM1-FGFR1 Fusion: Data from an Expanded Access Program
Authors: Monica Kasbekar, Valentina Nardi, Paola Dal Cin, Andrew M. Brunner, Yi-Bin Chen, Christine Connolly, Amir T. Fathi, Julia Foster, Molly Macrae, Steven L McAfee, Kristin McGregor, Rupa Narayan, Aura Y. Ramos, Tina T. Som, Megan Vartanian, Robb S Friedman, Karim Benhadji, Gabriela S. Hobbs
Journal: Blood (2019)
Giant Vesical Calculus
Authors: Harold R. Brodman
Journal: JAMA (1978)

<h3>To the Editor.—</h3> Although giant vesical calculus is reported to be uncommon in the Western world (239:2272, 1978), it is not uncommon in Java. During our tour of duty with Care-Medico at the R. S. U. Mangkubumen Hospital in Solo, Central Java, in 1975,<sup>1</sup>we had occasion to see several giant bladder calculi. The Javanese surgeons did not find them unusual. One patient, a 43-year-old man, had a calculus of enormous size. Plain abdominal roentgenographic examination demonstrated the large opaque calculus to be filling the pelvis (Figure). Chemical analysis was not available. Further study of the epidemiologic characteristics of genitourinary calculus disease may be fruitful in cluing etiology.
RAS Mutations Are Independently Associated with Decreased Overall Survival and Event-Free Survival in Patients with AML Receiving Induction Chemotherapy
Authors: Brian J Ball, Meier Hsu, Sean M. Devlin, Christopher Famulare, Sheng F Cai, Andrew Dunbar, Zachary D. Epstein-Peterson, Kamal Menghrajani, Jacob L Glass, Justin Taylor, Aaron D Viny, Aaron D Goldberg, Martin S. Tallman, Eytan M. Stein
Journal: Blood (2019)
High Platelet Counts, Thrombosis, Bleeding Signs, and Acquired Von Willebrand Syndrome at Diagnosis of Pediatric Chronic Myeloid Leukemia
Authors: Meinolf Suttorp, Ralf Knoefler, Hélène Deutsch, Franziska Paul, Oliver Tiebel, Markus Metzler, Frederic Millot
Journal: Blood (2019)
Abstract 18308: Prognostic Value of Stress Echocardiography Appropriateness Criteria for Evaluation of Coronary Artery Disease
Authors: Sanjeev Bhattacharyya, Vasilis Kamperidis, Navtej Chahal, Benoy Shah, Isabelle Roussin, Wei Li, Rajdeep Khattar, Roxy Senior
Journal: Circulation (2013)

Background: Appropriateness criteria for stress echocardiography (SE) have been published to reduce the rate of inappropriate testing. There are limited data validating the prognostic value of these criteria in clinical practice. Methods: 250 consecutive patients undergoing SE for evaluation of known or suspected coronary artery disease were classified into appropriate, uncertain and inappropriate categories according to appropriateness criteria guidelines. A positive SE was defined as the development of new wall motion abnormalities or a biphasic response. The primary end-point was the composite of myocardial infarction and death. Results: Of the 250 SE, 120 (48%) were dobutamine studies and 130 (52%) were exercise studies. Of the 250 patients, 156 (62.4%), 71 (28.4%) and 23 (9.2%) were classified as appropriate, inappropriate and uncertain, respectively. A significantly greater proportion of studies classified as appropriate 71(45.5%) demonstrated inducible ischaemia compared to inappropriate studies 9(12.7%) or uncertain studies 4(17.4%), p&lt;0.0001. During a median follow-up of 12.4 months (inter-quartile range 10.6 - 16.3 months), events occurred in 18 (11.5%), 2 (2.8%) and 0 patients classified as appropriate, inappropriate and uncertain respectively. Event-free survival was significantly reduced in patients with a SE demonstrating ischaemia compared to patients without inducible ischaemia, p &lt;0.0001. Kaplan Meier curves demonstrated reduced event-free survival in patients with whose studies were classified as appropriate compared to inappropriate (p=0.01) or uncertain (p=0.05). There was no difference in event free survival between those classified as uncertain or inappropriate (p=0.48). The only independent predictors of mortality or myocardial infarction were a positive SE (hazard ratio 5.39) and left ventricular ejection fraction (hazard ratio 0.95). Conclusion: Appropriateness criteria for evaluation of coronary artery disease have the ability to both determine the need for stress testing and identify patients at high risk of ischaemia, subsequent revascularisation and cardiac events.
Maternal Death from Aspiration Asphyxia
Authors: R. B. Parker
Journal: BMJ (1956)

<h3>Background</h3> Multiforme erythema is an acute eruptive dermatosis, sometimes recurrent, reaction to various causes of unknown mechanism, characterised by maculopapular skin lesions. It occurs at any age. <h3>Purpose</h3> The aim of this work is to assess the causality of suspected adverse drug reactions in patients with multiforme erythema. <h3>Material and methods</h3> We report two cases of multiforme erythema in children. A 10-years-old boy, without significant pathological history. The patient had flu-like symptoms treated with ibuprofen and ivy extract (product of homeopathy). Six days’ later, the patient had erythematous skin lesions spread on the back, lower limbs and face associated with fever, conjunctivitis and gingivostomatitis. The differential viral diagnosis was eliminated and the cutaneous histology revealed a toxidermia tending to a multiforme Erythema. After 21 days of hospitalisation and symptomatic treatment, the evolution was favourable. A 4-years-old girl, epileptic treated with valproic acid for 9 months and lamotrigine for 21 days. The onset of symptomatology followed the association of lamotrigine with valproic acid. After 3 weeks of combination, the patient has erythematous rash and an attack of the mucosa. The diagnosis of the multiforme erythema of drug origin was retained on the anamnestic, clinical and histological elements, and the elimination of the differential diagnosis. Following hospitalisation and symptomatic treatment, the evolution was favourable. The causality assessment of adverse drug reactions was conducted according to the French method. <h3>Results</h3> For the first case, the results showed that the intrinsic imputability is an I4 score for the two drugs and the extrinsic imputability is a B4 score for ibuprofen and B1 for the ivy extract. In the second case, lamotrigin was incriminated with an I5 and B4 imputability score. <h3>Conclusion</h3> In order to optimise the detection and the management of this toxidermia and to improve the prognosis there are two rules to follow. Close monitoring of products and drugs interactions described in the literature that may cause severe toxidermia. Early consultation of any dermatological, post-drug symptoms and hospitalisation of the patient in case of any suspicion of a link between the drug intake and the adverse effect. <h3>Reference and/or Acknowledgements</h3> 1. Moore N, et al. Adverse drug reaction monitoring: Doing it the French way. <i>The Lancet</i>1985;326(8463). www.who.int/medicines/areas/quality_safety/safety_efficacy/trainingcourses/2imputabilitefr.pdf No conflict of interest
Pollen season is reflected on symptom load for grass and birch pollen‐induced allergic rhinitis in different geographic areas—An EAACI Task Force Report
Authors: Oliver Pfaar, Kostas Karatzas, Katharina Bastl, Uwe Berger, Jeroen Buters, Ulf Darsow, Pascal Demoly, Stephen R. Durham, Carmen Galán, Regula Gehrig, Roy Gerth van Wijk, Lars Jacobsen, Nikos Katsifarakis, Ludger Klimek, Annika Saarto, Mikhail Sofiev, Michel Thibaudon, Barbora Werchan, Karl‐Christian Bergmann
Journal: Allergy (2019)

The effectiveness of allergen immunotherapy (AIT) in seasonal and perennial allergic rhinitis (AR) depends on the definition of pollen exposure intensity or time period. We recently evaluated pollen and symptom data from Germany to examine the new definitions of the European Academy of Allergy and Clinical Immunology (EAACI) on pollen season and peak pollen period start and end. Now, we aim to confirm the feasibility of these definitions to properly mirror symptom loads for grass and birch pollen-induced allergic rhinitis in other European geographical areas such as Austria, Finland and France, and therefore their suitability for AIT and clinical practice support.Data from twenty-three pollen monitoring stations from three countries in Europe and for 3 years (2014-2016) were used to investigate the correlation between birch and grass pollen concentrations during the birch and grass pollen season defined via the EAACI criteria, and total nasal symptom and medication scores as reported with the aid of the patient's hay-fever diary (PHD). In addition, we conducted a statistical analysis, together with a graphical investigation, to reveal correlations and dependencies between the studied parameters.The analysis demonstrated that the definitions of pollen season as well as peak pollen period start and end as proposed by the EAACI are correlated to pollen-induced symptom loads reported by PHD users during birch and grass pollen season. A statistically significant correlation (slightly higher for birch) has been found between the Total Nasal Symptom and Medication Score (TNSMS) and the pollen concentration levels. Moreover, the maximum symptom levels occurred mostly within the peak pollen periods (PPP) following the EAACI criteria.Based on our analyses, we confirm the validity of the EAACI definitions on pollen season for both birch and grass and for a variety of geographical locations for the four European countries (including Germany from a previous publication) analyzed so far. On this basis, the use of the EAACI definitions is supported in future clinical trials on AIT as well as in daily routine for optimal patient care. Further evaluation of the EAACI criteria in other European regions is recommended.
DNA Methylation-Based Classification Highlights the Role of the JAK-STAT Pathway in Acute Myeloid Leukemia
Authors: Brian Giacopelli, Min Wang, Ada C Cleary, Yue-zhong Wu, Anna Reister Schultz, James S. Blachly, Ann-Kathrin Eisfeld, Kevin R Coombes, Clara D. Bloomfield, Brian J. Druker, Jeffrey W. Tyner, John C. Byrd, Christopher C. Oakes
Journal: Blood (2019)
A Novel Hybrid Transplantation with Autologous Hematopoietic Stem Cells and Matched Unrelated Cord Blood Stem Cells Is Effecttive and Safe for Relapsed or Refractory Lymphoma: A Pilot Study
Authors: Yongqian Jia, Jian Li, Huan Tao, Pu Kuang, Jie Ji, Xinchuan Chen, Zhigang Liu, Tian Dong, Jianjun Li, Fang Liu, Zhongping Lu, Ting Liu, Ting Niu, Li Zhang, Fan Liu, Sha Zhao, Guochao Xu, Qiang Chen, Rong Tian, Jianchun Lu, Yamei Leng, Qiuhui Wu, Xu Xu, Yingli Wang
Journal: Blood (2019)
Targeting mTOR in Head and Neck Cancer—Response
Authors: J. Silvio Gutkind, Terry A. Day, Scott M. Lippman, Eva Szabo
Journal: Clinical Cancer Research (2019)

We thank Masterson and colleagues for the kind and insightful comments, and for highlighting our team's efforts aimed at translating the emerging information of the head and neck cancer (HNSCC) oncogenome into new precision therapeutic options for this disease ([1][1]).

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Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference
Authors: Markus Cornberg, Anna Suk‐Fong Lok, Norah A. Terrault, Fabien Zoulim
Journal: Hepatology (2019)

Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic hepatitis B virus (HBV) treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilizing cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase 3 trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss, 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity in predicting sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive and HBeAg-negative chronic hepatitis, treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with increase in bilirubin or INR should prompt temporary or permanent cessation of investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase 3 trials for hepatitis D virus (HDV) co-infection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalization of ALT is considered an intermediate goal. CONCLUSION: For HBV 'functional cure', sustained HBsAg loss with undetectable HBV DNA after completion of treatment is the primary goal and sustained undetectable HBV DNA without HBsAg loss after stopping treatment an intermediate goal.