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2019-08-18T20:01:11.334Z | 2011-10-01T00:00:00.000Z | 202650910 | s2ag/train | Title Page / Table of Contents
s HORMONE RESEARCH IN PÆDIATRICS Basel • Freiburg • Paris • London • New York • New Delhi • Bangkok • Beijing • Tokyo • Kuala Lumpur • Singapore • Sydney HRP_2011_076_S02_tivo.indd I 01.07.2011 11:02:11 This publication was sponsored by Eli Lilly and Company Ferring Pharmaceuticals Ipsen Merck Serono S.A. Novo Nordisk A/S Pfizer Endocrine Care Sandoz International GmbH S. Karger Medical and Scientifi c Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Shanghai • Singapore • Tokyo • Sydney Disclaimer Th e statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). Th e appearance of advertisements in the journal is not a warranty, endorsement, or approval of the products or services advertised or of their eff ectiveness, quality or safety. Th e publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage Th e authors and the publisher have exerted every eff ort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant fl ow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. Th is is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specifi ed fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2011 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) ISBN 978–3–8055–9835–4 e–ISBN 978–3–8055–9836–1 Electronic production of the abstract book by pharma service – a business unit of documediaS GmbH Günther-Wagner-Allee 13, D–30177 Hannover (Germany) www.pharmaservice.de Printed by Lindendruck Verlagsgesellschaft mbH Fössestrasse 97A, D–30453 Hannover (Germany) www.lindendruck.de Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com HRP_2011_076_S02_tivo.indd II 01.07.2011 11:02:29 Page Abstract No. Date Plenary Lectures 1 PL1 Strengths and Limitations of Evidence-based Medicine 1-2 Sunday, September 25 1 PL2 Frontiers in Diabetes 3-4 Monday, September 26 PL3 ESPE Award Session & Activities 1 no abstracts Monday, September 26 2 PL4 ESPE Award Session & Activities 2 5-6 Tuesday, September 27 2 PL5 New Paradigms in Molecular Medicine 7 Tuesday, September 27 2 PL6 Food for Thought before Going Home 8-9 Wednesday, September 28 Symposia 4 S1 Evidence-based Medicine in Growth Assessment In memory of Professor James Tanner 10-12 Sunday, September 25 4 S2 Early Life Origins of Health and Disease 13-15 Sunday, September 25 5 S3 New Insights in Phosphate Metabolism 16-18 Sunday, September 25 5 S4 Principles of Evidence-based Medicine 19-21 Monday, September 26 6 S5 Long Term Safety of Drugs 22-24 Monday, September 26 7 S6 Unexpected Ef fects of Hormones on the Brain 25-27 Monday, September 26 7 S7 Evidence-based Medicine in Childhood and Adolescent Diabetes ISPAD/ESPE 28-30 Tuesday, September 27 8 S8 The Cortisol-Cortisone Shuttle in Health and Disease 31-33 Tuesday, September 27 8 S9 Impact of Chronic Conditions on Growth 34-36 Tuesday, September 27 9 S10 Evidence-based Medicine in Thyroid Diseases 37-39 Wednesday, September 28 9 S11 New Insights in the Pathogenesis of PCOS APPES/ESPE 40-42 Wednesday, September 28 10 S12 Update on Growth Hormone Long Term Safety 43-46 Wednesday, September 28 New Perspectives 12 NP1 New Perspectives in Brain Imaging 47-48 Monday, September 26 12 NP2 New Perspectives in Molecular Analysis 49-50 Tuesday, September 27 ESPE Working Groups 13 WG1 ESPE Bone and Growth Plate Working Group 51-58 Sunday, September 25 15 WG2 ESPE Disorder of Sex Development Working Group 59-66 Sunday, September 25 17 WG3 ESPE Obesity Working Group: Long and Short-term Consequences of Childhood Obesity 67-69 Sunday, September 25 17 WG4 ESPE Paediatric and Adolescent Gynaecology Working Group: Amenorrhea in Adolescence 70-75 Sunday, September 25 19 WG5 ESPE Turner Syndrome Working Group: Ovarian Failure in Turner Syndrome 76-80 Sunday, September 25 Free Communications 20 FC1 Adipose Tissue and Obesity 81-86 Monday, September 26 22 FC2 Adrenal 87-92 Monday, September 26 23 FC3 Pituitary 93-98 Monday, September 26 26 FC4 Bone and Mineral Metabolism 99-104 Tuesday, September 27 28 FC5 Growth Hormone 105-110 Tuesday, September 27 30 FC6 Sexual Development 111-116 Tuesday, September 27 32 FC7 Cell Growth and Endocrine Oncology 117-122 Tuesday, September 27 34 FC8 Diabetes and the Beta Cell 123-128 Tuesday, September 27 36 FC9 Reproductive System 129-134 Tuesday, September 27 38 FC10 The X Chromosome 135-140 Tuesday, September 27 40 FC11 Diabetes Complications 141-146 Wednesday, September 28 42 FC12 Growth/Acid Labile Subunit 147-152 Wednesday, September 28 44 FC13 Puberty 153-158 Wednesday, September 28 46 FC14 Thyroid 159-164 Wednesday, September 28 Poster Presentations 49 P1-d1 Adrenal and HPA Axis 1 165-176 Sunday, September 25 53 P1-d2 Adrenal and HPA Axis 2 177-186 Monday, September 26 56 P1-d3 Autoimmune Endocrine Disease/Endocrine Oncology 1 187-192 Tuesday, September 27 58 P1-d1 Bone, Growth Plate and Mineral Metabolism 1 193-201 Sunday, September 25 61 P1-d3 Bone, Growth Plate and Mineral Metabolism 2 202-210 Tuesday, September 27 | v2 |
2019-03-19T13:07:13.819Z | 1987-01-01T00:00:00.000Z | 82402150 | s2ag/train | Molecular genetics of plant-microbe interactions : proceedings of the Third International Symposium on the Molecular Genetics of Plant-Microbe Associations, Montréal, Québec, Canada, July 27-31, 1986
Section I: Molecular Genetics of Agrobacterium and Plant Transformation.- "Ecology of Agrobacterium: plasmids and biovars".- "The Agrobacterium rhizogenes root-inducing system".- "Effect of the presence of the plasmid pSA and of auxin on the attachment of Agrobacterium tumefaciens to plant host cells".- "Dual regulation of virulence genes of Agrobacterium plasmid pTiC58".- "Overdrive, a T-DNA transmission enhancer on the A. tumefaciens tumor-inducing plasmid".- "Physical structure and genetics of the T-DNA in plants transformed by Agrobacterium tumefaciens".- "Mammalian metallothionein functions in plants".- "Tumorigenesis and root nodulation by Agrobacterium tumefaciens carrying Rhizobium symplasmids".- Supplementary articles (see Section VI).- Section II: Molecular Genetics of Phytopathogenic Bacteria and Fungi.- "Cutinase and pectinase in host-pathogen and plant-bacterial interaction".- "Siderophore biosynthesis, uptake and effect on potato growth of rhizosphere strains".- "A gene cluster in Xanthomonas campestris PV Campestris required for pathogenicity controls the excretion of enzymes".- "Direct analysis of the invasiveness of Xanthomonas campestris mutants generated by Tn4431, a transposon containing a promoterless luciferase cassette for monitoring gene expression".- "Analysis of the spontaneous mutation to avirulence by Pseudomonas solanacearum".- "Characterization of pathogenicity genes of Erwinia carotovora".- "Characterization of a novel esterase produced by plant pathogenic Streptomyces".- Supplementary articles (see Section VI).- Section III: Molecular Genetics of the Host = (Symbiosis/Pathogenicity).- "Induced symbiosis mutants of Pisum sativum".- "Plant host genetics of nodulation initiation in soybean".- "A mutant of pea (Pisum sativum) possibly disturbed in the production of a compound required for the induction of nitrogenase activity in bacteroids".- "Non-modulation mutants of soybean".- "Early nodulins in root nodule development".- "Peribacteroid membrane nodulins of soybean".- "Isolation of nodule specific c-DNA clones from Medicago sativa".- "Analysis of nodule-specific gene expression in ineffective alfalfa root nodules and callus cultures derived from ineffective root nodules".- "Nodule specific genes in Phaseolus vulgaris".- "Investigation of plant genes expressed during symbiotic nitrogen fixation".- "Rhizobium induced plant proteins in target root epidermal cells of Vigna unguiculata".- "Four soybean nodulin genes evolved from a common ancestor".- "Coordinated expression of nodule-specific and root genes in yellow lupin".- "Plant gene expression during effect and ineffective nodule development of the tropical stem-nodulated legume Sesbania rostrata".- "Expression of two enzymes involved in ureide formation in soybean regulated by oxygen".- "Probing cell wall structure in the soybean root nodule".- "Monoclonal antibodies to components of Rhizobium-induced pea nodules".- "Localization of the glutamine synthetase polypeptides in Phaseolus root nodules".- "Changes in protein and mRNA accumulation in potato tubers treated with an elicitor".- Section IV: Molecular Genetics of Rhizobium.- "Organization of the Rhizobium phaseoli genome".- "Rifampin resistance and nodulating competitiveness in Rhizobium meliloti".- "A method for isolating competition defective mutants in Rhizobium".- "Genetic determinants of nodulation in pR1e 1001a: nodD".- "Symbiotic mutants of Rhizobium meliloti which produce non-succinylated exopolysaccharide".- "Rhizobium mutants defective in lipopolysaccharide and infection".- "Analysis of three Rhizobium phaseoli genes, psi, psr and pss, which affect exopolysaccharide synthesis and symbiotic nitrogen fixation and/or nodulation".- "Involvement of pSym nodulation genes in production of surface and extracellular components of Rhizobium trifolii which interact with white clover root hairs".- "Rhizobium exopolysaccharides are essential for the formation of nitrogen fixing nodules in the Rhizobium-legume symbiosis".- "Coinoculation with symbiotically defective mutants of Rhizobium meliloti".- "Surface properties of Rhizobium meliloti associated with symbiosis".- "Degradative enzymes in Rhizobium meliloti".- "Identification of host specificity DNA regions determining the broad host range nodulation of Rhizobium strain NGR234".- "Nif, Fix and Nod gene clusters in Bradyrhizobium japonicum, and nifA-mediated control of symbiotic nitrogen fixation".- "Molecular genetics of nodulation of soybean by Bradyrhizobium japonicum".- "Characterization of genes essential for symbiotic nitrogen fixation from Bradyrhizobium japonicum strain I110".- "Nodulation genes of the stem nodulating Sesbania rostrata symbiont, strain ORS571".- "Nod-linked host specific gene for soybean (Peking) nodulation in Rhizobium fredii USDA193".- "Genomic organization of nodulation genes in Rhizobium phaseoli".- "Common and host specific nodulation genes in Rhizobium meliloti and their conservation in other Rhizobia".- "Host specific nodulation: effects of multiple nodD genes of Rhizobium meliloti".- "Nodulation genes of Rhizobium leguminosarum".- "Interactions between Rhizobium mililoti and Rhizobium trifolii nodulation genes: what is the basis for dominance by R. mililoti?".- "Multiple host-specificity loci in the broad host-range Rhizobium NGR234".- "Conserved nodulation genes are obligatory for non-legume nodulation".- "Characterization of symbiotic genes and regulation of their expression in Rhizobium leguminosarum pre".- "Regulation of the promoters in the nodulation region of the symbiosis plasmid pRL1J1 of Rhizobium leguminosarum".- "Narigenin induces the nodABC promoter of Rhizobium leguminosarum as well as Tsr factor production".- "An ntrC homologue in B. japonicum".- "Glutamine synthetases of Rhizobium leguminosarum".- "Molecular analysis of a Fix cluster from Rhizobium meliloti".- "Regulation of the nitrogen fixation (Nif) genes in Rhizobium meliloti".- "The unusual symbiosis between the nitrogen fixing bacterium ORS571 and its host Sesbania rostrata: regulation of nitrogen fixation and assimilation genes in the free living versus symbiotic state".- "Analysis of Azorhizobium sesbaniae ORS571 N2 fixation genes".- "Identification, characterisation and sequence analysis of the Rhizobium leguminosarum nifA gene".- "Analysis of hup DNA and Hup host range of Rhizobium leguminosarum BIO".- "Bioluminescence in root nodules of soybean controlled by nitrogenase promoters".- "In vivo cloning of genes from Bradyrhizobium japonicum".- "Genes for the catabolism and synthesis of a nodule-specific, opine-like compound are closely linked and on the Sym plasmid of Rhizobium meliloti".- "Molecular biology of genes involved in carbon metabolism in Rhizobium meliloti and Bradyrhizobium japonicum".- "Azorhizobium sesbaniae ORS571 conducts synergistic N2 fixation and nicotinic acid oxidation".- "At least three loci encode the leaf-curl phenotype in Rhizobium strain IC3342".- Section V: Molecular Genetics of the Other Diazotrophic Organisms.- "Use of heterologous hybridization in phylogenetic studies of symbiotic Anabaena strains".- "Chromobacterium lividum NCTC 10590 is a nitrogen-fixing Agrobacterium radiobacter".- "Studies on the diazotrophic nature of Agrobacterium".- "Developments in the genetic analysis of Azospirillum".- Section VI: Supplementary Articles for Sections I and II.- "Role of Vir genes in the excision of T-DNA from the ti-plasmid".- "Cloning vectors for Coryneform bacteria".- "Cloning of Serratia liquefaciens chitinase gene(s)".- Author Index. | v2 |
2019-11-22T00:50:09.442Z | 2019-11-13T00:00:00.000Z | 209286010 | s2ag/train | Synergistic Targeting of BTK and E-Selectin/CXCR4 in the Microenvironment of Mantle Cell Lymphomas
Mantle cell lymphoma (MCL) is a rare subtype of aggressive B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. Overexpression of B-cell receptor signaling through Bruton tyrosine kinase (BTK) is a hallmark of MCL (Pal Singh et al., 2018). Inactivation of BTK signaling with the small molecule inhibitor ibrutinib is currently the most broadly used treatment of B cell lymphoma. However, it induces only low rates of apoptosis in vitro at clinically achievable concentrations. Frequently, primary and acquired resistance is observed (Chiron et al., 2014; Wang et al., 2013). One of the molecular mechanisms of acquired resistance is the development of BTKC481S mutations (Martin et al., 2016). In addition, the tumor microenvironment (TME), in which mesenchymal stroma cells (MSC) and vascular endothelial cells (ECs) are specialized components, has increasingly been recognized as a central determinant of drug resistance, subclonal evolution and late progression/transformation of B-cell lymphomas (Balsas et al., 2017; Weis and Cheresh, 2011).
Although the pro-tumoral ecosystem that supports MCL is still poorly understood, it has been reported that MCL cells express high levels of functional CXCR4 and CXCR5 chemokine receptors and VLA-4 adhesion molecules (Kurtova et al., 2009) . Lymphoma cells also display high levels of CD44, one of E-selectin ligands, in co-culture with ECs (Cao et al., 2014). These findings strongly suggest the association of acquired BTK mutations and the TME with resistance to BTK-targeted therapy in MCL. Therefore, we hypothesize that disrupting the crosstalk of MCL cells and TME by blocking CXCR4/CXCL12 or E-selectin/CD44 might benefit BTK-targeted therapy against MCL.
In this study, we investigated the anti-lymphoma effect of a novel small-molecule multi-kinase inhibitor CG-806 which exerts promising enzymatic inhibitory activity against the C481S mutation and wild type BTK at extremely low doses (IC50s were 2.52 and 5 nM, respectively). CG-806 demonstrated impressive anti-lymphoma effects in MCL cell lines Z138, MINO, Jeko-1 and JVM2 (IC50s of 2.7, 3.87, 3.79 and 8.27 nM, respectively), all of which were much less sensitive to ibrutinib (IC50s ≈ 10,000 nM). Mechanistically, CG-806 not only suppressed BTK activation, but also its downstream signaling targets phospho-Stat3,-AKT,-ERK and -Src, as well as NF-κB and c-Myc, and surprisingly upregulated p53 in MCL cells but exerted no suppression of phospho-FLT3 and aurora kinase at tested doses in MCL cells, two of the other potential CG-806 targets. Interestingly, CG-806 triggered profound apoptosis in Z138 and MINO cells as evidenced by increased cleavage of caspase-3 and PARP and expression of annexin V (EC50s 4.91 and 6.35 nM, respectively), but showed resistance in Jeko-1 and JVM2 cells (EC50s 7,800 and 3260 nM, respectively), which was accompanied with marked upregulation of autophagy, implicating autophagy as a novel resistance mechanism to BTK inhibition. Interestedly, our previous studies demonstrated that TME components MSC/hypoxia mediated autophagy upregulation which was associated with resistance in AML cells (Zhang et al., 2018), and, on the other hand, upregulation of autophagy was also observed in FLT3 wild type AML cells after CG-806 treatment, which resulted in resistance to CG-806-triggered apoptosis induction (Zhang et al., unpublished). Nevertheless, suppression of autophagy with the ULK1 inhibitor SBI-0206965 (Egan et al., 2015) or a putative autophagy inhibitor Chloroquine (CQ) (Mauthe et al., 2018) partially enhanced CG-806-induced apoptosis in the resistant Jeko-1 cells, confirming a role for autophagy in resistance to BTK inhibitors in MCL.
Furthermore, CXCR4 and E-selectin ligand levels were upregulated by exposing MCL cells in either ibrutinib or CG-806, and co-culture of MCL cells Z138 with MSC or HUVEC cells partially protected MCL cells from CG-806-triggered apoptosis. Of note, blockade of CXCR4 or E-selectin with their antagonist plerixafor or GMI-1271, respectively, re-sensitized to CG-806-induced apoptosis in MCL cells, suggesting potential benefit of disrupting the crosstalk of TME and lymphoma cells in MCL therapy. Taken together, our findings may provide the basis for a new therapeutic strategy co-targeting TME, autophagy and BTK with the goal of overcoming the resistance to BTK-targeted therapy in MCL.
Zhang: Aptose Biosciences, Inc: Employment. Fogler:GlycoMimetics Inc: Employment, Equity Ownership. Rice:Aptose Biosciences, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Magnani:GlycoMimetics Inc: Employment, Equity Ownership. Borthakur:BMS: Research Funding; Tetralogic Pharmaceuticals: Research Funding; AstraZeneca: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Cyclacel: Research Funding; Janssen: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Consultancy; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Strategia Therapeutics: Research Funding; Bayer Healthcare AG: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Oncoceutics, Inc.: Research Funding; Agensys: Research Funding; GSK: Research Funding; Incyte: Research Funding; Polaris: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees. Andreeff:CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; AstaZeneca: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2021-07-07T06:16:39.963Z | 2021-06-30T00:00:00.000Z | 235746660 | s2ag/train | Epidemiology and future prediction of Korean liver, pancreatic and biliary cancer.
Lecture
Supported by a national policy on cancer prevention and screening in Korea, the incidence of all types of cancers peaked in 2011 and turned into a declining trend. The overall cancer mortality rate has also steadily decreased since 2002 due to advances in diagnostic and treatment modalities. In 2018, liver, pancreas, gallbladder and biliary tract cancer were the 6th (6.5% of all cancers), 8th (3.1%), and 9th (2.9%) most common cancers in Korea [1]. Although the incidence of hepatocellular carcinoma is decreasing due to vaccination and effective treatment for viral hepatitis, incidences of pancreatic and biliary tract cancer are rapidly increasing. Moreover, liver and pancreatic cancer ranked the 2nd and 5th most common causes of death in 2019 [2]. However, due to relatively small number of patients, liver, pancreatic and biliary tract cancer have not been given a priority in national health policy, despite being fatal. Moreover, there are no studies related to future predictions regarding long-term changes in incidence and mortality. Therefore, the purpose of this study was to predict epidemiologic features of liver, pancreatic, and biliary tract cancer to build evidence that could provide insight into health policy and budget allocation, including cancer prevention, diagnosis and treatment strategies.
Incidence and mortality rate of liver, pancreas, and biliary tract cancer in Korea from 1999 to 2017
Summary statistics of liver cancer (C22) was retrieved from annual report of cancer statistics published by Korea Central Cancer Registry [1]. For pancreatic and biliary tract cancer, incidence data was retrieved from Korea Central Cancer Registry, National Cancer Center. Individuals with corresponding International Statistical Classification of Diseases and Related Health Problems (ICD)-10 codes and international classification of diseases for oncology (ICD-O) morphology codes were categorized as follows; gallbladder cancer (C23), intrahepatic bile duct cancer (C22.1, excluding M8162/3), extrahepatic bile duct cancer (C24.0 and M8162/3), ampulla of Vater cancer (C24.1), and pancreatic cancer (C25). Individuals with a morphology code "M8162/3" were reclassified as extrahepatic bile duct cancer because changes in topographic classification of Klatskin tumor overestimated cases of intrahepatic bile duct cancer [3]. However, mortality data retrieved from Statistics Korea from 2002 to 2018 did not have an identifier to reclassify the bile duct cancer accordingly. Therefore, mortality rate analysis and future epidemiology prediction utilized the sum of intra- and extrahepatic bile duct cancer as a single category for consistent analysis. From 2009 to 2018, annual percentage change (APC) of age-standardized incidence rate (ASIR, per 100,000 population) of liver cancer was -4.1% (24.0 to 16.7) [1]. From 1999 to 2017 trends in ASIR of each cancer were as follows; 2.9 to 2.6 (gallbladder [GB], APC -1.03%, p < 0.0001), 2.0 to 2.7 (intrahepatic bile duct [IBD], APC 2.30%, p = 0.0033), 2.9 to 3.2 (extrahepatic bile duct [EBD], APC 0.93%, p = 0.0009), 0.9 to 0.9 (ampulla of Vater [AoV], APC -0.37%, p = 0.1992), and 5.6 to 7.1 (pancreas, APC 1.46%, p < 0.0001). Especially, APC of pancreatic cancer ASIR in females was significantly higher than in males (2.30% vs. 0.61%, p < 0.0001). Male to female ASR ratio decreased in GB (1.08 to 1.00), IBD (2.55 to 2.18), EBD (2.28 to 1.94), and pancreatic cancer (1.95 to 1.45). Age-standardized mortality rate (ASMR) of each cancer was as follows; 18.7 to 8.0 (liver), 2.4 to 1.6 (GB), 5.5 to 4.6 (IBD and EBD), 0.4 to 0.4 (AoV) and 5.5 to 5.6 (pancreas).
Predicting future epidemiology of liver, pancreatic, and biliary tract cancer in Korea until 2040
Incidence and mortality rate was predicted using an age-period-cohort model (λ(age, period) = g{fA (age) + fP (period) + fC (cohort)}; λ, incidence [mortality] rate as a function of age and calendar period; g, 'link' function; fA, function of age; fP, function of period [year of incidence or mortality]; fC, function of cohort [year of birth, i.e., cohort=period-age]) [4]. Due to inconsistent coding practice in the causes of death statistics, ICD-10 codes used for prediction on future incidence and mortality were categorized as follows; Liver cancer (C22.0, C22.9), GB cancer (C23), IBD and EBD cancer (C22.1, C24.0, C24.8, C24.9), AoV cancer (C24.1), and pancreatic cancer (C25). To adjust future demographic structure, estimated population by Statistics Korea was applied to calculate ASIRs and ASMRs. Predicted annual cases of newly diagnosed cancer from 2021 to 2040 increased in all types of cancers as follows; 12,169 to 13,089 (liver), 2,857 to 4,038 (GB), 6,600 to 7,964 (IBD and EBD), 935 to 1,376 (AoV), 8,578 to 16,170 (pancreas). Predicted ASIR increased only in pancreatic cancer (7.5 to 8.2), while other cancers had declining trends; 12.0 to 8.5 (liver), 2.3 to 1.7 (GB), 5.4 to 3.2 (IBD and EBD), and 0.8 to 0.6 (AoV). Predicted annual deaths from 2021 to 2040 decreased in liver cancer (7,119 to 6,037), while other cancers had increasing trends as follows; 1,822 to 2,391 (GB), 5,598 to 7,928 (IBD and EBD), 408 to 536 (AoV), and 6,598 to 11,023 (pancreas). Predicted ASMR decreased in all types of cancers; 6.5 to 3.2 (liver), 1.4 to 0.9 (GB), 4.3 to 2.9 (IBD and EBD), 0.3 to 0.2 (AoV), and 5.4 to 4.7 (pancreas).
Conclusion
Pancreatic cancer revealed an increasing trend in ASIR, and the projected cases in 2040 are expected to outnumber those of liver cancer where ASIR is rapidly declining. ASIRs of GB, IBD and EBD, and AoV cancer had declining trends. Predicted ASMRs tended to decrease in all types of cancers, and ASMR of pancreatic cancer surpasses that of liver cancer from 2026. Epidemiologic analysis and prediction should be conducted on an ongoing bases by researchers, including clinicians. Based on the accumulated results, we look forward to the establishment and implementation of a better national cancer policy in the future. | v2 |
2022-06-10T02:09:24.536Z | 2014-01-01T00:00:00.000Z | 249519660 | s2ag/train | Abstract 1 – Insights Into Pancreatic Cancer Metabolism
1 – Insights Into Pancreatic Cancer Metabolism NABEEL BARDEESY,MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASSACHUSETTS, USA Cancercellsdependonwidespreadchanges incellmetabolismtomaintain rapidgrowth.Themetabolic requirementsofpancreatic cancers may be particularly stringent because of their fibrotic and poorly vascularized tumor microenvironment and resulting hypoxia and limited nutrient availability. Accordingly, these tumors exhibit multiple alterations in nutrient acquisition and utilization that are required for malignant growth, including activation of autophagy, a process by which organelles and protein aggregates are recycled by engulfment in modified membranes and degraded in lysosomes. In this presentation, we discuss the mechanisms leading to autophagy activation and the output from this process that maintains energy homeostasis in pancreatic cancer.We also discuss howmutations in pancreatic cancer driver genes rewire tumor cell metabolism as part of their oncogenic program. The identification of these metabolic dependencies in pancreatic cancer suggests novel therapeutic strategies. Abstract 2 – TheHistoneDeacetylase SIRT6: Linking Epigenetics to CancerMetabolism RAUL MOSTOSLAVSKY,MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASSACHUSETTS, USA2 – TheHistoneDeacetylase SIRT6: Linking Epigenetics to CancerMetabolism RAUL MOSTOSLAVSKY,MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASSACHUSETTS, USA Efficient glucose metabolism is critical for maintaining cellular viability. Under normal nutrient and oxygen conditions, glucose is converted to pyruvate, entering the mitochondria for oxidative phosphorylation and ATP production. Under hypoxia or nutrient stress,metabolismis switchedtoglycolysis, increasing lactateproductionandreducingmitochondrial respiration—aswitchknown to play an important role in cancer cells, as defined by OttoWarburg decades ago. Little is known about whether chromatin plays a role in carbohydrate flux. Recently,wediscovered that themammalian histone deacetylase sirtuin 6 (SIRT6) is a chromatin factor that influences glucose metabolism and DNA repair. At the cellular level, SIRT6 inactivation leads to increased cellular glucose uptake, higher lactate production, and decreased mitochondrial activity. Our results indicate that SIRT6 directly regulates expression of several key glycolytic and ribosomal genes. SIRT6 corepresses hypoxia-inducible factor-1a, acting as a histone H3 lysine 9andH3 lysine 56deacetylase to inhibit expressionof their target genes and functioningas a tumor suppressor to inhibit the Warburg effect. Strikingly, our new studies indicate that SIRT6, in contrast to other histone deacetylases (HDACs), appears to regulate transcriptional elongation, a novel function for HDACs. Our work identified SIRT6 as a critical chromatin deacetylase at a nodal point between epigenetics and metabolism, functioning as an important tumor suppressor. Abstract 3 – Improving the Treatment of Prostate Cancer JOHANN DE BONO, INSTITUTE OF CANCER RESEARCH, THE ROYAL MARSDEN, SUTTON, UNITED KINGDOM3 – Improving the Treatment of Prostate Cancer JOHANN DE BONO, INSTITUTE OF CANCER RESEARCH, THE ROYAL MARSDEN, SUTTON, UNITED KINGDOM This presentation will focus on the improved understanding of castration-resistant prostate cancer and the delivery of precision medicine for this disease. Recent developments with abiraterone, enzalutamide, cabazitaxel, and radium-223 will be discussed. Dataonnovelagents includingAKT,p110b,andpoly(ADP-ribose)polymerase inhibitorsandcabozantinibwill alsobediscussed.The study of exome and transcriptome data in early clinical trials for advanced prostate cancer to drive the pharmacological audit trail will also be presented. TheOncologist 2014;19(Supplement 1):S1–S6 www.TheOncologist.com ©AlphaMed Press 2014 Abstract 4 – Curative Potential of Cell Transfer Immunotherapy for Cancer4 – Curative Potential of Cell Transfer Immunotherapy for Cancer STEVEN A. ROSENBERG, NATIONAL CANCER INSTITUTE, BETHESDA, MARYLAND, USA Adoptive cell transfer (ACT) immunotherapy for patients with metastatic melanoma using autologous tumor-infiltrating lymphocytes (TILs) mediated a 56% objective response rate, including 20% of patients with durable complete regression ongoing from6.7 to 10.3 years. Administration of autologous TILs to nine patients with human papillomavirus-inducedmetastatic cervical cancer mediated objective responses in three patients, including two complete regressions that are ongoing beyond a year. The ideal targets for ACT are the uniquemutations that occur in cancers (Table 1). Using deep exomic sequencing, a technique has been developed to identify any cancer mutation—presented on any of the patient’s major histocompatibility complex molecules—that gives rise to reactive T cells.We recently reported the successful application of this approach to treat a patient with ametastatic bile duct cancer. Because virtually all cancers containmutations, this approach is nowbeing vigorously studied to expand the current reach of cancer immunotherapy to common epithelial cancers. Genes encoding conventional a-b T-cell receptors or chimeric antigen receptors (CARs) can be efficiently transduced into autologous lymphocytes, although choosing suitable targets expressed on the cancer is critical to avoid toxicities to essential normal tissues. ACT using CARs to target the CD19 molecule present on normal B cells and on the great majority of B-cell lymphomas and leukemiaswas first reportedtosuccessfully treatapatientwith refractory lymphoma in2010; thatpatient remainsprogression free at 5 years. Durable complete and partial responses have been seen in patients with chemotherapy-refractory indolent and aggressive large B-cell lymphomas. Of 9 patients heavily pretreated with large cell lymphomas receiving ACT, 4 patients have had complete regressions (2 ongoing from 9 to 22 months), and 2 additional patients have had partial response. Cancer-testis antigens such as NY-ESO-1 and MAGE-A3 are expressed during fetal development and in 10%–80% of cancers frommultiple tissuesbutoftenarenotexpressed inadult normal tissues.ACT targetingNY-ESO-1 resulted ina67%response rate in 15 treated patients with refractory synovial cell sarcoma and a 53% response rate in 19 patientswithmelanoma including durable complete regressions. Shared mutations that are unique to an individual cancer type also represent excellent targets for cell transfer immunotherapy, andweare conducting a trial usinga CAR targeting the EGFRvIIImutation, expressed in∼40%ofpatients with high-grade glioblastoma. Table 1. Surgery Branch, National Cancer Institute program for the application of cell transfer therapy to awide variety of human cancers Receptor Type Cancers Status Mutations TCR All cancers Accruing MART-1 TCR Melanoma Closed gp100 TCR Melanoma Closed NY-ESO-1 TCR Epithelial and sarcomas Accruing CEA TCR Colorectal Closed CD19 CAR Lymphomas Accruing VEGFR2 CAR All cancers Accruing 2G-1 TCR Kidney Accruing IL-12 Cytokine Adjuvant for all receptors Accruing MAGE-A3 TCR Epithelial Accruing EGFRvIII CAR Glioblastoma Accruing SSX-2 TCR Epithelial In development Mesothelin CAR Pancreas and mesothelioma Accruing CSP4 (HMWAg) CAR Melanoma, TN breast, Pancreas In development HPV-16 and -17 TCR Cervix, anal, oropharyngeal In development Abbreviations: CAR, chimeric antigen receptor; HPV, human papillomavirus; TCR, T-cell receptor; TN breast, triple-negative breast. ©AlphaMed Press 2014 The Oncologist S2 | v2 |
2020-11-05T09:06:01.233Z | 2020-11-05T00:00:00.000Z | 228878150 | s2ag/train | Symptom Burden and Quality of Life in High-Risk Essential Thrombocythemia and Polycythemia Vera Patients Receiving Hydroxyurea or Pegylated Interferon Alfa-2a: Results of Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 Trials
Introduction
Essential thrombocythemia (ET) and polycythemia vera (PV) patients suffer from various symptoms that worsen quality of life (QOL), yet serial data on symptom changes resulting from therapy are sparse in the literature. Patient questionnaires from 2 large multicenter trials (MPN-RC 111, 112) were used to assess change in symptom burden and QOL over 12 months and impact of baseline symptom burden on subsequent change in ET / PV patients on hydroxyurea (HU) or pegylated interferon alfa-2a (PEG).
Methods
Trials
MPN-RC 111 was a single-arm, open-label, phase II trial evaluating response to PEG in high-risk ET / PV patients with HU resistance/intolerance or splanchnic vein thrombosis (SVT; NCT01259817). MPN-RC 112 was a randomized, open-label, phase III trial comparing response to PEG versus HU in cytoreductive therapy naïve high-risk ET / PV patients diagnosed < 5 years ago (NCT01258856).
Measures
Patients reported disease-related symptoms via the validated Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF), QOL via the European Organisation for the Research and Treatment of Cancer Core QOL Questionnaire (EORTC QLQ-C30), and (if applicable) PEG-related symptoms (flu-like symptoms, injection site irritation, blurry vision, vision change, flushing) at baseline, 3, 6, 9, and 12 months.
Analysis
Mixed models assessed mean changes from baseline in the MPN-SAF Total Symptom Score (TSS), MPN-SAF items, QOL, and PEG-related symptoms in MPN-RC 111, 112 PEG, and 112 HU patients. Mixed models also assessed the impact of baseline symptom burden (high [TSS ≥ 20] versus low) on subsequent change in PEG (MPN-RC 111 and 112) and HU patients.
Results
Patients
Of the 135 enrolled MPN-RC 111 patients, 20 with SVT and 1 with no questionnaires were excluded. Of the remaining 114, 64 (56%) / 50 (44%) had ET / PV. Patients were 51% / 48% female. Median age was 65 / 64 years, and median time since diagnosis was 38 / 55 months. 31% / 22% had prior thrombosis, and 19% / 56% had splenomegaly.
Of the 168 enrolled MPN-RC 112 patients (82 PEG, 86 HU), 2 with no questionnaires were excluded. Of the remaining 166, 79 (48%) / 87 (52%) had ET / PV. Patients were 50% / 33% female. Median age was 60 / 62 years, and median time since diagnosis was 3 / 3 months. 25% / 29% had prior thrombosis, and 11% / 37% had splenomegaly.
Symptoms
Questionnaire completion rates ranged from 90 - 99%, 87 - 100%, and 75 - 96% for on-treatment MPN-RC 111, 112 PEG, and 112 HU patients. At baseline, TSS (0 [absent] - 100 [worst imaginable]) and QOL (0 [very poor] - 100 [excellent]) means (SDs) were 19.5 (18.4) and 71.6 (20.1) for MPN-RC 111, 17.0 (13.6) and 67.9 (24.3) for MPN-RC 112 PEG, and 14.6 (11.4) and 73.8 (18.8) for MPN-RC 112 HU patients. On average, MPN-RC 111 patients had significant improvement of TSS, fatigue, abdominal pain, abdominal discomfort, dizziness, numbness, night sweats, and fever; MPN-RC 112 PEG patients had significant worsening of fever; and MPN-RC 112 HU patients had significant worsening of inactivity (no mean changes indicating improvement were observed). PEG patients had significant worsening of PEG-related symptoms.
The greatest improvements occurred in the 46 (40%), 27 (33%), and 23 (28%) MPN-RC 111, 112 PEG, and 112 HU patients with high baseline symptom burden. On average, PEG patients with high baseline symptom burden had significant improvement of TSS, fatigue, early satiety, abdominal pain, abdominal discomfort, inactivity, headache, concentration, dizziness, numbness, insomnia, cough, night sweats, itching, bone pain, fever, weight loss, and QOL, while those with low baseline symptom burden had significant worsening of TSS, early satiety, headache, itching, and bone pain. On average, HU patients with high baseline symptom burden had significant improvement of TSS, early satiety, abdominal discomfort, headache, dizziness, numbness, insomnia, itching, and weight loss, while those with low baseline symptom burden had significant worsening of TSS, early satiety, abdominal discomfort, inactivity, concentration, and sexual desire/function (Figures 1 and 2).
Conclusions
Although no statistical comparisons were made across trials, overall improvements were seen in MPN-RC 111 but not 112. Patients with high baseline symptom burden experienced the greatest improvements in symptom burden and QOL during treatment with PEG or HU, which may explain the improvements seen in the more advanced patients in MPN-RC 111 compared to 112.
Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Yacoub:Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Cara Therapeutics: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in private company; Incyte: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Hoffman:Protagonist: Consultancy; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding. Silver:PharmaEssentia: Speakers Bureau. Mesa:Bristol Myers Squibb: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Promedior: Research Funding; Sierra Oncology: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Novartis: Consultancy.
| v2 |
2017-10-27T08:41:57.735Z | 2001-01-01T00:00:00.000Z | 44850270 | s2ag/train | Mossbauer , EPR , and ENDOR Studies of the Hydroxylase and Reductase Components of Methane Monooxygenase from Methylosinus trichosporium OB 3 b
Soluble methane monooxygenase (MMO) isolated from Methylosinus trichosporium OB3b consists of three components: hydroxylase, reductase, and component B. The active-site diiron cluster of the hydroxylase has been studied with Mossbauer, ENDOR, and EPR spectroscopies. Mossbauer spectra of the oxidized cluster show that the two high-spin irons are antiferromagnetically coupled in accord with our preliminary study (Fox et al. J . Biol. Chem. 1988, 263, 10553-10556). Mossbauer studies also reveal the presence of two cluster conformations at pH 9. The excited-state S = 2 multiplet of the exchange-coupled cluster (Fe3+.Fe3+) gives rise to an integer-spin EPR signal near g = 8; this is the first quantitative study of such a signal from any system. Analysis of the temperature dependence of the g = 8 signal yields J = 15 f 5 cm-I for the exchange-coupling constant (Hex = JSleS2). This value is more than 1 order of magnitude smaller than those reported for the oxo-bridged clusters of hemerythrin and Escherichia coli ribonucleotide reductase (Hex = JSI.S2, J = 270 and 220 cm-I, respectively), suggesting that the bridging ligand of the hydroxylase cluster is not an unsubstituted oxygen atom. Mossbauer spectra of the hydroxylase in applied fields of up to 8 T reveal a paramagnetic admixture of a low-lying excited state into the ground singlet. Both the spectral shape and intensity are well represented by assuming that the spin expectation values for the cluster sites increase linearly with magnetic field. However, the origin of this effect is not fully explicable in the framework of the standard spin Hamiltonian including zero-field splittings and antisymmetric exchange. EPR studies of the uncomplexed mixed valence (Fe3+.Fe2+) hydroxylase show that it is composed of two slightly different cluster forms in an approximate 4: 1 ratio. The zero-field splitting (ZFS) of the ferrous site of the mixed valence hydroxylase is sensitive to complexation with products or inhibitors, while complexation by the component B perturbs the exchange coupling. The binding of the inhibitor dimethyl sulfoxide results in the smallest distribution of ZFS parameters and thus is investigated here in a correlated study using each of the three spectroscopic techniques. The data were analyzed with a spin Hamiltonian that includes exchange coupling ( J = 60 cm-l) and mixing of multiplets by zero-field splittings. The analysis shows that the orbital ground state of the ferrous site has predominantly d, symmetry; the z-axis of this orbital points along the z-direction of the cluster g-tensor. Mossbauer and 57Fe-ENDOR spectra indicate that the A-tensor of the ferric site is anisotropic; the 57Fe-ENDOR signals are the first reported for diiron-oxo clusters. Analysis of the Miissbauer spectra of the uncomplexed, reduced (Fe2+.Fe2+) hydroxylase cluster recorded in strong applied fields (up to 6.0 T) unambiguously shows that the two iron sites are inequivalent. Spectra of the oxidized cluster are also best fit by assuming that the irons of the cluster reside in inequivalent environments. Considered in light of the overall two-fold symmetry of hydroxylase revealed by ongoing structural studies, the present findings show that the hydroxylase contains two, probably identical, active-site diiron clusters whose individual iron atoms are structurally distinct. Mossbauer and EPR spectra of the [2Fe-2SI2+J+ cluster of the M M O reductase component are also reported and analyzed. Soluble methane monooxygenase (MMO, EC 1.14.13.25) consists of three protein components: a 40-kDa reductase containing both FAD and a [2Fe2S] cluster; a 16-kDa protein termed component B containing no metals or organic cofactors; and a 245-kDa hydroxylase (quaternary structure (afly)2) containing up to 4 mol of iron.] Soluble M M O catalyzes the 02-dependent oxidation of methane to methanoL2 In addition, a wide variety of other hydrocarbons are adventitiously ~ x i d i z e d . ~ Efficient reconstitution of NADH-linked catalytic turnover * Authors to whom correspondence should be directed. + Carnegie Mellon University. f University of Minnesota. (1) (a) Fox, B. G.; Froland, W. A.; Dege, J. E.; Lipscomb, J . D. J. Biol. Chem. 1989,264, 10023-10033. (b) Froland, W. F.; Andersson, K. K.; Lee, S.-K.; Liu, Y.; Lipscomb, J . D. In Applications of Enzyme Biotechnology; Kelly, J. W., Baldwin, T. O., Eds.; Plenum Press: New York, 1991; pp 39-53. (c) Fox, B. G.; Lipscomb, J. D. In Biological Oxidation Systems; Reddy, C . C . , Hamilton, G. A,, Madyastha, K. M., Eds.; Academic Press: New York, 1990; Vol. 1, pp 367-388. (2) Dalton, H. Adu. Appl. Microbiol. 1980, 26, 71-87. 0002-7863/93/1515-3688$04.00/0 requires all three protein component^.^ However, in the absence of the other components, the hydroxylase is able to catalyze hydroxylation reactions either upon chemical reduction and e x p o ~ u r e l ~ ~ ~ ~ to 0 2 or upon a d d i t i ~ n ~ ~ , ~ of H202, demonstrating that the complete active site required for oxygenase catalysis resides on the hydroxylase alone. All EPR and Mijssbauer studiesconducted to date are consistent with the presence of a spin-coupled diiron cluster in the hydroxylase active site.] Iron quantitation in combination with theobservation (3) (a) Rataj, M. J.; Knauth, J. E.; Donnelly, M. I. J. Biol. Chem. 1991, 266,18684-18690. (b) Fox, B.G.;Borneman, J.G.; Wackett,L.P.;Lipscomb, J. D. Biochemistry 1990, 29, 641945427. (c) Ruzicka, F.; Huang, D.-S.; Donnelly, M. I.; Frey, P. A. Biochemistry 1990, 29, 1696-1700. (d) Green, J.; Dalton, H. J. Biol. Chem. 1989, 246, 17698-17703. (4) (a) Fox, B. G.; Liu, Y.; Dege, J. E.; Lipscomb, J. D. J . Biol. Chem. 1991, 266, 540-550. (b) Froland, W. A.; Andersson, K. K.; Lee, S.-K.; Liu, Y.; Lipscomb, J. D. J . Biol. Chem. 1992, 267, 17588-17597. (c) Green, J.; Dalton, H. J. Biol. Chem. 1985, 260, 15795-15801, (5) Andersson, K. K.; Froland, W. A.; Lee, S.-K.; Lipscomb, J. D. New J. Chem. 1991, 15, 411-415. | v2 |
2020-09-26T13:05:53.361Z | 2020-09-20T00:00:00.000Z | 221913700 | s2ag/train | [Research value of 50 MHz high-frequency ultrasound on sonography of normal facial skin in adult].
Objective: To observe the differences in normal facial skin thickness and echo density by different ages and sites of healthy adults of the same sex using 50 MHz high-frequency ultrasound. Methods: From January to June 2019, 200 healthy adult volunteers with normal facial skin who were from Sichuan, Yunnan, Guizhou, and Chongqing and met the inclusion criteria were recruited by the Affiliated Hospital of Southwest Medical University with simple random sampling method, and then were included in this cross-sectional investigation study. Then 50 MHz high-frequency ultrasound was used to obtain skin ultrasonogram of volunteers' forehead, canthus, eyelid, and cheek. According to the ages, 100 female volunteers were divided into 20-29 years old (30 females), 30-39 years old (25 females), 40-49 years old (20 females), and 50-70 years old (25 females) groups; 100 male volunteers were divided into 20-29 years old (30 males), 30-39 years old (25 males), 40-49 years old (20 males), and 50-70 years old (25 males) groups. The thickness of full-skin, the upper dermal echo density, and the lower dermal echo density of the female and male volunteers'forehead, canthus, eyelid, and cheek were recorded respectively. Data were statistically analyzed with one-way analysis of variance, analysis of variance for repeated measurement, least significant difference test, and Bonferroni correction. Results: (1) The thickness of full-thickness skin in forehead, canthus, eyelid, and cheek of female and male volunteers in 20-29 years old group were (1.86±0.26), (1.36±0.11), (1.24±0.25), and (1.90±0.21) mm, (2.45±0.37), (1.64±0.19), (1.44±0.16), and (2.53±0.26) mm, respectively, in 30-39 years old group were (1.98±0.24), (1.43±0.13), (1.15±0.15), and (2.12±0.13) mm, (2.34±0.27), (1.63±0.27), (1.50±0.38), and (2.43±0.40) mm, respectively, in 40-49 years old group were (1.90±0.21), (1.43±0.18), (1.24±0.27), and (1.98±0.12) mm, (2.14±0.24), (1.54±0.25), (1.28±0.14), and (2.39±0.36) mm, respectively, in 50-70 years old group were (1.64±0.25), (1.36±0.19), (1.16±0.12), and (1.89±0.29) mm, (2.28±0.27), (1.73±0.25), (1.58±0.18), and (2.38±0.32) mm, respectively. There were no statistically significant differences between female volunteers in the 4 groups and male volunteers in the 4 groups in thickness of full-thickness skin in canthus, eyelid, and cheek (F=0.677, 0.666, 0.136, 0.697, 0.294, 0.888, P>0.05). The thickness of full-thickness skin in forehead and cheek of the female volunteers in the 4 groups and male volunteers in the 4 groups was similar (P>0.05), and was significantly higher than that of canthus and eyelid (P<0.05). The thickness of full-thickness skin in canthus and eyelid of female volunteers in 20-29 years old, 40-49 years old, and 50-70 years old group was similar (P>0.05), while thickness of full-thickness skin in canthus and eyelid of male volunteers in the 4 groups was similar (P>0.05). (2) The upper dermal echo density of forehead, canthus, eyelid, and cheek of female volunteers in 50-70 years old group was significantly lower than that in 20-29 years old and 30-39 years old groups (P<0.05). The upper dermal echo density of forehead, canthus, eyelid, and cheek of male volunteers in 50-70 years old group was significantly lower than that in 20-29 years old group (P<0.05). The upper dermal echo density of forehead, canthus, eyelid, and cheek of female and male volunteers in 20-29 years old and 30-39 years old groups was similar (P>0.05). The upper dermal echo density of forehead and cheek of female volunteers in 20-29 years old, 40-49 years old, and 50-70 years old groups was significantly lower than that of canthus and eyelid (P<0.05). The echo density of upper dermis of cheek of male volunteers in the 4 groups was significantly lower than that of canthus and eyelid (P<0.05). The upper dermal echo density of canthus and eyelid of female volunteers in the 4 groups and male volunteers in the 4 groups was similar (P>0.05), the upper dermal echo density of forehead and cheek was similar (P>0.05). (3) The lower dermal echo density of forehead, canthus, eyelid, and cheek of female volunteers in 50-70 years old group was significantly higher than that in 20-29 years old and 30-39 years old groups (P<0.05). The lower dermal echo density of forehead, canthus, eyelid, and cheek of male volunteers in 50-70 years old group was significantly higher than that in 20-29 years old group (P<0.05). The echo density of the lower dermis of forehead, eyelid, and cheek of female and male volunteers in 20-29 years old, 30-39 years old, and 40-49 years old groups was similar (P>0.05). The lower dermal echo density of forehead and cheek of female volunteers in the 4 groups was significantly lower than that of canthus and eyelid (P<0.05). The lower dermal echo density of forehead and cheek of male volunteers in 30-39 years old, 40-49 years old, and 50-70 years old groups was significantly lower than that of canthus and eyelid (P<0.05). The lower dermal echo density between canthus and eyelid and between forehead and check of female volunteers in the 4 groups and male volunteers in the 4 groups was similar (P>0.05). Conclusions: The 50 MHz high-frequency ultrasonography shows that the thickness of full-thickness skin of canthus, eyelid, and cheek is similar in all age groups of female and male adult volunteers with normal facial skin. In the same age group, the thickness of full-thickness skin of forehead and cheek of male and female volunteers is significantly higher than that of canthus and eyelid. The upper dermal echo density of forehead, canthus, eyelid, and cheek of female and male volunteers shows a decreasing trend with age, while the lower dermal echo density shows an increasing trend with age. In addition, the echo density of upper and lower dermis of canthus and eyelid was significantly higher than that of cheek in all the four age groups. | v2 |
2019-12-14T06:52:40.945Z | 2013-01-01T00:00:00.000Z | 209350290 | s2ag/train | INTERNAL STRUCTURE , STRATIGRAPHIC RANGE AND PHYLOGENETIC RELATIONSHIPS OF CERTAIN AMERICAN EOCENE FORAMINIFERA
The inte rnal s tructure of toootypes of Cnmt' rlna cutenula. (Cushman and Ja rvis) a nd E oconuloides Imr\'ulus (Cushman) and of s peci me ns of Eoconuloidc8 well s i Cole a nd Bermudez and lIelicosteg ina l)oiygYralis (Barke r ) Is discu ssed a nd illustrated and notes are given on thei r stratigraph ic ranges. In t he int!'oduclory r emarks a postulate by H ofke r (196 8) concerning the phyloge netic J'c la tionship of the genua LepidocYCUnR and related genera is rejected . LellidocycUna ecuR(lorens is H ofker Is without <Iucatlon a synonym of H elicolepidinR Sll iralis Tobler. The phylogenetic relationships proposed by B arker and Grimsdale (19 36) for the lepidocycline and helicolepid lne lineages are maintained a.nd re-emphasized. INTRODUCTION This article is an attempt to clarify certa in misconceptions concerning the internal structure and stratigraphic range of several species of American Eocene Foraminifera. Such data are essenti al to an understanding of the phylogenetic relationships which have been postulated. Barker and Grimsdale (1936, p. 244) proposed a phylogenetic scheme in which the subgenus Polylepidina of the genus Lepidocyclina was derived from the Helicostegilla lineage. Helieostegilla had as its ancestor A mpllistegina lopeztrigoi D. K. Palmer [= Eocolluloides par\"IIlus (Cushman) of this article]. The proposal of Barker and Grimsdale has been accepted generally, as their postulate seemed to sati fy both the stratigraphic appearance of the genera and the progressive development of the internal lructures by which these genera are interrelated (Cole, 1960a, p. 62). Recentl y, Hofker ( 1968, p. 24, 27) stated that Lepidocyclilla (Polylepidilla) antil/ea Cushman, the earliest known species of Lepidocyclilla, could not have been derived from Helicostegilla, as L. alltil/ea does not possess siphonate apertures. Hofker (1968, p. 22) also wrote: "Lepidoeyclilla is known from the upper Eocene in the species L . alltillea (see Cole, 1960a, p. 62); so I believe that Lepidocyclina ecuadorell sis . somewhat older than L. antil/ea and may have been the ancestor of it. .. " In my 1960a article I stated ( p. 60): "Several of these specimens [Lepidocyelina alltil/ea] . . . have the trochoid spire and apertures which supposedly characterize Eulinderilla," a synonym of Lepido• The deDartment of Geological Sciences of Cornell Uni ,oeraity supported this research in part and contributed to the cost of publication. eyclina (Polylepidilla) . In 1963 (Cole, p. 20, pI. 7, figs. 5, 6) I published illustrations which show the siphonate apertures of Lepidocyclina (Polylepidina ) alltillea Cushman. Moreover, in my 1960a article ( p. 62) cited by Hofker ( 1968, p. 22) I wrote: "During the upper middle Eocene the first subgenus, Polylepidina, of the genus Lepidocyclina was derived ... " The middle Eocene age of L epidocyclilla (Poiylepidina) alltillea has long been established in surface outcrop (Cole, 1956, Table 4; 1958a, p. 190; Grimsdale, 1959, p. 17) and in well s (Cole, 1938, p. 48 ; 1944, p. 34; Gravell and Hanna, 1938, p. 1007). The specimens which Hofker ( 1968, p. 22) identified as Lepidocyclina eeuadorensis are strikingly similar to specimens from northwest Peru which L. Rutten (1928, p. 945) named Lepidocyclina vicllayalensis. M. G . Rutten ( 1935, p. 544) transferred this species to the genus A ctinosiphon. Cole ( 1960a, p. 60) stated " . . . Lepidocyclina vichayalensis Rutten (1928, p. 945) was based on specimens of Helicolepidina nortolli Vaughan." Later, Cole (1962, p. 147 ) concluded that H . lIortolli was a synonym of H elicolepidilla spiralis Tobler. The specimens illustrated by Hofker (1968, pI. II , fig. 3; pI. 14, fig. 2) as Lepidocyclina eCl/adorellsis should be compared with topotypes of H elicolepidina nortolli (Cole, 1962, pI. 24, figs. 1-3). All of these specimens have Type IIIb embryonic apparatuses (Cole, 1962, p. 146), which is characteristic of upper Eocene specimens (Cole, 1962. p. 147 ) of Helicolepidina spiralis. One specimen (Hofker, 1968, pI. 14, fi g. 2) shows the row of spiral chambers (about two rows below the second embryonic chamber and continuing across the illustration to the right ) best, but the spiral chambers also appear in figure I , plate 14 (Hofker, 1968) to the right of the embryonic chambers. The embryonic apparatus, the possession of a sequence of spiral chambers beyond the embryonic apparatus, and the shape and alignment of the equatorial chambers in Lepidocyclilla eCl/adorensis are characteri stic of Helicolepidina, not Lepidocyclina. In unit 4 assigned by Cushman and Stainforth (1951, p. 34) to a reefal facies of upper middle Eocene age, Hofker (1968, pI. 8, fi g. 4) found specimens which he correctly identified as H elicolepidilia spiralis in association with abundant specimens 78 COLE-ST UDIE S ON AMERICAN EOCENE FOHAMINIFERA which he referred incorrectly to the genus L epidocyclina (his LepidocyC/illa ecuadorellsis = Helicolepidina spira/is). Other specimens in unit 4 were identified as H elicolepidilla paucispira, a species placed by Cole (1960a, p. 59) in the synonymy of H elicostegina polygyralis (Barker). Hofker (1968, p. 21) in one place correctly observed that unit 4 is upper Eocene. However, he modified this statement by writing: " ... Van der Vlerk (see later) believes that unit 4 is from the uppermost part of the Middle Eocene." Unfortunately, Hofker and Van der Vlerk identified L epidocyC/illa ecuadorensis (= He/icolepidina spira/is) incorrectly. Therefore, the statistics (Vlerk, ill Hofker, 1968, p. 27, 28) upon which Van der Vlerk based the middle Eocene age of unit 4 are meaningless, as his statistical method is based on an analysis of the embryonic chambers of LepidocyC/ina, whereas the measurements given were made on | v2 |
2019-02-01T14:08:45.874Z | 2018-11-29T00:00:00.000Z | 59593140 | s2ag/train | Efficacy and Toxicity of JCAR014 in Combination with Durvalumab for the Treatment of Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma
Introduction
Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have shown high overall response rates (ORR) in otherwise treatment-refractory CD19+ B-cell non-Hodgkin lymphoma (NHL); however, not all patients (pts) achieve complete remission (CR). PD-L1 expression on tumor cells and/or other tissues could impair the function of PD-1+ CAR-T cells and the efficacy of CD19 CAR-T cell immunotherapy. PD-1 pathway blockade may enhance the function and antitumor activity of CD19 CAR-T cells. Here we report preliminary data from a phase 1 dose-finding study (NCT02706405) of the safety and feasibility of combination therapy with JCAR014 CD19-specific 4-1BB-costimulated CAR-T cells and escalating doses of durvalumab, an anti-PD-L1 monoclonal antibody, in adults with relapsed/refractory aggressive B-cell NHL.
Methods
Pts are treated in one of two groups. All pts receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine followed by infusion of JCAR014. Pts in group 1 receive the first infusion of durvalumab (225 mg, 750 mg, or 1500 mg) 21-28 days after treatment with JCAR014. Pts in group 2 receive the first dose of durvalumab (7.5 mg, 22.5 mg, 75 mg, 225 mg, 750 mg, or 1500 mg) 1 day prior to JCAR014 infusion. Up to 10 doses of durvalumab are administered after JCAR014 at the highest identified safe dose at 4-week intervals until toxicity or disease progression. We evaluated the safety, tolerability, and efficacy of the combination therapy and the pharmacokinetic profile of JCAR014 after infusion. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.03, with the exception of cytokine release syndrome (CRS), which was graded according to consensus criteria (Lee, Blood 2014). Positron emission tomography/computed tomography was performed approximately 1, 2, 4, 6, 9, and 12 months after JCAR014 infusion and the best anti-tumor response was reported according to the Lugano criteria (Cheson, JCO 2014).
Results
Patient characteristics are shown in Table 1. Fifteen pts have been treated, including 6 in group 1 who received post-JCAR014 durvalumab doses of 225 mg (n = 3) and 750 mg (n = 3), and 9 in group 2 who received pre-JCAR014 durvalumab doses of 7.5 mg (n = 1), 22.5 mg (n = 1), 75 mg (n = 3), or 225 mg (n = 4). Durvalumab dose escalation is ongoing. JCAR014 manufacturing was successful for all pts. All pts received 2 x 106 JCAR014 CAR-T cells/kg, except the first 2 pts treated on the study who received 7 x 105 CAR-T cells/kg. Of the 13 pts who received JCAR014 at 2 x 106 CAR-T cells/kg, 5 pts (38%) developed CRS (2 grade 1, 2 grade 2, and 1 grade 4) and one (8%) developed grade 1 neurotoxicity. CRS and/or neurotoxicity occurred within 4 weeks of JCAR014 infusion, and were not observed when durvalumab was administered after JCAR014. With the exception of B cell aplasia, no autoimmune adverse events were observed.
Twelve of 13 pts who received 2 x 106 CAR-T cells/kg were evaluable for response. One patient, who had grade 4 CRS and biopsy evidence of extensive CAR-T cell infiltration into persistent sites of disease, elected to receive hospice care and died on day 32 after JCAR014 infusion without full response evaluation. The overall response rate was 50% (5 CR, 42%; 1 PR, 8%). Of the 5 pts who achieved CR, 3 were in CR at the first restaging after JCAR014 and 2 subsequently converted to CR after the first post-JCAR014 durvalumab infusion. Only one patient who achieved CR has relapsed (median follow-up 10.6 months, range 3.7-11.8). Continued stable disease or evidence of regression was seen in 4 of 6 (67%) initially non-responding pts who continued durvalumab therapy (median 5 doses, range 1-6).
CAR-T cell counts expanded in the peripheral blood within 14 days of JCAR014 infusion in all pts. Higher peak and day 28 CAR-T cell copy numbers in blood by qPCR were observed in responding pts. CAR-T cells were detected for a median of 5.1 months (range, 1.7 to 9.1 months) in responding pts. In vivo re-accumulation of CAR-T cells after the first post-JCAR014 durvalumab dose was observed in the blood of two patients in group 2.
Conclusion
The combination of JCAR014 with durvalumab for the treatment of adult pts with aggressive B-cell NHL appears safe; however, dose escalation is ongoing. Complete responses were observed both at initial restaging after JCAR014 infusion, and also subsequently in pts continuing durvalumab therapy after initially failing to achieve CR.
Hirayama: DAVA Oncology: Honoraria. Hay:DAVA Oncology: Honoraria. Till:Mustang Bio: Patents & Royalties, Research Funding. Kiem:Homology Medicine: Consultancy; Magenta: Consultancy; Rocket Pharmaceuticals: Consultancy. Shadman:Verastem: Consultancy; Beigene: Research Funding; Mustang Biopharma: Research Funding; Gilead Sciences: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Research Funding. Cassaday:Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Pfizer: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Kite Pharma: Research Funding; Incyte: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Riddell:Cell Medica: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Adaptive Biotechnologies: Consultancy; NOHLA: Consultancy. Maloney:Roche/Genentech: Honoraria; Juno Therapeutics: Research Funding; Janssen Scientific Affairs: Honoraria; GlaxoSmithKline: Research Funding; Seattle Genetics: Honoraria. Turtle:Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; Bluebird Bio: Consultancy; Gilead: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Caribou Biosciences: Consultancy; Aptevo: Consultancy.
| v2 |
2019-04-17T15:47:44.701Z | 2004-02-25T00:00:00.000Z | 118213920 | s2ag/train | Integrable Hamiltonian Systems: Geometry, Topology, Classification
BASIC NOTIONS Linear Symplectic Geometry Symplectic and Poisson Manifolds The Darboux Theorem Liouville Integrable Hamiltonian Systems. The Liouville Theorem Non-Resonant and Resonant Systems Rotation Number The Momentum Mapping of an Integrable System and Its Bifurcation Diagram Non-Degenerate Critical Points of the Momentum Mapping Main Types of Equivalence of Dynamical Systems THE TOPOLOGY OF FOLIATIONS ON TWO-DIMENSIONAL SURFACES Generated by Morse Functions Simple Morse Functions Reeb Graph of a Morse Function Notion of an Atom Simple Atoms Simple Molecules Complicated Atoms Classification of Atoms Symmetry Groups of Oriented Atoms and the Universal Covering Tree Notion of a Molecule Approximation of Complicated Molecules by Simple Ones Classification of Morse-Smale Flows on Two-Dimensional Surfaces by Means of Atoms and Molecules ROUGH LIOUVILLE EQUIVALENCE OF INTEGRABLE SYSTEMS WITH TWO DEGREES OF FREEDOM Classification of Non-degenerate Critical Submanifolds on Isoenergy 3-Surfaces The Topological Structure of a Neighborhood of a Singular Leaf Topologically Stable Hamiltonian Systems Example of a Topologically Unstable Integrable System 2-Atoms and 3-Atoms Classification of 3-Atoms 3-Atoms as Bifurcations of Liouville Tori The Molecule of an Integrable System Complexity of Integrable Systems LIOUVILLE EQUIVALENCE OF INTEGRABLE SYSTEMS WITH TWO DEGREES OF FREEDOM Admissible Coordinate Systems on the Boundary of a 3-Atom Gluing Matrices and Superfluous Frames Invariants (Numerical Marks) r, e, and n The Marked Molecule is a Complete Invariant of Liouville Equivalence The Influence of the Orientation Realization Theorem Simple Examples of Molecules Hamiltonian Systems with Critical Klein Bottles Topological Obstructions to Integrability of Hamiltonian Systems with Two Degrees of Freedom ORBITAL CLASSIFICATION OF INTEGRABLE SYSTEMS WITH TWO DEGREES OF FREEDOM Rotation Function and Rotation Vector Reduction of the Three-Dimensional Orbital Classification to the Two-Dimensional Classification up to Conjugacy General Concept of Constructing Orbital Invariants of Integrable Hamiltonian Systems CLASSIFICATION OF HAMILTONIAN FLOWS ON TWO-DIMENSIONAL SURFACES UP TO TOPOLOGICAL CONJUGACY Invariants of a Hamiltonian System on a 2-Atom Classification of Hamiltonian Flows with One Degree of Freedom up to Topological Conjugacy Classification of Hamiltonian Flows on 2-Atoms with Involution up to Topological Conjugacy The Pasting-Cutting Operation Description of the Sets of Admissible delta-Invariants and Z-Invariants SMOOTH CONJUGACY OF HAMILTONIAN FLOWS ON TWO-DIMENSIONAL SURFACES Constructing Smooth Invariants on 2-Atoms Theorem of Classification of Hamiltonian Flows on Atoms up to Smooth Conjugacy ORBITAL CLASSIFICATION OF INTEGRABLE HAMILTONIAN SYSTEMS WITH TWO DEGREES OF FREEDOM. THE SECOND STEP Superfluous t-Frame of a Molecule (Topological Case). The Main Lemma on t-Frames The Group of Transformations of Transversal Sections. Pasting-Cutting Operation The Action of GP on the Set of Superfluous t-Frames Three General Principles for Constructing Invariants Admissible Superfluous t-Frames and a Realization Theorem Construction of Orbital Invariants in the Topological Case. A t-Molecule Theorem on the Topological Orbital Classification of Integrable Systems with Two Degrees of Freedom A Particular Case: Simple Integrable Systems Smooth Orbital Classification LIOUVILLE CLASSIFICATION OF INTEGRABLE SYSTEMS WITH NEIGHBORHOODS OF SINGULAR POINTS l-Type of a Four-Dimensional Singularity The Loop Molecule of a Four-Dimensional Singularity Center-Center Case Center-Saddle Case Saddle-Saddle Case Almost Direct Product Representation of a Four-Dimensional Singularity Proof of the Classification Theorems Focus-Focus Case Almost Direct Product Representation for Multidimensional Non-degenerate Singularities of Liouville Foliations METHODS OF CALCULATION OF TOPOLOGICAL INVARIANTS OF INTEGRABLE HAMILTONIAN SYSTEMS General Scheme for Topological Analysis of the Liouville Foliation Methods for Computing Marks The Loop Molecule Method List of Typical Loop Molecules The Structure of the Liouville Foliation for Typical Degenerate Singularities Typical Loop Molecules Corresponding to Degenerate One-Dimensional Orbits Computation of r- and e-Marks by Means of Rotation Functions Computation of the n-Mark by Means of Rotation Functions Relationship Between the Marks of the Molecule and the Topology of Q3 INTEGRABLE GEODESIC FLOWS ON TWO-DIMENSIONAL SURFACES 409 Statement of the Problem Topological Obstructions to Integrability of Geodesic Flows on Two-Dimensional Surfaces Two Examples of Integrable Geodesic Flows Riemannian Metrics Whose Geodesic Flows are Integrable by Means of Linear or Quadratic Integrals. Local Theory Linearly and Quadratically Integrable Geodesic Flows on Closed Surfaces LIOUVILLE CLASSIFICATION OF INTEGRABLE GEODESIC FLOWS ON TWO-DIMENSIONAL SURFACES The Torus The Klein Bottle The Sphere The Projective Plane ORBITAL CLASSIFICATION OF INTEGRABLE GEODESIC FLOWS ON TWO-DIMENSIONAL SURFACES Case of the Torus Case of the Sphere Examples of Integrable Geodesic Flows on the Sphere Non-triviality of Orbital Equivalence Classes and Metrics with Closed Geodesics THE TOPOLOGY OF LIOUVILLE FOLIATIONS IN CLASSICAL INTEGRABLE CASES IN RIGID BODY DYNAMICS Integrable Cases in Rigid Body Dynamics Topological Type of Isoenergy 3-Surfaces Liouville Classification of Systems in the Euler Case Liouville Classification of Systems in the Lagrange Case Liouville Classification of Systems in the Kovalevskaya Case Liouville Classification of Systems in the Goryachev-Chaplygin-Sretenskii Case Liouville Classification of Systems in the Zhukovskii Case Rough Liouville Classification of Systems in the Clebsch Case Rough Liouville Classification of Systems in the Steklov Case Rough Liouville Classification of Integrable Four-Dimensional Rigid Body Systems The Complete List of Molecules Appearing in Integrable Cases of Rigid Body Dynamics MAUPERTUIS PRINCIPLE AND GEODESIC EQUIVALENCE General Maupertuis Principle Maupertuis Principle in Rigid Body Dynamics Classical Cases of Integrability in Rigid Body Dynamics and Related Integrable Geodesic Flows on the Sphere Conjecture on Geodesic Flows with Integrals of High Degree Dini Theorem and the Geodesic Equivalence of Riemannian Metrics Generalized Dini-Maupertuis Principle Orbital Equivalence of the Neumann Problem and the Jacobi Problem Explicit Forms of Some Remarkable Hamiltonians and Their Integrals in Separating Variables EULER CASE IN RIGID BODY DYNAMICS AND JACOBI PROBLEM ABOUT GEODESICS ON THE ELLIPSOID. ORBITAL ISOMORPHISM Introduction Jacobi Problem and Euler Case Liouville Foliations Rotation Functions The Main Theorem Smooth Invariants Topological Non-Conjugacy of the Jacobi Problem and the Euler Case REFERENCES SUBJECT INDEX | v2 |
2022-11-22T06:17:25.335Z | 2022-11-21T00:00:00.000Z | 253733050 | s2ag/train | Prothrombin complex concentrate in cardiac surgery for the treatment of coagulopathic bleeding.
BACKGROUND
Coagulopathy following cardiac surgery is associated with considerable blood product transfusion and high morbidity and mortality. The treatment of coagulopathy following cardiac surgery is challenging, with the replacement of clotting factors being based on transfusion of fresh frozen plasma (FFP). Prothrombin complex concentrate (PCCs) is an alternative method to replace clotting factors and warrants evaluation. PCCs are also an alternative method to treat refractory ongoing bleeding post-cardiac surgery compared to recombinant factor VIIa (rFVIIa) and also warrants evaluation. OBJECTIVES: Assess the benefits and harms of PCCs in people undergoing cardiac surgery who have coagulopathic non-surgical bleeding.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase and Conference Proceedings Citation Index-Science (CPCI-S) on the Web of Science on 20 April 2021. We searched Clinicaltrials.gov (www.
CLINICALTRIALS
gov), and the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch/), for ongoing or unpublished trials. We checked the reference lists for additional references. We did not limit the searches by language or publication status.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and non-randomised trials (NRSs). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Eighteen studies were included (4993 participants). Two were RCTs (151 participants) and 16 were NRSs. Both RCTs had low risk of bias (RoB) in almost all domains. Of the 16 NRSs, 14 were retrospective cohort analyses with one prospective study and one case report. The nine studies used in quantitative analysis were judged to have critical RoB, three serious and three moderate. 1. PCC versus standard treatment Evidence from RCTs showed PCCs are likely to reduce the number of units transfused compared to standard care (MD -0.89, 95% CI -1.78 to 0.00; participants = 151; studies = 2; moderate-quality evidence). Evidence from NRSs agreed with this, showing that PCCs may reduce the mean number of units transfused compared to standard care but the evidence is uncertain (MD -1.87 units, 95% CI -2.53 to -1.20; participants = 551; studies = 2; very low-quality evidence). There was no evidence from RCTs showing a difference in the incidence of red blood cell (RBC) transfusion compared to standard care (OR 0.53, 95% CI 0.20 to 1.40; participants = 101; studies = 1; low-quality evidence). Evidence from NRSs disagreed with this, showing that PCCs may reduce the mean number of units transfused compared to standard care but the evidence is uncertain (OR 0.54, 95% CI 0.30 to 0.98; participants = 1046; studies = 4; low-quality evidence). There was no evidence from RCTs showing a difference in the number of thrombotic events with PCC compared to standard care (OR 0.68 95% CI 0.20 to 2.31; participants = 152; studies = 2; moderate-quality evidence). This is supported by NRSs, showing that PCCs may have no effect on the number of thrombotic events compared to standard care but the evidence is very uncertain (OR 1.32, 95% CI 0.87 to 1.99; participants = 1359; studies = 7; very low-quality evidence). There was no evidence from RCTs showing a difference in mortality with PCC compared to standard care (OR 0.53, 95% CI 0.12 to 2.35; participants = 149; studies = 2; moderate-quality evidence). This is supported by evidence from NRSs, showing that PCCs may have little to no effect on mortality compared to standard care but the evidence is very uncertain (OR 1.02, 95% CI 0.69 to 1.51; participants = 1334; studies = 6; very low-quality evidence). Evidence from RCTs indicated that there was little to no difference in postoperative bleeding (MD -107.05 mLs, 95% CI -278.92 to 64.83; participants = 151, studies = 2; low-quality evidence). PCCs may have little to no effect on intensive care length of stay (RCT evidence: MD -0.35 hours, 95% CI -19.26 to 18.57; participants = 151; studies = 2; moderate-quality evidence) (NRS evidence: MD -18.00, 95% CI -43.14 to 7.14; participants = 225; studies = 1; very low-quality evidence) or incidence of renal replacement therapy (RCT evidence: OR 0.72, 95% CI 0.14 to 3.59; participants = 50; studies = 1; low-quality evidence) (NRS evidence: OR 1.46, 95% CI 0.71 to 2.98; participants = 684; studies = 2; very low-quality evidence). No studies reported on additional adverse outcomes. 2. PCC versus rFVIIa For this comparison, all evidence was provided from NRSs. PCC likely results in a large reduction of RBCs transfused intra-operatively in comparison to rFVIIa (MD-4.98 units, 95% CI -6.37 to -3.59; participants = 256; studies = 2; moderate-quality evidence). PCC may have little to no effect on the incidence of RBC units transfused comparative to rFVIIa; evidence is very uncertain (OR 0.16, 95% CI 0.02 to 1.56; participants = 150; studies = 1; very low-quality evidence). PCC may have little to no effect on the number of thrombotic events comparative to rFVIIa; evidence is very uncertain (OR 0.51, 95% CI 0.23 to 1.16; participants = 407; studies = 4; very low-quality evidence). PCC may have little to no effect on the incidence of mortality (OR 1.07, 95% CI 0.38 to 3.03; participants = 278; studies = 3; very low-quality evidence) or intensive care length of stay comparative to rFVIIa (MD -40 hours, 95% CI -110.41 to 30.41; participants = 106; studies = 1; very low-quality evidence); evidence is very uncertain . PCC may reduce bleeding (MD -674.34 mLs, 95% CI -906.04 to -442.64; participants = 150; studies = 1; very low-quality evidence) and incidence of renal replacement therapy (OR 0.29, 95% CI 0.12 to 0.71; participants = 106; studies = 1; very low-quality evidence) comparative to rFVIIa; evidence is very uncertain. No studies reported on other adverse events. AUTHORS' CONCLUSIONS: PCCs could potentially be used as an alternative to standard therapy for coagulopathic bleeding post-cardiac surgery compared to FFP as shown by moderate-quality evidence and it may be an alternative to rFVIIa in refractory non-surgical bleeding but this is based on moderate to very low quality of evidence. | v2 |
2019-11-22T00:55:54.994Z | 2019-11-13T00:00:00.000Z | 209226800 | s2ag/train | Dual Inhibition of MDM2 and XPO1 Synergizes to Induce Apoptosis in Acute Myeloid Leukemia Progenitor Cells with Wild-Type TP53 through Nuclear Accumulation of p53 and Suppression of c-Myc
Background. MDM2 is frequently overexpressed in acute myeloid leukemias (AML) and suppresses p53-mediated apoptosis while p53 mutations are relatively rare in AML. MDM2 inhibitors as a monotherapy have shown limited efficacy in clinical trials in AML (~25% response rate) (Andreeff, Clin Cancer Res 2015). XPO1 transports around 300 proteins, including p53 and other tumor suppressors, from the nucleus to the cytoplasm. Overexpression of XPO1 is associated with unfavorable outcomes in AML (Kojima, Blood 2013). p53 activation or XPO1 inhibition have been reported to decrease c-Myc protein levels through diverse mechanisms (Porter Mol Cell 2017 and Tabe PLoSOne 2015).
Objective: We investigated anti-leukemia effect of dual MDM2 and XPO1 inhibition, with the intent to maximize the pro-apoptotic functions of p53, using the MDM2 inhibitor milademetan (Daiichi-Sankyo), and selinexor, a recently FDA-approved XPO1 inhibitor or its analog eltanexor (Karyopharm).
Results: Treatment with milademetan and selinexor (1:1 molar ratio) induced synergistic apoptosis in AML cell lines with wild-type p53 (ED50, 89.3 ± 18.6 nM, combination index (CI), 0.60 ± 0.08). Activity in p53 mutant AML required 40-fold higher ED50 (3572 ± 1986 nM), reflected in an antagonistic CI of 6.94 ± 3.06. Knockdown of wild-type p53 by shRNA in OCI-AML3 (OCI-AML3 shp53) cells or presence of TP53 mutation (p.R248W) in MOLM-13 cells eliminated the synergistic effects, suggesting that normal p53 function is a major determinant of sensitivity to combined treatment.
Next, we treated primary AML samples with milademetan and selinexor or eltanexor and observed that effects were mutation-agnostic (e.g. RAS and FLT3) except for TP53. Combined treatment significantly reduced AUC determined by absolute live cell numbers compared to each drug alone, and induced synergistic apoptosis in primary AML samples with wild-type p53 (ED50 values, 27.2 - 937.4 nM, CI, 0.51 ± 0.07), with similar efficacies in complex and non-complex karyotype AMLs (279.6 ± 94.7 vs 256.6 ± 56.4 nM, P = 0.84). In contrast, combined treatment showed antagonistic effects in primary AML samples with loss-of-function TP53 mutations (CI > 1.0). Immature CD34+CD38- AML cells were more susceptible to combined treatment than CD34- AML cells (apoptosis induction, 76.2 ± 6.7% vs 47.5 ± 6.8%, P = 0.0002)
Mechanistically, combined inhibition increased p53 protein levels and accumulated p53 but not MDM2 protein in the nucleus compared to each drug alone. Combined treatment induced more TP53 target genes (MDM2, CDKN1A, BBC3, FAS and Bax) in OCI-AML3 cells with control shRNA compared with OCI-AML3 shp53 cells. Combinatorial inhibition showed much enhanced reduction of c-Myc mRNA and protein levels in OCI-AML3 shC cells compared with OCI-AML3 shp53 cells (82% vs 32%). In confirmation, combined inhibition reduced c-Myc protein levels profoundly in wild-type p53 primary AMLs (ANOVA P < 0.0001). In contrast, c-Myc reduction was not observed in primary AMLs with p53-inactivating mutations. Intriguingly, OCI-AML3 cells overexpressing c-Myc by lentiviral transduction showed greater sensitivity to XPO1 inhibitors and the combination compared to empty-vector controls, and baseline levels of c-Myc protein also negatively correlated with ED50 for combined treatment in primary AML samples (Spearman R = -0.5357, P = 0.0422).
Conclusion: These preclinical data suggest that dual inhibition of MDM2 and XPO1 induces synergistic apoptosis through accumulation of nuclear p53 and suppression of c-Myc in wild-type p53 AMLs. A clinical trial testing this concept in AML is under development.
Ishizawa: Daiichi Sankyo: Patents & Royalties: Joint submission with Daiichi Sankyo for a PTC patent titled "Predictive Gene Signature in Acute Myeloid Leukemia for Therapy with the MDM2 Inhibitor DS-3032b," United States, 62/245667, 10/23/2015, Filed. Daver:Novartis: Consultancy, Research Funding; Agios: Consultancy; Jazz: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Pfizer: Consultancy, Research Funding; Astellas: Consultancy; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Consultancy. Lesegretain:Daiichi-Sankyo Inc.: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Andreeff:NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy.
| v2 |
2017-10-17T16:34:39.636Z | 2017-03-01T00:00:00.000Z | 38885030 | s2ag/train | Processed Food-An Experiment That Failed.
Opinion Viewpoint buy previously unaffordable luxuries for her grandson including toi- letries, fresh produce, winter blankets, and a nightlight. Like Beatrice, single women making less than $10 000 yearly headed many of the families we served. The good news for these women and their children was 2-fold. First, these types of families are the EITC’s target population and, as such, received thousands of dollars in tax credit. Second, for those who filed in prior years, StreetCred saved them money previously lost to the for-profit tax- filing industry by providing free services in the comfort of a trusted setting: their pediatrician’s office. These women expressed both gratitude and practical impact as they reported their ability to not only more fully meet their children’s basic needs, but also take a first step toward financial stability by paying off loans, which are stories consistent with national data on the ways taxpayers use EITC monies. 7 Moreover, StreetCred empowered families with EITC edu- cation. Some clients expressed enthusiasm about working more hours in the coming year to qualify for a larger EITC on their next tax return. Other single mothers learned that they, not their ex- -earned-income-tax-credit. Published January 15, 2016. Accessed July 7, 2016. ARTICLE INFORMATION Published Online: January 17, 2017. doi:10.1001/jamapediatrics.2016.3868 Conflict of Interest Disclosures: None reported. Additional Contributions: We thank Barry Zuckerman, MD (Boston University School of Medicine); Paul Wise, MD, MPH (Stanford University); and James Perrin, MD (Harvard Medical School), for editing assistance and manuscript review. They did not receive compensation for their contributions. REFERENCES 1. Center on Budget and Policy Priorities. Policy basics: the earned income tax credit. http://www .cbpp.org/research/federal-tax/policy-basics-the VIEWPOINT Robert H. Lustig, MD, MSL Department of Pediatrics, University of California, San Francisco; and Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco. Corresponding Author: Robert H. Lustig, MD, MSL, Division of Pediatric Endocrinology, University of California, San Francisco, 550 16th St, PO Box 0434, San Francisco, CA 94143 ([email protected]). husbands, should claim the children as tax-return dependents be- cause they served as primary caretakers. StreetCred is another example of how the US health care sys- tem can be a gateway to the public benefits, community resources, and financial stability supporting low-income parents, like Bea- trice, in one of the most important jobs in the United States: raising healthy children. The trust and regular contact between families and their children’s medical professionals present a special opportunity to screen for and address the social determinants of health. Street- Cred aims to make accessing programs, such as the EITC, cheaper, faster, and easier to understand. The program’s short-term goals are 2-fold: (1) expand free tax-preparation services to other clinics and hospitals serving low-income families with children and (2) expand its services portfolio with additional asset-building tools so families might truly break the cycle of poverty. Innovative programs extend- ing beyond the traditional boundaries of pediatric health services remain an important approach to promoting the health and devel- opment of our patients growing up poor. 5. Council on Community Pediatrics. Poverty and child health in the United States. Pediatrics. 2016; 137(4):e20160339. 2. Marr C, Huang C-C, Sherman A, Debot B. EITC and child tax credit promote work, reduce poverty, and support children’s development, research finds. Center on Budget and Policy Priorities website. http://www.cbpp.org/research/federal-tax /eitc-and-child-tax-credit-promote-work-reduce -poverty-and-support-childrens. Published October 1, 2015. Accessed July 7, 2016. 6. Holzer HJ, Shanzenbach DW, Duncan GJ, Ludwig J; National Poverty Center. National Poverty Center Working Paper Series, 07-04: The economic costs of poverty in the United States: subsequent effects of children growing up poor. http://www.npc.umich .edu/publications/u/working_paper07-04.pdf. Published January 2007. Accessed July 7, 2016. 3. US Internal Revenue Service. About EITC. http://www.eitc.irs.gov/EITC-Central/abouteitc. Accessed April 1, 2015. 7. Goodman-Bacon A, McGranahan L. How do EITC recipients spend their refunds? Econ Perspect. 4. Weinstein P, Patten B. The Price of Paying Taxes II: How Paid Tax Preparer Fees are Diminishing the Earned Income Tax Credit (EITC). Washington, DC: The Progressive Policy Institute; 2016. Processed Food—An Experiment That Failed Those of us who have participated in science know that 9 of every 10 experiments are failures. Now imagine that the last 50 years has been a grand clinical research experi- ment, with the American population as unwitting partici- pants,conductedby10principalinvestigators—Coca-Cola, Pepsico, Kraft, Unilever, General Mills, Nestle, Mars, Kellogg, Proctor & Gamble, and Johnson & Johnson. In 1965, these corporations posed the hypothesis that pro- cessed food is better than real food. To determine if the ex- perimentwasasuccessorafailure,wehavetoexaminethe outcomevariables.Inthiscase,thereare4:foodconsump- tion, health/disease, environment, and cash flow, divided into companies, consumers, and society. Processed food is defined by 7 food engineering crite- ria; it is mass produced, is consistent batch to batch, is con- sistentcountrytocountry,usesspecializedingredientsfrom specialized companies, consists of prefrozen macronutri- ents, stays emulsified, and has long shelf life or freezer life. 1 Furthermore, 11 nutritional properties distinguish pro- cessed food. 2 (1) Too little fiber. When fiber (soluble and insoluble) is consumed within food, it forms a gelatinous barrier along the intestinal wall. This delays the intestine’s ability to absorb nutrients, instead feeding the gut micro- biome. Attenuation of the glucose rise results in insulin re- duction. Attenuation of fructose absorption reduces liver fataccumulation.(2)and(3)Toofewω-3andtoomanyω-6 fatty acids. ω-3s are precursors to docahexaenoic and ei- cosapentanoicacids(anti-inflammatory).Conversely,ω-6s are precursors of arachidonic acid (proinflammatory). Our ratio of ω-6 to ω-3 fatty acids should be approximately 1:1. Currently, our ratio is about 25:1, favoring a proinflamma- tory state, which can drive oxidative stress and cell dam- age. (4) Too few micronutrients. Antioxidants, such as vi- tamins C and E, quench oxygen radicals in peroxisomes to preventcellulardamage,whileothers,suchascarotenoids and α-lipoic acid, prevent lipid peroxidation. (5) Too many JAMA Pediatrics March 2017 Volume 171, Number 3 (Reprinted) Copyright 2017 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/peds/936064/ by a UCSF LIBRARY User on 04/05/2017 jamapediatrics.com | v2 |
2019-12-12T08:03:39.592Z | 2019-11-13T00:00:00.000Z | 209261540 | s2ag/train | Preliminary Results from a Phase 1 First-in-Human Study of AMG 673, a Novel Half-Life Extended (HLE) Anti-CD33/CD3 BiTE® (Bispecific T-Cell Engager) in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)
Background: AMG 673 is a novel half-life extended (HLE) BiTE® (bispecific T-cell engager) construct that binds both CD33 and CD3 and is genetically fused to the N-terminus of a single-chain IgG Fc region, thereby potentially increasing the half-life of the molecule. AMG 673 redirects T cells toward CD33+ cells, with the induced proximity leading to T-cell‒mediated cytotoxicity against acute myeloid leukemia (AML) blasts. Anti-AML activity of other CD33/CD3 bispecific T-cell engager molecules has been previously reported (Blood, 2018, 132, 25; Blood, 2018, 132, 1455). The objectives of this ongoing study are to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AMG 673 in adult patients aged ≥18 years with relapsed/refractory (R/R) AML.
Methods: This is an ongoing first-in-human, open-label, phase 1, sequential dose escalation study (NCT03224819). AMG 673 was administered as two, short, and intermittent intravenous (IV) infusions during a 14-day cycle in adult patients with R/R AML. Patients received treatment cycles of AMG 673 until disease progression or unacceptable toxicities. T-cell activation, cytokine, and AMG 673 levels in patients' blood were evaluated by validated assays. Results were summarized descriptively by the dosing cohorts and potential associations between PK, PD, safety, and preliminary efficacy were evaluated.
Results: As of June 14, 2019, 30 patients had enrolled in 10 cohorts and were treated with AMG 673 (dose range, 0.05-72 μg IV per dose). The median age was 67.5 (range: 25.0-84.0) years; 20/30 (67%) patients had received ≥4 prior anti-AML treatments, baseline myelosuppression at study entry was common (grade ≥3 neutropenia 21/30 [70%], thrombocytopenia 25/30 [83%], leukopenia 14/30 [47%]), and 7/30 (23%) patients had undergone hematopoietic stem cell transplant (HSCT) before enrolling in the study.
Patients received a median of 1.5 (range: 1.0-6.0) cycles of AMG 673; 27/30 (90%) patients discontinued treatment due to disease progression (n=21), patient request (n=2), protocol-specified criteria (n=2), or adverse events (AEs; n=2). A total of 3 patients were still receiving AMG 673 at the time of data analysis. The most common treatment-related AE was cytokine release syndrome (CRS) reported in 15/30 (50%) patients (grade 1, n=6; grade 2, n=5; grade 3, n=4; no grade 4 CRS). Treatment-related serious AEs were reported in 11/30 (37%) patients, and 15/30 (50%) patients experienced treatment-related AEs of grade ≥3, with the most common being abnormal hepatic enzymes (n=5, 17%), CRS (n=4, 13%), leukopenia (n=4, 13%), thrombocytopenia (n=2, 7%), and febrile neutropenia (n=2, 7%). Two deaths, unrelated to AMG 673, were reported on days 19 and 28 after the last dose.
Assessment of bone marrow in treated patients showed a decrease in blasts in 12/27 (44%) evaluable patients, of which 6 experienced ≥50% reduction in blasts compared with baseline (Figure 1). One patient achieved complete remission with incomplete hematologic recovery (CRi) with 85% reduction in bone marrow blasts at a dose of 36 µg.
Dose-related increases in Cmax and AUC were observed following AMG 673 infusions. Preliminary half-life estimates for AMG 673 were longer than those observed for canonical CD33-specific BiTE® molecule with short half-lives. Upregulation of T-cell activation markers CD25 and CD69 on T-cell subsets and cytokine release post-infusion were observed at higher doses. Preliminary associations between AMG 673 exposures, T-cell activation, safety, and clinical response have been evaluated.
Conclusions: Preliminary data of AMG 673 dosed up to 72 µg provide early evidence of the molecule's acceptable safety profile, drug tolerability, and anti-leukemic activity. An association was observed between PK/PD relationships that were consistent with the biological activity of AMG 673. These preliminary results support further dose escalation of the AMG 673 HLE BiTE® molecule in patients with R/R AML.
Subklewe: AMGEN: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Morphosys: Research Funding; Janssen: Consultancy; Celgene: Consultancy, Honoraria; Miltenyi: Research Funding; Oxford Biotherapeutics: Research Funding; Pfizer: Consultancy, Honoraria. Stein:Celgene: Speakers Bureau; Stemline: Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Walter:Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Seattle Genetics: Research Funding; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Race Oncology: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy. Wei:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria. Vachhani:AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau. Dai:Amgen: Employment, Equity Ownership. Hindoyan:Amgen Inc.: Employment, Other: stock ownership. Agarwal:Amgen: Employment, Equity Ownership; AbbVie: Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Khaldoyanidi:Amgen: Employment, Equity Ownership; BMS: Equity Ownership. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding.
| v2 |
2018-04-03T02:32:06.852Z | 2017-01-04T00:00:00.000Z | 205178210 | s2ag/train | Planned early birth versus expectant management (waiting) for prelabour rupture of membranes at term (37 weeks or more).
BACKGROUND
Prelabour rupture of membranes (PROM) at term is managed expectantly or by planned early birth. It is not clear if waiting for birth to occur spontaneously is better than intervening, e.g. by inducing labour.
OBJECTIVES
The objective of this review is to assess the effects of planned early birth (immediate intervention or intervention within 24 hours) when compared with expectant management (no planned intervention within 24 hours) for women with term PROM on maternal, fetal and neonatal outcomes.
SEARCH METHODS
We searched Cochrane Pregnancy and Childbirth's Trials Register (9 September 2016) and reference lists of retrieved studies.
SELECTION CRITERIA
Randomised or quasi-randomised controlled trials of planned early birth compared with expectant management (either in hospital or at home) in women with PROM at 37 weeks' gestation or later.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion, extracted the data, and assessed risk of bias of the included studies. Data were checked for accuracy.
MAIN RESULTS
Twenty-three trials involving 8615 women and their babies were included in the update of this review. Ten trials assessed intravenous oxytocin; 12 trials assessed prostaglandins (six trials in the form of vaginal prostaglandin E2 and six as oral, sublingual or vaginal misoprostol); and one trial each assessed Caulophyllum and acupuncture. Overall, three trials were judged to be at low risk of bias, while the other 20 were at unclear or high risk of bias.Primary outcomes: women who had planned early birth were at a reduced risk of maternal infectious morbidity (chorioamnionitis and/or endometritis) than women who had expectant management following term prelabour rupture of membranes (average risk ratio (RR) 0.49; 95% confidence interval (CI) 0.33 to 0.72; eight trials, 6864 women; Tau² = 0.19; I² = 72%; low-quality evidence), and their neonates were less likely to have definite or probable early-onset neonatal sepsis (RR 0.73; 95% CI 0.58 to 0.92; 16 trials, 7314 infants;low-quality evidence). No clear differences between the planned early birth and expectant management groups were seen for the risk of caesarean section (average RR 0.84; 95% CI 0.69 to 1.04; 23 trials, 8576 women; Tau² = 0.10; I² = 55%; low-quality evidence); serious maternal morbidity or mortality (no events; three trials; 425 women; very low-quality evidence); definite early-onset neonatal sepsis (RR 0.57; 95% CI 0.24 to 1.33; six trials, 1303 infants; very low-quality evidence); or perinatal mortality (RR 0.47; 95% CI 0.13 to 1.66; eight trials, 6392 infants; moderate-quality evidence).
SECONDARY OUTCOMES
women who had a planned early birth were at a reduced risk of chorioamnionitis (average RR 0.55; 95% CI 0.37 to 0.82; eight trials, 6874 women; Tau² = 0.19; I² = 73%), and postpartum septicaemia (RR 0.26; 95% CI 0.07 to 0.96; three trials, 263 women), and their neonates were less likely to receive antibiotics (average RR 0.61; 95% CI 0.44 to 0.84; 10 trials, 6427 infants; Tau² = 0.06; I² = 32%). Women in the planned early birth group were more likely to have their labour induced (average RR 3.41; 95% CI 2.87 to 4.06; 12 trials, 6945 women; Tau² = 0.05; I² = 71%), had a shorter time from rupture of membranes to birth (mean difference (MD) -10.10 hours; 95% CI -12.15 to -8.06; nine trials, 1484 women; Tau² = 5.81; I² = 60%), and their neonates had lower birthweights (MD -79.25 g; 95% CI -124.96 to -33.55; five trials, 1043 infants). Women who had a planned early birth had a shorter length of hospitalisation (MD -0.79 days; 95% CI -1.20 to -0.38; two trials, 748 women; Tau² = 0.05; I² = 59%), and their neonates were less likely to be admitted to the neonatal special or intensive care unit (RR 0.75; 95% CI 0.66 to 0.85; eight trials, 6179 infants), and had a shorter duration of hospital (-11.00 hours; 95% CI -21.96 to -0.04; one trial, 182 infants) or special or intensive care unit stay (RR 0.72; 95% CI 0.61 to 0.85; four trials, 5691 infants). Women in the planned early birth group had more positive experiences compared with women in the expectant management group.No clear differences between groups were observed for endometritis; postpartum pyrexia; postpartum antibiotic usage; caesarean for fetal distress; operative vaginal birth; uterine rupture; epidural analgesia; postpartum haemorrhage; adverse effects; cord prolapse; stillbirth; neonatal mortality; pneumonia; Apgar score less than seven at five minutes; use of mechanical ventilation; or abnormality on cerebral ultrasound (no events).None of the trials reported on breastfeeding; postnatal depression; gestational age at birth; meningitis; respiratory distress syndrome; necrotising enterocolitis; neonatal encephalopathy; or disability at childhood follow-up.In subgroup analyses, there were no clear patterns of differential effects for method of induction, parity, use of maternal antibiotic prophylaxis, or digital vaginal examination. Results of the sensitivity analyses based on trial quality were consistent with those of the main analysis, except for definite or probable early-onset neonatal sepsis where no clear difference was observed.
AUTHORS' CONCLUSIONS
There is low quality evidence to suggest that planned early birth (with induction methods such as oxytocin or prostaglandins) reduces the risk of maternal infectious morbidity compared with expectant management for PROM at 37 weeks' gestation or later, without an apparent increased risk of caesarean section. Evidence was mainly downgraded due to the majority of studies contributing data having some serious design limitations, and for most outcomes estimates were imprecise.Although the 23 included trials in this review involved a large number of women and babies, the quality of the trials and evidence was not high overall, and there was limited reporting for a number of important outcomes. Thus further evidence assessing the benefits or harms of planned early birth compared with expectant management, considering maternal, fetal, neonatal and longer-term childhood outcomes, and the use of health services, would be valuable. Any future trials should be adequately designed and powered to evaluate the effects on short- and long-term outcomes. Standardisation of outcomes and their definitions, including for the assessment of maternal and neonatal infection, would be beneficial. | v2 |
2021-09-28T15:28:24.926Z | 2021-06-28T00:00:00.000Z | 239667800 | s2ag/train | Future instruments and sustainable outposts for deep space, Moon and Mars: Highlights and lessons from geologists supporting Apollo astronauts
<p>A fundamental goal of international human and robotic space exploration is to establish human outposts and bases on the Moon and Mars.  We seek to provide a <em>planetary science</em> perspective on lessons learned from the Apollo Lunar Exploration Program.</p>
<p><strong>1) Why?:</strong> What is the legacy, the long-term impact of our efforts? Apollo revealed the Earth as a planet, showed the inextricable links of the Earth-Moon system, and made the Solar System our neighborhood. We now ask: What are our origins and where are we heading?: We seek to understand the origin and evolution of the Moon, the Moon’s links to the earliest Earth history, and its lessons for exploration and understanding of Mars. These perspectives impel us to learn the lessons of off-Earth, long-term, long-distance resupply and self-sustaining presence, in order to prepare for the exploration of Mars.</p>
<p><strong>2) Where?:</strong> The combination of Transformative Lunar Science (TLS) questions [1] and exploration operational requirements compel us to explore the South Polar Region (SPR) of the Moon. The <em>scientific goals </em>are clear: 1) What is the origin, nature and abundance of polar volatile deposits and what do they tell us about internal/external sources and volatile history? [2-3] 2) What is the nature/composition/age of the South Pole-Aitken basin, and how does this inform us about lunar interior/chronology/bombardment history, and early Solar System dynamics? [4-5] The <em>scientific objectives </em>are: 1) explore, document/sample volatile deposits in permanently shadowed and stratigraphically related regions. 2) explore/document/sample/date SPA ejecta/pre-SPA crustal materials.  <em>E</em><em>xploration operational goals/objectives</em> are clear: 1) Define regions that optimize realization of scientific goals/objectives. 2) Define regions of continuous/near-continuous solar illumination to provide power to survive lunar night, establish long-term presence. 3) Explore SPR to establish the nature/abundance/mode of occurrence/“grade” of candidate volatile deposits. 4) Characterize surface physical properties/trafficability in order to optimize scientific/operational activities. 5) Prepare for dedicated human/robotic exploration missions to other parts of the Moon and Mars. 6) Test nascent technologies required for sustained human Moon/Mars presence (habitation/energy storage/radiation protection/ISRU).</p>
<p><strong>3) How?:</strong> Necessary is the development of a conceptual/operational framework built on a firm foundation of existing knowledge and data, and inclusion/optimization of new ideas/technologies. This permits us to continue the exploration to the next logical stages following the remarkably successful Apollo Lunar Exploration Program and multiple followon orbital/surface robotic missions. What are foundation pillars? a) Science and Engineering Synergism (SES): Apollo was successful because of the shoulder-to-shoulder engineer-scientist work culture that developed, and enabled longer-duration stay times and EVAs, significant mobility, additional equipment and experiments, and significantly greater sample return. SES requires concentrated/dedicated effort, but the rewards are clear, essential and <em>synergistic</em>.  SES maps out into operations at all levels of mission planning and execution. b) Human-Robotic Partnerships: Exploration is not a technique contest, but a partnership. The US sent 21 robotic missions prior to Apollo 11. The key to continual success lies in developing an architecture that complements and optimizes robotic and human capabilities.  c) Exploration Guidelines: Define human and robotic strengths and weaknesses, and optimize exploration plans. Longer-term stays mean both increased interactions with Earth and exploration independence of the Astronauts. Avoid “creeping determinism” [6], and encourage the Apollo T<sup>3</sup> approach (Train ‘em/Trust ‘em/Turn ‘em loose). Science and operational goals and objectives require exploration of broad areas: build in extensive Apollo LRV-like mobility. New remote-sensing technologies will enable more in situ characterization, sample analysis and selection but Earth laboratory technology advances will always outpace in situ analysis. Build in significant sample return mass from the beginning. d) Exploration Architectures: Individual missions are viewed as integrated elements in an operational strategy/architecture that is designed to accomplish the overarching goals. Candidate elements: I) <em>Precursor</em> (What do we need to know before we send humans?). II) <em>Context</em> (What are robotic mission requirements for final landing site selection/regional context for results?). III) <em>Infrastructure/Operations</em> (What specific robotic capabilities are required to optimize human scientific exploration performance?). IV) <em>Interpolation</em> (How do we use robotic missions to interpolate between human traverses?). V) <em>Extrapolation</em> (How do we use robotic missions to extrapolate beyond the human exploration radius?). VI) <em>Progeny </em>(What targeted robotic successor missions might be sent to the region to follow up on discoveries during exploration and from post-campaign analysis?). The NASA Commercial Lunar Payload Services (CLPS) Program complements the Artemis Program in this manner. e) Flexibility and Adaptability: <em>Science is the exploration of the unknown.</em></p>
<p><strong>Site Selection/Traverse Planning Guidelines</strong><strong>:</strong> Landing site selection always involves a balance of mission goals and objectives, and landing/operation safety/success. Science and Engineering Synergism (SES) is the key to this success as demonstrated during Apollo, and should be implemented throughout the exploration architecture. The same principles apply to traverse planning. SES ensures that science/engineering data needed for key decisions will be available and optimizes decisions. SES also optimizes the long-term goal of lunar base siting: for example, Mons Malapert, an inviting target for base siting due to favorable illumination/power, is difficult to traverse with Lunokhod and Apollo LRV-type vehicles [7].</p>
<p><strong>Surface Operations</strong><strong>:</strong> New instrumentation and technologies will significantly enhance exploration planning and accomplishment of goals. A multispectral laser reflectometer on the surface can confirm the presence of water ice and its location and distribution on scales relevant to human operations (cm to m), and be used to direct sampling and ISRU efforts undertaken by Artemis astronauts, a capability [9] highly complementary to orbital approaches. The parallel operations of robotic rovers, CLPS payload deliveries, and human activities will require continuous engineering and science operations/analysis centers on Earth. Lessons from the ISS should be incorporated, while also recognizing the human exploration capabilities of the Astronauts on the Moon [6]. </p>
<p><strong>References: </strong>1. Pieters et al. (2018)*; 2. Zuber et al (2012) Nature 486, 378;<strong> </strong>3. Li et al. (2019) PNAS 115, 8907;<strong> </strong>4. Moriarty & Pieters (2018) JGR 123, 729;<strong> </strong>5. Ivanov et al. (2018) PSS 162, 190;<strong> </strong>6. Krikalev et al. (2010) Acta Astro. 66, 70;<strong> </strong>7. Mazarico et al., 2020, LSSW;<strong> </strong>8. Baslievsky et al. (2019) SSR 53, 383; 9. Cremons et al. (2020) LSSW. *http://www.planetary.brown.edu/pdfs/5480.pdf</p> | v2 |
2021-11-25T16:22:19.411Z | 2021-11-05T00:00:00.000Z | 244546430 | s2ag/train | Evidence of NF-ΚB Pathway Activation in Patients with Advanced, High Molecular Risk Myelofibrosis
Introduction: Patients with myelofibrosis who discontinue treatment with the JAK1/2 inhibitor ruxolitinib have a poor prognosis that is often associated with advanced phases of disease and severe cytopenias. While these patients are more likely to have high molecular risk genomic markers, biological drivers of disease in this advanced population are not well characterized. PAC203, a Phase 2 dose-finding study in patients with symptomatic myelofibrosis who were intolerant of or resistant to ruxolitinib, represents an opportune cohort for analyzing the association between high molecular risk (HMR) mutations and disease phenotype. Patients had advanced disease at study entry, with profound cytopenias and high mutational burden [O'Sullivan J et al. Blood (2019) 134 (Sup_1):4214.]. Here, we analyzed the interaction between high-risk mutations and cytokine profiles of patients treated in PAC203.
Methods: Cytokine and mutation data were available in 108 (of total 164 recruited; 161 treated) patients. Using the Myriad RBM platform, a microsphere-based immuno-multiplexing technology, 47 cytokines were assessed. Mutation profiles were determined using an ISO accredited Illumina TruSeq Custom Amplicon Panel, composed of mutational-hotspots/exons from 32 genes (~36,000 bp, 287 amplicons). CALR mutation screening was carried out independently. Accepted coverage was achievement of a depth of ≥100 reads per base in ≥95% of targeted bases. The initial analysis assessed possible relationships between individual plasma cytokine levels and specific somatic gene mutation and clinical demographic data. An unsupervised approach was then used applying hierarchical agglomerative clustering to identify related sets of cytokines. Associations between cluster scores, based on the median overall cytokine concentration within each cluster for each patient, and clinical and genomic data was assessed.
Results: The median baseline platelet count was 64 x10 9/L (38% with platelets <50 x10 9/L) and baseline Hb <10g/dL in 68% of patients. The median age was 68 (37-87) years. The mutation profile of this cohort was previously described, with JAK2 V617F mutations (78%) the most prevalent driver mutation, followed by CALR mutations (13%), MPL mutations (7%), and patients were "triple-negative" in 2% of cases. Non-MPN driver mutations (NDM) were present in 76%, most commonly mutated-ASXL1 and -TET2 (27% and 24% respectively). Overall, 41% of patients had a high molecular risk mutation (HMR; IDH1/2, SRSF2, ASXL1, SRSF2, U2AF1Q157), splicing factor (SF) gene mutations were detected in 32% of patients and RAS pathway mutations (KRAS/NRAS) were found at a higher frequency than previously in MF cohorts (18%).
Analysis of cytokine data using unsupervised learning identified 6 clusters (Figure 1). Among these, elevations in clusters 2 (p=0.009) and 4 (p=0.006) were associated with presence of HMR mutations. Higher cluster 2 scores were also associated with driver mutation variant allele frequencies≥50%, p=0.007. Notably, the pro-inflammatory cytokines in cluster 2 linked to HMR mutations (HMR+) represented a transcriptional cluster regulated by the NF-κB pathway. The presence of a HMR mutation was associated with higher IL-8 levels (40.5pg/ml) as compared with absence (24.5pg/ml), p<0.0001. Elevated tumour necrosis factor-alpha (TNF- α) and IL-18 levels were also associated with HMR mutations; TNF-α 61pg/ml in HMR+ vs. 48.5pg/ml for HMR-. Although RAS-pathway mutations were not associated with a specifc cluster scores, these patients did have higher levels of the NF-kB-associated cytokine IL12P40 (1.1ng/ml) as compared with RAS-pathway wild-type patients (0.6ng/ml), p=0.001. There was no association between cytokine cluster scores and recent exposure to RUX at trial entry.
Conclusions: In this high-risk cohort of previously RUX-treated MF patients enriched for HMR and RAS-pathway mutations, we report for the first time a relationship between HMR somatic gene mutations and an NF-κB directed pro-inflammatory cytokine signature, implicating the activation of a distinct biological signaling pathway operative in this molecularly-defined cohort.
Figure 1 Figure 1.
Gerds: CTI BioPharma: Research Funding; AbbVie: Consultancy; Sierra Oncology: Consultancy; PharmaEssentia Corporation: Consultancy; Constellation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Harrison: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Buckley: CTI Biopharm: Current Employment. List: CTI Biosciences: Consultancy; Halia Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company; Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Aileron Therapeutics: Consultancy. Mead: Celgene/BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau.
| v2 |
2019-03-17T13:04:43.363Z | 2016-12-02T00:00:00.000Z | 79739610 | s2ag/train | Pharmacodynamic Profile of a Recombinant ADAMTS13 (BAX930) in Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome (USS))
Introduction The plasma metalloprotease, ADAMTS13, regulates the size of VWF multimers by cleaving VWF at Tyr1605-Met1606 in the A2 domain. A recombinant ADAMTS13 (rADAMTS13, BAX930), manufactured using a plasma-free method, may provide an important alternative replacement therapy for patients with ADAMTS13 deficiencies, such as hereditary thrombotic thrombocytopenic purpura (hTTP). In contrast to plasma infusions, which are currently the standard treatment of hTTP, rADAMTS13 can be infused at lower volumes and contains no additives of human or animal origin. The safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of rADAMTS13 have been evaluated in a first-in-human phase 1 prospective, open-label, multicenter, dose escalation trial in patients with hTTP (plasma ADAMTS13 activity Methods Subjects were assigned to one of three dose cohorts, receiving a single dose of rADAMTS13 at 5, 20 or 40 U/kg BW. PK parameters were assessed for ADAMTS13 activity (using FRETS-VWF73 and the commercially available Technozym assay) and ADAMTS13 antigen (ADAMTS13:Ag) at standardized time points (pre-infusion; 15, 30, 60 minutes and at regular intervals up to 12 days post-infusion). PD effects including the time course of VWF:RCo and VWF:Ag levels and VWF structural analysis were also performed. Results Fifteen patients with hTTP were treated with single injections of rADAMTS13 at doses of 5 U/kg (3 subjects), 20 U/kg (3 subjects), and 40 U/kg (9 subjects, 2 of whom were adolescents [ rADAMTS13 was well tolerated; there were no related serious or non-serious AEs. No binding or inhibitory anti-ADAMTS13 antibodies related to rADAMTS13 infusion were detected. Four possibly related AEs (nausea, flatulence, decreased VWF:RCo and VWF:Ag) were observed and all resolved without treatment. PK parameters were estimated based on data from the 7 adult subjects in the 40 U/kg dose cohort. The incremental recovery (IR; mean ± SD) was 0.023 ± 0.004 (U/mL x kg/U); T1/2 (mean ± SD) was 60.5 ± 13.5 hours; and AUC(0-inf) (mean ± SD) was 54.5±14.9 hours x U/mL (ADAMTS13 activity via FRETS). ADAMTS13 activity measurements by FRETS and chromogenic assays were comparable. Cmax values obtained from the 3 dosing cohorts demonstrated a dose response consistent with dose proportionality, with means of 0.08, 0.42 and 0.96 U/mL for the 5, 20, and 40 U/kg dose groups, respectively. The estimated clearances for the two adolescent subjects were 64.9 and 54.5 mL/h, respectively, which were within the range observed with adult subjects (n=7; range: 44.4 - 115 mL/h).[1] There was a dose-dependent increase in ADAMTS13-mediated VWF cleavage products observed over time, in line with the dose-dependent increases of ADAMTS13:Ag and activity markers. Specifically, ultra-large VWF multimers, a typical biomarker in hTTP subjects, were detected in the samples collected prior to dosing and decreased in the first 24 hours post-dose at the higher doses of 20 U/kg or 40 U/kg rADAMTS13. In parallel, the intermediate size VWF multimer fraction increased. ADAMTS13-mediated VWF cleavage products were detectable in all subjects up to 3 hours, 24 hours, and 48 hours after injection of 5 U/kg, 20 U/kg, and 40 U/kg, respectively. In all dosing groups, changes in VWF were accompanied by an increase in the platelet count and a decrease of LDH during the first 96 hours after rADAMTS13 injection. Taken together, these findings provide evidence of in vivo ADAMTS13 activity following rADAMTS13 administration. Conclusion In this first-in-man, phase 1 study, rADAMTS13 was safe and well tolerated, demonstrated a PK profile comparable to that estimated from plasma infusion studies, and showed evidence of PD activity in vivo, including effects on VWF multimers, platelet count, and serum LDH. [1] There were differences in sampling schedules between adults (extensive sampling) and adolescents (sparse sampling). Disclosures Scully:Baxalta, now part of Shire: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ablynx: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Knoebl:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Rice:Selexys: Other: Participation in multi-center research trial; Ablynx: Other: Participation in multi-center research trial; Apellis/Synergy: Other: Data Safety Monitoring Committee member; Alexion: Membership on an entity9s Board of Directors or advisory committees, Other: Participation in registry studies; Novartis Pharma: Speakers Bureau; Incyte: Other: Participation in multi-center research trial. Windyga:Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Other: Speaker9s honorarium; Baxalta, now part of Shire: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Investigator Clinical Studies, Patents & Royalties, Research Funding, Speakers Bureau; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Schneppenheim:Baxalta, now part of Shire: Membership on an entity9s Board of Directors or advisory committees. Kremer Hovinga:NovoNordisk: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity9s Board of Directors or advisory committees, Research Funding; CSL-Behring: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Maggiore:Quintiles: Employment. Doralt:Baxalta, now part of Shire: Employment. Martell:Baxalta, now part of Shire: Employment. Ewenstein:Shire: Employment, Equity Ownership. | v2 |
2019-11-22T01:08:49.625Z | 2019-11-13T00:00:00.000Z | 209267460 | s2ag/train | POLARGO: A Randomized Phase III Study Evaluating Polatuzumab Vedotin Plus Rituximab, Gemcitabine, and Oxaliplatin in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Who Had Received One or More Previous Therapies
Introduction: The antibody-drug conjugate polatuzumab vedotin (pola) targets CD79b on B-cell malignancies. Pola in combination with bendamustine and rituximab (BR) improved complete response (CR) rate and overall survival (OS) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), compared with BR alone (CR rate: 40% vs 18%, respectively, p=0.026; median OS: 12.4 vs 4.7 months, respectively, p=0.0023; Sehn et al. ASH 2018). Based on these results, pola + BR was recently approved by the FDA for patients with R/R DLBCL after at least two prior therapies.
NCCN guidelines (2019) suggest multiple second-line and subsequent treatment options for patients with R/R DLBCL; in practice, a wide range of options are used (Herrera et al. Hematol Oncol 2019). One recommended option is rituximab plus gemcitabine and oxaliplatin (R-GemOx; Mounier et al. Haematol 2013; Cazelles et al. Hematol Oncol 2019). Platinum-based chemotherapies such as oxaliplatin are a preferred salvage approach for patients with R/R DLBCL (Tilly et al. Ann Oncol 2015). The safety of pola combined with platinum-based therapies in R/R DLBCL has not yet been assessed, and both pola and platinum-based therapies are associated with neuropathy. In the POLARGO study, we will assess the safety and efficacy of pola in combination with R-GemOx, compared with R-GemOx alone, in patients with R/R DLBCL.
Methods: POLARGO (MO40598) is a multicenter, open-label, Phase III study, comprising two stages: 1) a safety run-in stage evaluating pola + R-GemOx in 10 patients and 2) a randomized controlled trial (RCT) stage comparing pola + R-GemOx with R-GemOx alone in an expected 206 patients. In the RCT stage, patients will be recruited from 80─90 sites globally.
Patients must have histologically confirmed R/R DLBCL, confirmed availability of archival or freshly collected tumor tissue (RCT stage), and ECOG performance status of 0-2. Relapse is defined as disease that recurs following a response lasting ≥ 6 months from completion of the last line of therapy. Refractory is defined as disease that progressed during previous therapy or stable disease for up to 6 months from completion of the last line of therapy. Patients will be excluded if they have had allogeneic stem-cell transplantation (SCT) and/or have planned autologous/allogeneic SCT. Patients with baseline peripheral neuropathy greater than grade 1 (as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 [NCI CTCAE v5.0]) will be excluded.
The primary endpoint of the safety run-in stage is the safety and tolerability of pola (1.8mg/kg) + R-GemOx (R, 375mg/m2; Gem, 1000mg/m2; Ox, 100mg/m2) administered in 21-day cycles, as assessed by the incidence, nature, and severity of adverse events (AEs; NCI CTCAE v5.0), with a focus on peripheral neuropathy.
If pola + R-GemOx is tolerable in the safety run-in stage, new patients will be enrolled in the RCT stage. At randomization, patients will be stratified by number of previous lines of systemic therapy for DLBCL, outcome of last systemic therapy (relapsed vs refractory), and age (≤70 years vs >70 years). Patients will be randomized (1:1) to receive up to eight 21-day cycles of either pola + R-GemOx or R-GemOx alone.
The primary endpoint of the RCT stage is OS, defined as the time from randomization to death from any cause. The secondary efficacy endpoints are: best overall response, progression-free survival, duration of objective response, event-free survival, CR rate and objective response rate (according to Lugano 2014 criteria), as determined by the investigator and an independent review committee. Safety will be assessed by recording the incidence, nature, and severity of AEs (NCI CTCAE v5.0), with a focus on peripheral neuropathy. Dose interruptions, reductions, and intensity will be used to determine tolerability. The impact of treatment on health-related quality of life will be assessed. PET-CT and CT scans will be obtained at screening, during, and after the treatment period; 28 days after the last dose of study drug; and then every two (PET-CT), and six (CT) months during follow-up for up to 2 years.
McMillan: Sandoz: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria; Pfizer: Honoraria, Research Funding; MSD: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; BMS: Honoraria. Matasar:Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy. Sancho:Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Viardot:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hernandez:F. Hoffmann-La Roche Ltd: Employment. Perretti:F. Hoffmann-La Roche Ltd: Employment. Haioun:Servier: Honoraria; Miltenyi: Honoraria; Takeda: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria.
Polatuzumab vedotin (POLIVY, Genentech, Inc.) is a CD79b-directed antibody-drug conjugate. It was approved by the FDA in June 2019 in combination with bendamustine and rituximab for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma after at least two prior therapies.
| v2 |
2018-04-03T00:10:44.311Z | 2008-06-27T00:00:00.000Z | 9465120 | s2ag/train | Carbonyl propargylation from the alcohol or aldehyde oxidation level employing 1,3-enynes as surrogates to preformed allenylmetal reagents: a ruthenium-catalyzed C-C bond-forming transfer hydrogenation.
Over the past half century, numerous protocols for carbonyl propargylation using allenylmetal reagents have been developed.[1] Allenic Grignard reagents were used by Prevost et al.[2a] in carbonyl additions to furnish mixtures of β-acetylenic and α-allenic carbinols, which led to them to coin the term “propargylic transposition.”[2a,b] Subsequent studies by Chodkiewicz and co-workers[2c] demonstrated relative stereocontrol in such additions. Shortly thereafter, Lequam and Guillerm[2d] reported that isolable allenic stannanes provide products of carbonyl propargylation upon exposure to chloral. Later, Mukaiyama and Harada[2e] demonstrated that stannanes generated in situ from propargyl iodides and stannous chloride reacted with aldehydes to provide mixtures of β-acetylenic and α-allenic carbinols. Related propargylations employing allenylboron reagents were first reported by Favre and Gaudemar,[2f] and propargylations employing allenylsilicon reagents were first reported by Danheiser and Carini.[2g] Asymmetric variants followed (Scheme 1). Allenylboron reagents chirally modified at the boron center engage in asymmetric propargylation, as was first reported by Yamamoto and co-workers[2h] and Corey et al.[2i] Allenylstannanes chirally modified at the tin center also induce asymmetric carbonyl propargylation, as was first reported by Minowa and Mukaiyama.[2j] Axially chiral allenylstannanes, allenylsilanes, and allenylboron reagents propargylate aldehydes enantiospecifically, as was first described by Marshall et al.,[2k,l] and Hayashi and coworkers,[2m] respectively. Finally, asymmetric aldehyde propargylation using allenylmetal reagents may be catalyzed by chiral Lewis acids or chiral Lewis bases, as was first reported by Keck et al.,[2n] and Denmark and Wynn,[2o] respectively.
Scheme 1
Chirally modified allenylmetal reagents for carbonyl propargylation. Tf =trifluoromethanesulfonyl, Ts =para-toluenesulfonyl.
Here, we report a new approach to carbonyl propargylation based on ruthenium-catalyzed C–C bond-forming transfer hydrogenation.[3–5] Specifically, upon exposure of 1,3-enynes 1a–1g to alcohols 2a–2o in the presence of [RuHCl(CO)(PPh3)3]/dppf (dppf =1,1′-bis(diphenylphosphino)ferrocene), hydrogen shuffling between reactants occurs to generate nucleophile–electrophile pairs that regioselectively combine to furnish products of carbonyl propargylation.[6] Under related transfer hydrogenation conditions and employing isopropanol as the terminal reductant, 1,3-enynes couple to aldehydes to furnish identical products of carbonyl propargylation. The observed regiochemistry is unique with respect to related enyne–carbonyl reductive coupling reactions that are catalyzed by rhodium[5,7] and nickel complexes, [8,9,10] which favor coupling at the acetylenic terminus of the enyne. Significantly, this protocol enables carbonyl propargylation from the alcohol or aldehyde oxidation level in the absence of preformed allenylmetal reagents (Scheme 2).
Scheme 2
Divergent regioselectivity observed in metal-catalyzed enyne–carbonyl coupling.
In connection with our efforts to exploit catalytic hydrogenation in C–C coupling reactions beyond hydroformylation,[5] we recently demonstrated that C–C bond formation may be achieved under the conditions of iridium- and ruthenium-catalyzed transfer hydrogenation.[11] These processes enable direct carbonyl allylation from the alcohol or aldehyde oxidation level by using commercially available allenes or dienes as allyl donors. Seeking to develop corresponding carbonyl propargylations, diverse iridium and ruthenium complexes were assayed for their ability to catalyze the coupling of enyne 1a and alcohol 2a. Gratifyingly, both [{Ir(cod)Cl}2]/biphep (biphep =diphenylphosphine, cod =cycloocta-l,5-diene) and [RuHCl(CO)(PPh3)3]/dppf catalyze the desired coupling. The ruthenium-based catalyst was most effective and, under optimized conditions, enyne 1a coupled to benzylic, allylic, and aliphatic alcohols 2a–2o to form homopropargyl alcohols 3a–3o in good to excellent yields (Table 1). To probe the scope of the enyne coupling partner, enynes 1b–1g were coupled to benzyl alcohol 2b under standard reaction conditions. Good to excellent yields of propargylation products 3p–3u were observed (Table 2). Substitution at the olefinic terminus of the enyne was found to diminish conversion to product. Finally, carbonyl allylation can also be achieved from the aldehyde oxidation level by employing isopropanol as the terminal reductant. Under standard reaction conditions, aldehydes 4a–4c couple to enyne 1a to provide the products of carbonyl propargylation 3a–3c, respectively, in good to excellent yield. Thus, carbonyl propargylation may be achieved from either the alcohol or aldehyde oxidation level (Table 3). The coupling products 3a–3u are remarkably resistant to over-oxidation to form the corresponding β,γ-acetylenic ketones. However, such over-oxidation is observed if cationic ruthenium complexes are employed as catalysts. This result suggests that, for the neutral ruthenium complexes employed in this study, the alkyne moiety of the coupling product blocks a coordination site required for β hydride elimination of the carbinol C–H bond. Other aspects of the catalytic mechanism, including determination of the structural and interactive features of the ruthenium complex that influence relative and absolute stereocontrol, are currently under investigation.
Table 1
Carbonyl propargylation from the alcohol oxidation level by ruthenium-catalyzed transfer hydrogenation.a
Table 2
Coupling of enynes 1b–1g to benzyl alcohol 2b by ruthenium-catalyzed transfer hydrogenation.a
Table 3
Carbonyl propargylation from the aldehyde oxidation level by ruthenium-catalyzed transfer hydrogenation.a
A general catalytic mechanism is likely to involve the following steps:[11] a) alcohol dehydrogenation to generate a ruthenium hydride is followed by b) enyne hydrometalation to generate an allenyl metal–aldehyde/nucleophile–electrophile pair, which undergoes c) carbonyl addition with propargylic transposition. Consistent with this interpretation, the coupling of enyne 1a to [D]-2b under standard reaction conditions provides [D]-3b, in which deuterium is incorporated at the benzylic position (>95%), the allylic methyl group (56%), and the allylic methine position (24%), thus suggesting reversible olefin-hydrometalation [Eq. (1)].
(1)
Our collective studies on hydrogenative and transfer hydrogenative C–C coupling define a departure from the use of preformed organometallic reagents in carbonyl addition chemistry.[5,11] For such transfer hydrogenative coupling reactions, hydrogen embedded within isopropanol or an alcohol substrate is redistributed among reactants to generate nucleophile–electrophile pairs, thus enabling carbonyl addition from the aldehyde or alcohol oxidation level. In this way, carbonyl additions that transcend the boundaries of oxidation level are devised. In the present study, we have demonstrated that 1,3-enynes serve as allenylmetal equivalents under the conditions of transfer hydrogenative coupling, thus also enabling carbonyl propargylation from the alcohol or aldehyde oxidation level. These studies contribute to a growing body of catalytic methods for the direct functionalization of carbinol C–H bonds.[11,12] Future studies will focus on the development of related alcohol–unsaturate C–C coupling processes. | v2 |
2022-06-09T06:12:50.542Z | 2007-01-01T00:00:00.000Z | 249467640 | s2ag/train | IP REGULATION OF INDUCIBLE NITRIC OXIDE SYNTHASE AND CATIONIC AMINO ACID TRANSPORT BY p38a AND p38p MAP KINASES IN RAT CULTURED AORTIC SMOOTH MUSCLE CELLS
Previous studies suggest that induction of nitric oxide synthase (iNOS) and cationic amino acid transport (CAT) may be regulated by the p38 mitogen activated protein kinase (MAPK) pathway in cultured rat aortic smooth muscle cells (RASMC) (Baydoun et al., 1999). This conclusion was based on the fact that both processes could be inhibited by SB203580, a potent inhibitor of the p38 MAPK. There is, however, growing concern over the selectivity of this compound since it also inhibits other parallel signalling pathways including the c-Jun N-terminal kinases (JNK; Clerk and Sugden, 1998). We have therefore extended our original studies by examining the effects of SB203580-sensitive isoforms of p38 on the induction of both iNOS and CATs by transfecting wild-type p38a or p380 MAPKs into RASMCs. Briefly, RASMC rats were plated out in 24-well plates and allowed to grow to -40-60% confluency before transfection with either p38a or p38j constructs in a pcDNA vector. Transfections were carried out using an integrin-binding polycationic peptide in the presence of lipofectin. Cells wer? activated for 24h with LPS (100 gg mLV1) and IFN-y (50 U mL') 3h, 6h, 12h and in the supernatant In spontaneously hypertensive rat (SHR), the endothelium-dependent relaxation to acetylcholine (ACh) of the aorta due to the of a concomitant endothelium-dependent Vanhoutte, The present study was designed to determine whether or not a diffusible substance (or substances) is involved in these endothelium-dependent contractions. Capsaicin activates a non-specific cation channel, the VR1 (vanilloid) receptor that has been cloned from rat dorsal root ganglia. Recent studies suggest that VRl-immunoreactivity occurs on neuronal fibres of the human colon (Yiangou et al., 2001) and intrinsic neurones of the rat and porcine intestine. The present confocal immunohistochemical study was performed to probe the neurochemical identity and possible functional significance of VRl in the myenteric plexus of the guinea-pig ileum and colon. Sensory neural dysfunction is common in patients with peripheral neuropathy, a major complication of diabetes mellitus 2001). A key measure of sensory neurone function is stimulus-evoked neuropeptide release. We investigated the effect of cannabinoids on capsaicin-evoked release of calcitonin gene-related peptide (CGRP) from rat paw skin in vitro, which is mediated by the vanilloid VR1 receptor (Kilo et al, 1997), comparing non-diabetic and diabetic animals. The study employed the synthetic CB,/CB2 receptor agonist CP55940, the endocannabinoid anandamide, which activates both CB, and VR1 receptors and the CB, receptor selective antagonist SR141716A (Pertwee, 2001). Capsaicin-sensitive sensory nerves are widely distributed in the cardiovascular system (Maggi & Meli, 1988). In the mesenteric arterial bed calcitonin gene-related peptide (CGRP) is released upon activation of sensory nerves producing vasodilatation (Kawasaki et al., 1988). Preliminary investigations using synthetic cannabinoids in the mesenteric bed indicate the presence of a functional cannabinoid receptor that attenuates sensory neurotransmission (Duncan et a!, 2001). Noladin ether (NE), reported to be an endogenous cannabinoid, binds weakly to CB, and CB2 receptors but exerts cannabimimetic effects in vWvo (Hanus et al, 2001). The aim of the present study was to determine if this endocannabinoid mimics the actions of synthetic cannabinoids previously shown in the rat mesenteric arterial bed. Our data demonstrate a novel inhibition of electrically evoked CGRP release by (S)-AMPA superfusion, which is reversed by the CB, antagonist (SRI). AMPA inhibition may be due to the release of endogenous cannabinoids from second order neurones, acting retrogradely to inhibit the electrically evoked CGRP release. Central N/OFQ to N/OFQ ([Nphe']) this we have confirmed the ability of to block N/OFQ-induced food intake, to investigate the involvement of N/OFQ in the mediation of physiological feeding behaviour. hypothesized if the on dark-phase Arc (activity-regulated cytoskeleton associated protein) is an effector immediate early gene whose mRNA is selectively localised in neuronal dendrites. Its expression has been shown to be induced by neuronal stimulation and by agonist stimulation of 5-HT2A receptors (Pei et al., 2000). Regulation of the 5-HT2A receptor is atypical in that both agonists and antagonists induce a decrease in receptor density. Mianserin is a tetracyclic antidepressant, which has shown these properties when administered both in vitro (Newton and Elliott, 1997) and in vivo (Blackshear and Sanders-Bush, 1982). The aim of the present study was to identify the functional consequences of this down-regulation induced by mianserin, as indicated by Arc mRNA expression stimulated by 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane (DOI), a selective 5-HT2MC agonist. Peptidergic neurones accumulate amines via an unusual uptake process designated Transport-P. Our work so far has identified two types of compounds which act as ligands for Transport-P: Group A compounds, exemplified by prazosin, are accumulated in a cooperative manner. Group B compounds, which include phenylethylamines, are accumulated non-cooperatively by the same uptake process. We studied the structural properties of this group by examining a large series of compounds for their ability to inhibit competitively the uptake of prazosin (1 uM) in immortalised gonadotrophin-releasing hormone neurones (GTl-l GnRH cells) as previously described in detail (Al-Damluji & Kopin, 1998). All the compounds were soluble in warm DMSO at 0.1 M. The results were as follows: L-3,4-dihydroxyphenylalanine (L-DOPA) is still the mainstay of pharmacological treatment of Parkinson's disease. Apart from its ability to readily generate dopamine (DA), however, L-DOPA may also increase noradrenaline (NA) synthesis or release. Release of NA by L-DOPA was determined: a) in isolated, electrically field- stimulated (EFS) vasa deferentia treated with yohimbine and desipramine (3 and I gM respectively); b) by microdialysis technique in rat frontal cortex. Striatal dopamine loss in Parkinson's disease produces excess glutamate release from subthalamic efferents leading to over-activity of basal ganglia output nuclei such as the substantia nigra pars reticulata (SNr). Activation of GABAB receptors on subthalamonigral terminals may counteract this and so help to restore normal motor fimction. The aims of this study were to examine (i) whether GABAB receptor activation either locally (SNr) or distally (3rd ventricle; 3V) alleviates akinesia in a rodent model of PD and (ii) whether GABAB receptor activation reduces glutamate release in the SNr. (SNr) (ALUs; 90 min of anti-akinetic efficacy, different 1-way ANOVA. of pre-treatment the CGP 46381 g), intranigral (800 ng) using a t-test. | v2 |
2021-11-25T16:07:39.731Z | 2021-11-05T00:00:00.000Z | 244539100 | s2ag/train | Completed Induction Phase Analysis of Magnify: Phase 3b Study of Lenalidomide + Rituximab (R 2) Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma
Background: Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide combined with rituximab (R 2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with iNHL (RELEVANCE : N Engl J Med 2018;379:934 and AUGMENT: J Clin Oncol. 2019;37:1188).
Methods: MAGNIFY is a multicenter, phase 3b trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. In the induction phase, lenalidomide 20 mg PO on days 1-21 of a 28-day cycle + rituximab IV at 375 mg/m 2/week cycle 1 and then every 8 weeks starting with cycle 3 (R 2) are administered for 12 cycles. Patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) were randomized 1:1 to R 2 vs rituximab maintenance for 18 months. Data presented here are the complete analysis from the induction phase in efficacy-evaluable patients with FL grades 1-3a or MZL (FL grade 3b, tFL, and MCL not included). The focus of this interim analysis was overall response rate (ORR) by 1999 IWG criteria in the induction intention-to-treat population.
Results: As of March 5, 2021, 394 patients (318 [81%] FL gr1-3a; 76 [19%] MZL) were enrolled. The median follow-up was 40.6 mo (range, 0.6-79.6). Median age was 66 y (range, 35-91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% (n = 279) with 42% (n = 164) CR/CRu (Table). All patients have completed R 2 induction (n = 232, 59%) or discontinued study treatment (n = 162, 41%). 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs) (n = 54, 14%) or progressive disease (n = 42, 11%). The majority of patients who have completed induction have been randomized and entered maintenance (n = 217). Median duration of response in the induction period was not reached (95% CI, 43.9 mo-NR), and median progression-free survival in the induction safety population (n = 393) was 50.5 mo (95% CI, 39.5-NR). Efficacy results are reported in the table by histology subgroups (FL vs MZL), and rituximab-refractory, double-refractory, and early relapse statuses. Most common all-grade AEs were 47% fatigue, 43% neutropenia, 37% diarrhea, 30% nausea, and 30% constipation. Grade 3/4 AEs occurring in ≥ 5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, and 5% fatigue.
Conclusions: These data represent complete analysis of all patients in the induction phase of MAGNIFY which continue to support that R 2 is active with a tolerable safety profile in patients with R/R FL grade 1-3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients.
Figure 1 Figure 1.
Lansigan: Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Andorsky: Abbvie: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Epizyme: Research Funding. Coleman: immunomedics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Abbvie: Research Funding; Bristol Myers: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; BeiGene: Research Funding; Innocare: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning: Sanofi: Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Nowakowski: Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Curis: Consultancy; Selvita: Consultancy; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Karyopharm Therapeutics: Consultancy; Ryvu Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Kyte Pharma: Consultancy; Roche: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; MorphoSys: Consultancy. Gharibo: BMS: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ahn: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; ADC therapeutics: Current equity holder in publicly-traded company. Li: BMS: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Sharman: BeiGene: Consultancy; TG Therapeutics: Consultancy; Lilly: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy; AbbVie: Consultancy.
| v2 |
2017-04-16T06:24:50.682Z | 2008-01-01T00:00:00.000Z | 8636450 | s2ag/train | Inhibition of MammalianTarget of Rapamycin by Rapamycin Causes the Regression of Carcinogen-Induced SkinTumor Lesions
Purpose: The activation of Akt/mammalian target of rapamycin (mTOR) pathway represents a frequent event in squamous cell carcinoma (SCC) progression, thus raising the possibility ofusing specific mTOR inhibitors for the treatment of SCC patients. In this regard, blockade of mTORwith rapamycin prevents the growth of human head and neck SCC cells when xenotransplanted into immunodeficient mice. However, therapeutic responses in xenograft tumors are not always predictive of clinical anticancer activity. Experimental Design: As genetically defined and chemically induced animal cancer models often reflect better the complexity of the clinical setting, we used here a two-step chemical carcinogenesis model to explore the effectiveness of rapamycin for the treatment of skin SCC. Results: Rapamycin exerted a remarkable anticancer activity in this chemically induced cancer model, decreasing the tumor burden of mice harboring early and advanced tumor lesions, and even recurrent skin SCCs. Immunohistochemical studies on tumorbiopsies and clustering analysis revealed that rapamycin causes the rapid decrease in the phosphorylation status of mTOR targets followed by the apoptotic death of cancer cells and the reduction in the growth and metabolic activity of the surviving ones, concomitant with a decrease in the population of cancer cells expressing mutant p53. This approach enabled investigating the relationship among molecular changes caused by mTOR inhibition, thus helping identify relevant biomarkers for monitoring the effectiveness of mTOR inhibition in the clinical setting. Conclusions:Together, these findings provide a strong rationale for the early evaluationof mTOR inhibitors as a molecular targeted approach to treat SCC. Cancer arises in multistep process resulting from the sequential accumulation of genetic defects and the clonal expansion of selective cell populations (1). For example, in the case of human head and neck squamous carcinomas (HNSCC), tumor progression often involves the sequential genetic or epigenetic inactivation of multiple tumor suppressor genes, such as p16 (9p21), APC (5q21-22), and p53 (17p13; ref. 2), concomitant with changes in the activation state of signaling pathways that promote the aberrant growth of the cancerous cells. The latter frequently result from the overexpression and/or activity of cell surface receptors, including epidermal growth factor receptors, hepatocyte growth factor receptors (c-Met), and receptors for numerous cytokines, chemokines, and inflammatory mediators (3–5). These receptors share the ability to promote the activation of several intracellular signaling pathways, including the Ras-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase biochemical route and the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (mTOR) pathway, which in turn promote cell proliferation and survival (6). This emerging knowledge on the nature of the signaling networks driving the unrestricted growth of cancerous cells has now enabled the development of novel therapies targeting key signaling molecules whose dysregulation contribute to tumor progression in each cancer type. In particular, the widespread activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway in HNSCC progression has raised the possibility of using specific mTOR inhibitors and their derivatives for the treatment of HNSCC patients (7, 8). In this regard, blockade of mTOR with rapamycin exerts a potent antitumoral effect and even prevents minimal residual disease in several human HNSCC xenograft models (9–11). However, effectiveness in human xenograft tumors is not always predictive of a clinical anticancer activity (12, 13). Genetically defined and chemically induced animal cancer models are often more difficult to treat than xenotransplanted human tumors in immunocompromised mice but reflect better the more complex and challenging situation of the clinical setting (12–14). Thus, in this study, we took advantage of the well-established two-step chemical carcinogenesis model, in which squamous carcinogenesis (SCC) is initiated by the topical application of a tobacco-related chemical carcinogen Cancer Therapy: Preclinical Authors’Affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Craniofacial and Dental Research, NIH, Bethesda, Maryland Received 3/17/08; revised 8/18/08; accepted 8/19/08. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Requests for reprints: J. Silvio Gutkind, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, 30 Convent Drive, Building 30, Room 212, Bethesda, MD 20892-4330. Phone: 301-496-6259; Fax: 301-402-0823; E-mail: [email protected]. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-0703 www.aacrjournals.org Clin Cancer Res 2008;14(24) December15, 2008 8094 Research. on April 15, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from [7,12-dimethylbenz(a)anthracene (DMBA)] to the skin followed by the prolonged treatment with phorbol esters [12-O-tetradecanoylphorbol-13-acetate (TPA); ref. 15], to explore the effectiveness of rapamycin for the treatment of skin SCC lesions. We show here that rapamycin exerts a potent anticancer activity in this chemically induced cancer model, as chronic administration of rapamycin decreases the tumor burden of mice harboring early and advanced primary tumor lesions and even recurrent SCC. Indeed, the inhibition of mTOR with rapamycin results in the regression of carcinogeninduced skin SCC, thus providing a strong rationale for the early clinical evaluation of rapamycin and its derivatives in SCC patients. Materials andMethods Reagents. DMBA was purchased from Sigma and phorbol ester TPA was from Alexis Biochemicals. Rapamycin was provided by the Developmental Therapeutics Program (National Cancer Institute). Antibodies. Polyclonal rabbit antibodies against phospho-Akt (pAkt; S473), phospho-S6 (pS6), eIF4E, and cyclin D1 were purchased from Cell Signaling. Rat monoclonal anti-mouse CD31 (BD Pharmingen), polyclonal rabbit anti-mouse CD3 (Dako), rat monoclonal antiF4/80 (Serotec), rabbit polyclonal anti-p53 (Novocastra), rabbit polyclonal anti-glucose transporter 1 (Chemicon), polyclonal rabbit anti-vascular endothelial growth factor (Santa Cruz Biotechnology), and mouse monoclonal anti-proliferating cell nuclear antigen (PCNA; Zymed) were used when indicated. Animals. All animal studies were carried out according to NIHapproved protocols, in compliance with the Guide for the Care and Use of Laboratory Animals. Six-week-old female FVB/N mice were obtained from Taconic Farm, Inc., housed in appropriate sterile filter-capped cages, and fed and watered ad libitum . All handling, tumor induction, and treatment procedures were conducted in a laminar flow biosafety | v2 |
2016-10-31T15:45:48.767Z | 2007-01-01T00:00:00.000Z | 107169730 | s2ag/train | Evaluating Court Processes for Determining Indigency
* We appreciate the assistance we received in visioning, collecting, and assessing the information used in this evaluation. We are especially grateful for the help and guidance we received from the Project Oversight Committee, beginning with their ideas for what needed to be evaluated and concluding with comments and corrections to earlier drafts. The Oversight Committee members included: Steven Burns (Lancaster County District Court Judge), Kerry Eagan (Lancaster County Chief Administrative Officer), James Foster (Committee Chair and Lancaster County Court Judge), Peggy Gentles (Lancaster County Court Judicial Administrator), Dennis Keefe (Lancaster County Public Defender), Gary Lacey (Lancaster County Attorney), Catherine Reech (Lancaster County Court Screener), Toni Thorson (Lancaster County Juvenile Court Judge), Mike Thurber (Lancaster County Corrections Director), and Janice Walker (Nebraska State Court Deputy Administrator). We would also like to acknowledge the following for their assistance: Kimberly Applequist (University of Nebraska Public Policy Center), Pamela Casey (National Center for State Courts), Ian Christensen (University of Nebraska Public Policy Center), Carly Duvall (University of Nebraska Public Policy Center), Jenn Elliott (University of Nebraska Public Policy Center), Carol Flango (National Center for State Courts), Roger Hanson (Independent Law and Society Researcher, Williamsburg, VA), Patrick J. DornKennedy (University of Nebraska Public Policy Center), Katie Novak (University of Nebraska Public Policy Center), David Rottman (National Center for State Courts), Nancy Shank (University of Nebraska Public Policy Center), and Ann Skove (National Center for State Courts). 1. 372 U.S. 335 (1963). 2. E.g., Argersinger v. Hamlin, 407 U.S. 25 (1972); Scott v. Illinois, 440 U.S. 367 (1979); Glover v. United States, 531 U.S. 198 (2001); Alabama v. Shelton, 535 U.S. 654 (2002). 3. E.g., Alexander v. State, 527 S.W. 2d 927 (Ark. 1975); Carey v. Zayre of Beverly, Inc., 324 N. E. 2d 619 (Mass. 1975); Brown v. Multnomah County Dist. Court, 570 P. 2d 52 (Or. 1977); State v. Ponce, 611 P. 2d 407 (Wash. 1980); State v. Jones, 404 So. 2d 1192 (La. 1981); State v. Novak, 318 N.W. 2d 364 (Wis. 1982); Canaday v. State, 687 P.2d 897 (Wyo. 1984); State v. Buchholz, 462 N. E. 2d 1222 (Ohio 1984); State v. Orr, 375 N.W. 2d 171 (N.D. 1985); Commonwealth v. Thomas, 507 A.2d 57 (PA 1986); State v. Lynch, 796 P. 2d 1150 (Okla. 1990); Hlad v. State, 585 So. 2d 928 (Fla. 1991); In re Advisory Opinion to the Governor, 666 A. 2d 813 (R.I. 1995); Peeler v. Hughes & Luce, 909 S. W. 2d 494 (Tex, 1995); People v. Monge, 941 P.2d 1121 (Cal. 1997); Russell v. Armitage, 697 A.2d 630 (Vt. 1997); State v. Woodruff, 951 P. 2d 605 (N.M. 1997); El Pueblo de Puerto Rico v. Amparo Concepcion, 98 TSPR 93 (PR 1998); State v. Stott, 586 N.W. 2d 436 (Neb. 1998); Johnson v. State, 735 A. 2d 1003 (MD.1999); Ex parte Lareed Shelton, 851 So. 2d 96 (Ala. 2000); In re Welfare of G.L.H., 614 N.W. 2d 718 (Minn. 2000); Barnes v. State, 570 S.E. 2d 277 (Ga. 2002); City of Urbana v. Andrew N.B., 813 N.E. 2d 132 (Ill. 2004); People v. Russell, 684 N. W. 2d 745 (Mich. 2004); Lucero v. Kennard, 125 P.3d 917 (Utah, 2005). 4. Robert L. Spangenberg & Marea L. Beeman, Indigent Defense Systems in the United States, 58 LAW & CONTEMP. PROBS. 31 (1995)[hereinafter Spangenberg & Beeman, Indigent Defense Systems]; Spangenberg Group, Indigent Defense Services in the State of Nevada: Findings and Recommendations (Dec. 13, 2000) (available at http://www.spangenberggroup.com/reports/report_ 121301.pdf); Spangenberg Group, Determination of Eligibility for Public Defense (2002) [hereinafter Spangenberg Group, Determination of Eligibility] (available at http://www.abanet.org/ legalservices/downloads/sclaid/indigentdefense/determinationofeligibility.pdf#search=%22Determination%20of%20Eligibility%20f or%20Public%20Defense%22). 5. Spangenberg Group, Determination of Eligibility, supra note 4. The Sixth Amendment to the Constitution guarantees all people accused of a crime the right to legal counsel. In the landmark 1963 decision Gideon v. Wainright,1 the United States Supreme Court affirmed the right of indigent defendants to have counsel provided. But Gideon did not end the Supreme Court’s discussion of the circumstances in which the state is required to provide defendants with an attorney when they claim not to have the means to pay for one.2 Nor did it end the states’ examination of the requirement of any legal assistance paid for by taxpayers.3 Moreover, it is not mandated by constitutional law, congressional statute, or U.S. Supreme Court interpretation how states will fund these programs (will it be a state or local, e.g., county, responsibility?) or the procedures by which a defendant will be deemed indigent. States and counties have developed a range of programs designed to provide counsel to indigent defendants (the most well known is the public defender model; other examples are the appointment from a roster of practicing attorneys and contracts with willing practitioners). States and counties have also developed a range of procedures to assess whether a defendant is unable to afford an attorney without assistance.4 A 2002 report by the Spangenberg Group documents the variability across states with regard to various aspects of indigency determinations, including how presumptions of indigency are determined (i.e., what factors are taken into consideration, such as the defendant’s income in relation to federal poverty guidelines, assets, complexity of the case, resources of relatives and friends, whether the defendant can afford to pay bail, etc.), whether or not formal guidelines are in place, who makes the determination (the public defender’s office or the court), whether the court utilizes a financial questionnaire or affidavit, whether the client’s claim is investigated, and so on.5 The specific purpose of this article is to report on an evaluEvaluating Court Processes for Determining Indigency | v2 |
2020-11-05T09:10:20.987Z | 2020-11-05T00:00:00.000Z | 228822530 | s2ag/train | Ibrutinib Induces Durable Remissions in Treatment-Naïve CLL Patients with 17p Deletion/TP53 Mutations: Five Year Follow-up from a Phase 2 Study
Introduction: Bruton's tyrosine kinase (BTK) inhibitors and the BCL-2 antagonist venetoclax have significantly improved the outcome of CLL patients, including patients with high risk CLL who had dismal outcome with chemo-immunotherapies. Nonetheless, CLL patients with 17p deletion and/or TP53 mutations may continue to have an increased risk for treatment failure with BTK inhibitors or venetoclax when compared to CLL patients with lower-risk disease. For example, the median progression free survival (PFS) of ibrutinib-treated relapsed and refractory CLL patients in the PCYC-1102 study was 52 months for the entire population, but only 26 months for those with 17p deletion. In a phase-2 study of ibrutinib in CLL patients with 17p deletion/TP53 mutations (NCT01500733) it was noted that the 5-year PFS was 19% for relapsed and refractory patients, but 74% in treatment-naïve CLL patients, indicating that remission duration is substantially longer in patients with 17p deletion/TP53 mutation when ibrutinib is used in the frontline disease setting. Here, we reviewed the long-term outcome of treatment -naïve CLL patients with 17p deletion and/or TP53 mutation receiving ibrutinib, alone or in combination with rituximab on an investigator-initiated Phase-2 trial (NCT02007044).
Patients: 27 treatment-naïve CLL patients with 17p deletion and/or TP53 mutation received ibrutinib, alone (n=15) or in combination with rituximab (n=12). Responses were evaluated according to the 2008 iwCLL criteria, with the exception that lymphocytosis was not the sole criterion for disease progression. PFS was defined as the time from start of treatment to progression, death or last follow-up.
Results: The median age was 62 years, 67% were male, 78% had unmutated IGHV, and 33% advanced stage disease (Rai stage III-IV). After a median follow-up of 61 months, median progression free and overall survival were not reached, and the estimated 5-year progression free and overall survival were 66% and 85%, respectively (Figure). This is markedly better than the published 5-year PFS of 15.3% in 17p deleted CLL patients after fludarabine, cyclophosphamide and rituximab (FCR). Most common reason for treatment discontinuation was disease progression, which occurred in 6 patients (22%), with a median time to progression of 39 months (range, 10 - 53 months). Objective responses were noted in all except one patient (overall response rate 96%), with complete remissions in 10 patients (37%), and partial remissions in 16 patients (59%). Median levels of CLL bone marrow infiltration declined from 76% at baseline, to 26% after 12 months, and 14% after 24 months of therapy. Remission duration was not different in patients achieving complete or partial remissions, suggesting that deep remissions are not a prerequisite for durable remissions. Venetoclax-based therapy, which generally induces deeper remissions, does not seem to induce more durable remissions (2-year PFS 74% with venetoclax plus obinutuzumab in treatment-naïve CLL with 17p deletion and/or TP53 mutation), although cross-trial comparisons are problematic, especially given that venetoclax was administered as a fixed-duration regimen. Future research will determine if combination therapy results in a further survival improvement.
Conclusions: Our data demonstrate that frontline therapy with ibrutinib results in long-term remissions in high-risk CLL patients with 17p deletion and/or TP53 mutations, despite the lack of deep remissions, with an estimated 5-year PFS of 66%.
Jain: Aprea Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding. Kadia:Ascentage: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Cyclacel: Research Funding; Incyte: Research Funding; Cellenkos: Research Funding; Astellas: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Andreeff:Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding. Thompson:AbbVie: Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria. Kantarjian:Janssen: Honoraria; Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Ascentage: Research Funding; BioAscend: Honoraria; Delta Fly: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. O'Brien:Eisai: Consultancy; Amgen: Consultancy; Regeneron: Research Funding; KITE: Research Funding; GlaxoSmithKline: Consultancy; Vida Ventures: Consultancy; Janssen Oncology: Consultancy; Vaniam Group LL: Consultancy; Gilead: Consultancy; Sunesis: Research Funding; Pfizer: Research Funding; Alexion: Consultancy; Acerta: Research Funding; Pharmacyclics: Research Funding; Verastem: Consultancy; AbbVie: Consultancy; Aptose Biosciences: Consultancy; Celgene: Consultancy; TG Therapeutics: Research Funding; Juno Therapeutics: Consultancy; Astellas: Consultancy. Burger:Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau.
| v2 |
2019-03-18T14:06:38.717Z | 2018-11-21T00:00:00.000Z | 81732120 | s2ag/train | Long-Term Carfilzomib for High-Risk Patients with Newly Diagnosed Multiple Myeloma: A Pooled Analysis of Two Phase 1/2 Studies
INTRODUCTION: High-risk cytogenetic abnormalities, such as del(17p), t(4;14), and/or t(14;16), are associated to an unfavorable prognosis. Several trials investigating current approved regimens have shown that high-risk multiple myeloma (MM) patients have shorter progression-free survival (PFS) and overall survival (OS) as compared to standard-risk patients. Carfilzomib, a second generation proteasome inhibitor, demonstrated to be able to improve the survival of high-risk MM patients in the relapse setting. Here we present a pooled analysis of two phase 1/2 studies to investigate the role of carfilzomib in high-risk, newly diagnosed (ND) MM patients.
METHODS: Transplant ineligible patients with NDMM enrolled in the IST-CAR 561 and IST-CAR 506 studies were pooled together and analyzed. All patients received 9 28-day induction cycles of carfilzomib, either 70 mg/m2 once weekly (IST-CAR 561) or 36 mg/m2 twice weekly (IST-CAR 506), combined with weekly cyclophosphamide (300 mg/m2) and dexamethasone (40 mg) (CCyd). After the induction phase, patients proceeded to maintenance with single-agent carfilzomib until progressive disease or intolerable toxicity. The primary objective was to compare response to treatment, PFS, PFS-2 and OS in standard versus high-risk FISH, defined by the presence of del(17p), t(4;14), and/or t(14;16). A 15% cut-off point was used for detection of translocation [t(4;14) and t(14;16)] and 10% for detection of del(17p).
RESULTS: 121 NDMM patients were enrolled in the IST-CAR 561 (n=63) and in the IST-CAR 506 (n=58) study. Cytogenetic data were available in 94 patients: 37 (31%) had high-risk chromosomal abnormalities by FISH, including 10% of patients with t(4;14), 3% with t(14;16) and 18% with del(17p), while 57 patients (47%) were classified as standard-risk.
After the induction phase, no difference in terms of overall response rate (ORR; 86% vs. 92%; p=0.52) and at least near complete response (39% vs. 41%; p=1) was observed between standard and high-risk patients.
After a median follow-up of 39 months, median PFS from enrollment was NR in standard-risk patients and 27.8 months in high-risk ones (HR: 0.76; p=0.38) (Figure 1); at 3 years, 52% and 43% of patients, respectively, were alive and free from progression. The PFS benefit for the comparison between standard and high-risk patients was more pronounced in patients who received once weekly carfilzomib at 70 mg/m2, (median: NR vs. 39.6 months; HR: 0.78, p=0.63) as compared to those treated with twice weekly carfilzomib at 36 mg/m2 (median: NR vs. 24.2 months; HR: 0.52, p=0.12).
Median PFS-2 from enrollment was NR in standard-risk patients and 44.1 months in high-risk ones (HR: 0.66; p=0.26), without significant differences in the once weekly (median, NR vs. 39.6; p=0.27) and the twice weekly group (median; NR vs. 44.1; p=0.63).
Median OS from enrollment was NR in standard-risk patients and 47.5 months in high-risk ones (HR:0.71; p=0.36) (Figure 1). In patients who received once weekly carfilzomib, median OS was NR and 47.5 months (HR:0.66, p=0.48) in standard and high-risk patients, respectively, while median OS in the twice weekly group was NR in standard-risk patients and 44.1 months (HR:0.73; p=0.55) in high-risk ones.
CONCLUSION: In transplant ineligible patients with NDMM, carfilzomib combined with cyclophosphamide and dexamethasone as initial treatment mitigated the poor prognosis of high-risk FISH in terms of PFS, PFS-2 and OS. The median PFS of high-risk patients treated with CCyd compares favorably with those reported with current standard of care. As compared to twice weekly carfilzomib at 36 mg/m2, once weekly carfilzomib, at the dose of 70 mg/m2, confirmed to be effective in high-risk patients. These data support the use of carfilzomib for the treatment of high-risk NDMM patients.
Figure 1. Figure 1.
Larocca: Janssen-Cilag: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Petrucci:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Gaidano:AbbVie: Other: Advisory Board; Janssen: Other: Advisory Board, Speakers Bureau. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Offidani:Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Caravita di Toritto:Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Amgen: Other: Advisory Board; Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding; Takeda: Other: Advisory Board. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Palumbo:Takeda: Employment. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.
| v2 |
2019-04-29T13:17:45.844Z | 2012-01-01T00:00:00.000Z | 136078540 | s2ag/train | Study the Effect of Ambient Oxygen Pressure on Structural and Optical Properties of Pure SnO2Thin films Prepared by Pulsed Laser Deposition
Polycrystalline pure SnO2 thin films were deposited on glass substrates at fixed substrate temperature (400C°) by (Nd-YAG )pulsed laser deposition (PLD) with pulse energy(5000 mJ), pulse width(10ns) at a different ambient oxygen pressure (10 -1 ,10 -2 ,10 -3 ) torr. The effect of ambient oxygen pressure on the structural and optical properties of SnO2 thin films was studied. (XRD) X-ray diffraction and AFM (atomic force microscopy) methods were used to examine the structure and morphology of the films in this work. From (XRD) X-ray diffraction of the SnO2 films, it was found that the deposited films showed some differences compared with the oxygen pressure and the intensities of the peaks of the crystalline phases decreased with the increase of oxygen. From AFM images, the distinct variations in the morphology of the thin films were also observed, from the transmittance of SnO2 it was found that the optical transmission of SnO2 films at high oxygen pressure is low than for low ambient oxygen pressure. :ةصلاخلا طادها ساشدس ةدعسد ذدٍا ةديعاعص تايدظسا ًدما ىبيدهشج هدج يدقٍلا شرذدصقلا ذيسكوا يٌاث تاسىمبلا دذعحو قيقشلا ءاشغلا 022 ةرضميه يعبٍلا كار نىيىرذٍلا سضيمب بيهشحلا ةطهاىب ةقاطب 0222 سضديملا ةعبٌ ضشاو, لىع يمو 12 ةديٌاث ىٌادٌ ذدٍا ًي دسكولال ةد محخو غىطغدظ 10 -2 ,10 -3 , 10 -1 ةديبيكشحلا اىدخلا ًدما ًي دسكوىا ػغدظ شيثادج ةدهاسد ثدىج .قدبئص.همو) ةيدششى ةرشدصبلاو ةعد وا دىديس لاىعحده ب ةيدششوا ةدي اششىبىغو بديكشج ادو هدج كدىعلا ازدم يد شرذدصقلا ذيدسكوا يٌادث ةيٍيدسلا (XRD) ةدرسزلا يىدقلا شده وو (AFM) ي ذدعو شرذدصقلا ذيدسكوا يٌادث ةيدششى ةيٍيدسلا ةعد ىا دىديس غادىٌا ًدو . تا لاحخوا طعب تشهظ ةبهشىلا ةيششوا ًي سكوىا ػغظ شيغحب تاذ و . ًي دسكوىا دادرضب كدقج ةرسىمبلا ساىغلأل هىقلا شرذدصقلا ذيدسكوا يٌادث ةدررا ٌ ًدو . ةدقيقشلا ةيدششوا ةدي اششىبىغ يد ضيىحو تا لاحخ اٍظسى ةرسزلا يىقلا شه و سىص ًو ا ػغدظ ةدلاس يد ادىو كدقا يلادعلا ًي دسكوىا ػغدظ ذدٍا شرذدصقلا ذيدسكوا يٌاث ءاشغل ةرشصبلا ةررا ٍلا ىٌا اٌذعو ًي دسكوى .ةميمقلا 1-Introduction: Pulsed laser deposition (PLD) is a thin film deposition method which uses short and intensive laser pulses to evaporate target material. The ablated particles escape from the target and condense on the substrate. The deposition process occurs in a vacuum chamber to minimize the scattering of the particles[1,4]. Earlier a seemingly esoteric technique of Pulsed Laser Deposition (PLD) has emerged as a potential methodology for growing nanostructures of various materials including semiconductors[1]. Since it is a cold-wall processing, which excites only the beam focused areas on the target enabling a clean ambient, it is highly suited for the growth of nanostructures with high chemical purity and controlled Stoichiometry. The other characteristics of PLD such as its ability to create high-energy source particles, permitting high quality film growth at low substrate temperatures [2], simple and inexpensive experimental setup, possible operation in high ambient gas pressure, and sequential multi-target and multiof kerbala university , vol. 10 no.3 scientific . 2012 Journal 011 component materials' congruent evaporation make it particularly suited for the growth of oxide thin films and nanostructures. Tin oxide ( 2 SnO ) is an n-type semiconductor with band gap of eV Eg 00 . 4 62 . 3 at room temperature [3]. The ( 2 SnO ) research for its applications has been mainly focused on this films. Up to date, ( 2 SnO ) thin films have been achieved by a variety of deposition techniques such as chemical vapor deposition (CVD) [5,6], sol-gel processing [7,8],reactive sputtering [9] and pulsed laser deposition (PLD) [10,11]. Among these fabrication techniques, PLD has attached much attention. It is well known that ambient oxygen pressure is one of the key experimental parameters in the process of PLD. In this paper,( 2 SnO ) thin films were prepared by PLD and the influence of ambient oxygen pressure (10 -1 ,10 -2 ,10 -3 ) torr on structural and optical properties of 2 SnO thin films were reported. 2-Experimental procedures: SnO2 thin films were prepared by pulsed laser deposition system with a titanium target of 99.99% purity on microscope glass slides as substrates. The target was pressed less than 5 ton to form a target with 2.5 cm diameter and 0.4 cm thickness. Microscope glass slides were used as the substrates for thin films. Prior to deposition, the glass slides were sequentially cleaned in an ultrasonic bath with ethanol. Finally they were rinsed with distilled water and dried. The substrate is placed in front of the target with its surface parallel to that of the target the substrate deposited at temperature 400 o C with Oxygen pressure (10 -1 ,10 -2 ,10 -3 ) torr. The pulsed laser deposition is carried out inside a vacuum chamber generally at three different oxygen pressures. Nd-YAG laser (Huafei Tangda Technelogy-Diamond-288 pattern EPLS) second harmonic generation with laser wavelength (1064/532)nm, pulse energy (100-1000)mJ, pulse width (10ns). The focused Nd-YAG SHG Q-switching laser beam coming through a window is incident on the target surface making an angle of 45° with it, given in Fig (1) below. 1. Nd:YAG Laser Head. 6. Flexible tube KF16 2. O2 cylinder gas 7. Quartz Chamber. 3. Stainless steel Flange. 8. Substrate holder 4. N2 cylinder gas. 9. Vacuum system 5. Nd:YAG laser Power supply 10.Variac devices Figure (1): Pulsed laser deposition (PLD) system 1 | v2 |
2020-11-05T09:10:22.449Z | 2020-11-05T00:00:00.000Z | 228922990 | s2ag/train | Phase I Trial of MB-CART2019.1, a Novel CD20 and CD19 Targeting Tandem Chimeric Antigen Receptor, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
Background
CD19 redirected chimeric antigen receptor (CAR) T-cell therapy has proven efficacy in relapsed or chemotherapy-refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, targeting a single B-cell antigen leads to selective pressure with potential antigen-escape and subsequent relapse. A tandem CAR targeting CD20 and CD19 (pLTG1497) has been developed to overcome this limitation. Preclinical evaluation showed improved anti-lymphoma activity. Thus, we initiated a first-in-human, phase I clinical study of autologous pLTG1497-transduced CAR T-cells (MB-CART2019.1) in r/r B-NHL patients.
Aims
In this phase I prospective multi-center trial (NCT03870945) we aimed to evaluate the maximum tolerated dose (MTD) of MB-CART2019.1 in adult patients with CD20 and CD19 positive r/r B-NHL as determined by dose limiting toxicities (DLTs).
Methods
This was a 6+3 trial design with two predefined dose levels (DL1 1x106 and DL2 2.5x106 CAR T-cells/kg body weight, respectively). Secondary endpoints included adverse events (AEs) and best overall response rate (ORR). Pharmacodynamic assessments included maximum concentration (Cmax) of CAR T-cells, time to peak expansion (tmax), AUC (d0 to d28), and persistence. MB-CART2019.1 was produced by lentiviral transduction of autologous fresh leukapheresis in the closed automated CliniMACS Prodigy® System (Miltenyi Biotec, Bergisch Gladbach, Germany). Re-infusion (Day 0) of fresh MB-CART2019.1 was scheduled 14 days after leukapheresis. Fludarabine/cyclophosphamide lymphodepleting chemotherapy was administered from day -5 to -3.
Results
A total of 12 patients, 6 per dose level have been enrolled and treated between February and December 2019, 5 female and 7 male patients. Median age was 72 y (range 20, 78 y), with 10 patients >65 y and 8 >70 y. Histologies included aggressive B-NHL (11) and mantle cell lymphoma (1). Five (5) patients had refractory disease at study entry and IPI was ≥3 in 7 patients. Median time from leukapheresis to re-infusion was 14 d (range 13, 14 d). No DLT and no cytokine release syndrome (CRS) or neurotoxicity grade ≥3 were observed. One patient in dose level 1 experienced a grade 5 AE, which was due to disease progression. CRS grade 1 occurred in 3/6 patients on DL1 and DL2 each, and CRS grade 2 in 2 patients on DL2. Tocilizumab was given in 1 patient. Neurotoxicity grade 1 occurred in 1 patient on DL2. The above described CRS and neurotoxicity resolved completely. Mean Cmax of MB-CART2019.1 was 348.3 cells/µl (range 3.9, 830.4 cells/µl) on DL1 and 692 cells/µl (range 5.3, 3147.8 cells/µl) on DL2. Mean tmax was 15.8 d (range 9, 21 d) on DL1 and 11.5 d (range 9, 14 d) on DL2. Mean AUC was 3155 d*cells/µl (DL1) and 4339 d*cells/µl (DL2). Persistence of MB-CART2019.1 was observed in 12/12 patients until data cut-off. Altogether 9/12 patients (ORR 75%) responded to MB-CART2019.1 with 5/12 CRs. In DL1 3/6 patients responded (ORR 50%) and in DL2 6/6 patients (ORR 100%). The 3 patients without response to MB-CART2019.1 had a mean AUC0-28 of 870 d*cells/µl, whereas mean AUC0-28 in 9 responders was 4843 d*cells/µl reflecting the correlation between the pharmacodynamic parameters and the clinical response. Responses are ongoing in 5/9 patients, with a maximum duration of response of 330 days at data cut-off.
Summary/Conclusions
In this first-in-human dose finding study of MB-CART2019.1 no DLT and no severe (grade ≥3) CRS or neurotoxicity were observed. Feasibility and safety were very good in this cohort of elderly r/r B-NHL patients. The sustained expansion of tandem CAR T-cells was accompanied by efficacy: all patients (6/6) treated on DL2 responded and all 5 patients with CR (5/5) are in ongoing remission by the time of this report. Based on the promising risk-to-benefit ratio observed in our study, evaluation of MB-CART2019.1 at a dose of 2.5x106/kg body weight in clinical phase II and phase III trials for patients with relapsed aggressive B-NHL is underway.
Borchmann: Miltenyi Biotec B.V. & Co. KG: Honoraria. Balke-Want:Miltenyi Biotec B.V. & Co. KG: Honoraria. Ayuk:Celgene: Consultancy, Honoraria; Kite/Gilead: Honoraria; Therakos/Mallinckrodt: Honoraria, Research Funding; Neovii: Research Funding; Novartis: Honoraria. Holtkamp:Miltenyi Biomedicine GmbH: Current Employment. Preussner:Miltenyi Biomedicine GmbH: Ended employment in the past 24 months. Zadoyan:Miltenyi Biomedicine GmbH: Current Employment. Hanssens:Miltenyi Biomedicine GmbH: Current Employment. Kaiser:Miltenyi Biotec B.V. & Co. KG: Current Employment. Jurk:Miltenyi Biotec B.V. & Co. KG: Current Employment. Bürger:Miltenyi Biotec B.V. & Co. KG: Current Employment. Schneider:Lentigen Technology Inc., A Miltenyi Company: Current Employment, Patents & Royalties. Dropulic:Lentigen Technology Inc., A Miltenyi Company: Current Employment. Overstijns:Miltenyi Biomedicine GmbH: Current Employment, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec B.V. & Co. KG: Current Employment, Membership on an entity's Board of Directors or advisory committees. Scheid:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding. Holtick:Miltenyi Biotec B.V. & Co. KG: Honoraria. Miltenyi:Miltenyi Biomedicine GmbH: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lentigen Technology Inc., A Miltenyi Company: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Miltenyi Biotec B.V. & Co. KG: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
| v2 |
2020-12-14T20:14:16.395Z | 2020-11-05T00:00:00.000Z | 228880260 | s2ag/train | Practice Patterns and Real-Life Outcomes for Patients with Acute Promyelocytic Leukemia
Background: Despite a potential for cure, a large proportion of patients with acute promyelocytic leukemia (APL) succumb early to hemorrhagic and thrombotic complications. Prompt initiation of all-trans retinoic acid (ATRA) has been associated with improved outcomes. However, little is known about the patterns of care and clinical outcomes of patients with APL in the United States (US) outside of the controlled trial setting.
Method s : We identified APL patients (pts) included in the Vizient Clinical Database/Resource Manager (CDB/RM™), which includes patient demographics, hospital characteristics, charge-level medication usage, procedures and mortality data from over 100 academic health centers and affiliated hospitals. Initial inpatient encounters of adult APL pts (≥18 years) during 2014-2015 (most recent years available) were identified by ICD-10 code (C92.40; C92.42) or ICD-9 codes for acute myeloid leukemia (AML; 250.00, 205.02) plus receipt of ATRA for ≥3 days as monotherapy, or in combination with arsenic trioxide (ATO) or an anthracycline. The 3-day minimum ATRA requirement is intended to exclude AML patients who may have therapy initiated while awaiting diagnostic confirmation. Pts were excluded if information on discharge disposition or medication administration were missing or if patients had an ICD-9/10 code consistent with relapsed AML/APL. Primary outcome was a composite of in-hospital death or discharge to hospice. Pearson's Chi-square test was used to compare categorical variables in bivariate analysis. Multivariable logistic regression was used to examine associations between patient, hospital, and treatment characteristics with the primary outcome. We lacked information on laboratory test results needed to assess the impact of treatment on clinical outcomes.
Results: We identified 486 pts treated at 76 hospitals. Patient demographic, treatment and hospital characteristics are shown in Table 1. Median length of stay was 30 days (interquartile range [IQR]: 22-36 days). Pts received a median of 26 days of ATRA (IQR: 12-34 days). The majority of pts was treated with ATRA + ATO (240 pts; 49.4%) or ATRA + anthracycline (146 pts; 30.0%), which are the standard of care for lower- and higher-risk APL, respectively. Forty-two pts (9.3%) received ATRA monotherapy and 58 (11.9%) were treated with ATRA + ATO + anthracycline. Forty-eight pts (9.9%) required endotracheal intubation.
Overall, 54 (11.1%) pts experienced our composite adverse outcome of in-hospital death or transfer to hospice (45 pts [9.3%] died in the hospital; 9 pts [1.9%] were discharged to hospice). Among 45 pts who died in the hospital, median time to death was 17 days (IQR: 5-24 days) with 31.1% of deaths occurring during the first 7 days of hospitalization. Half of the pts (n=18; 50%) who died in the ATRA monotherapy group died within 5 days of admission. In bivariate analyses, age ≥66 years (22.9% vs. 7.9%; p<0.001), endotracheal intubation (64.6% vs. 5.3%; p<0.001), and ATRA monotherapy (42.9% vs. 8.1%; p<0.001) were associated with an increased risk of poor outcome (i.e. inpatient death or discharge to hospice). Similar results were obtained from the multivariable logistic regression model (Table 2).
Discussion: A substantial proportion (11%) of adults treated for APL in this large inpatient dataset died or were discharged to hospice. This likely underestimates the full mortality rate of APL, because our APL case definition excluded pts who received <3 days of ATRA therapy, which may have been due to early mortality. Age≥66 years, receipt of ATRA monotherapy or ATRA + anthracycline was associated with higher odds of adverse outcomes. The higher mortality with ATRA + anthracycline compared to ATRA + ATO is likely due to an inherently higher disease risk, but the database lacked laboratory results (e.g. white blood cell count) needed to confirm that hypothesis. Early complications related to coagulopathy or differentiation syndrome that precluded co-administration of ATO or anthracycline could be a potential explanation for the high early mortality rate in pts receiving ATRA monotherapy.
Wang: Celgene/BMS: Research Funding. Podoltsev:Kartos Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Incyte: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Boehringer Ingelheim: Research Funding; CTI biopharma: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squib: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Arog Pharmaceuticals: Research Funding; Blueprint Medicines: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding. Huntington:Genentech: Consultancy; DTRM: Research Funding; Astrazeneca: Honoraria; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy; Pharmacyclics: Honoraria; TG Therapeutics: Research Funding. Neparidze:Janssen: Research Funding; GlaxoSmithKline: Research Funding; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member ; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Ma:BMS: Consultancy; Celgene/BMS: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Zeidan:Acceleron: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; CCITLA: Other; Leukemia and Lymphoma Society: Other; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Taiho: Consultancy, Honoraria; Aprea: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Davidoff:Celgene: Research Funding; Amgen: Consultancy; AbbVie: Consultancy.
| v2 |
2020-12-14T20:14:23.220Z | 2020-11-05T00:00:00.000Z | 228835000 | s2ag/train | Inhibition of EZH1 and EZH2 Restores Chemosensitivity of Leukemia Stem Cells in Acute Myeloid Leukemia By Recruitment of Quiescent AML Stem/Progenitor Cells
Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2), is a highly conserved histone methyltransferase that targets lysine-27 of histone H3. EZH2 is one of the key determinants of cellular sensitivity to DNA damage, and therefore an abnormal accumulation of EZH2 represses tumor suppressors, including genes related to cell cycle inhibition, apoptosis, senescence, and differentiation. Similar to EZH2, EZH1 is part of the PRC2 complex and shares target genes.
Acute myeloid leukemia (AML) is a heterogeneous disease associated with high mortality, dependent on molecular subtype and therapy. Bcl-2 family proteins have been established as key mediators of apoptosis in AML with venetoclax, a small molecule BH3 mimetic, selectively inhibiting Bcl-2. Combinatorial therapy of venetoclax and hypomethylating agents (Ven/HMA) has revolutionized the treatment of elderly patients with AML, yielding response rates over 70%, but overall survival remains short. Since PRC2 is required for AML cell survival (Basheer et al., 2019; Neff et al., 2012), targeting both EZH1 and EZH2 (EZH1/2) concomitantly could be efficient in disrupting oncogenic signals. A recent study using a murine AML model demonstrated that genetic deletion of EZH1/2 depleted quiescent leukemic stem cell (LSC) and prolonged survival of leukemia bearing mice (Fujita at al., 2018). AML LSC are located in BM niches and are mainly non-cycling. Thus, overcoming LSC dormancy as well as LSC mobilization from the BM may be critical steps that improve long-term survival of patients with AML. Here, we hypothesized that EZH1/2 is required to regulate LSC dormancy and increase efficacy of Ven/HMA therapy in AML. To test this hypothesis, we utilized pharmacological inhibition of EZH1/2 by a potent and selective EZH1/2 dual inhibitor, DS-3201 (valemetostat; Daiichi Sankyo, Inc.). Granulocyte colony-stimulating factor (G-SCF) has been shown to not only recruit leukemia cells into cell cycle (Andreeff et al, 1990), but also disrupt AML-stromal interactions for stem cell mobilization. Clinically, G-CSF is a critical component of the FLAG-Ida protocol (Petti et al, 1997). Therefore, we hypothesized that G-CSF will also recruit quiescent LSC into cycle, and the alternative mechanism may act synergistically with EZH1/2 inhibition.
To assess if inhibition of EZH1/2 results in recruitment of LSC into the cell cycle and subsequently improves efficacy of Ven/HMA in AML in vitro, we first confirmed the nuclear expression of EZH1/2 in human AML cell lines. All cell lines expressed EZH1/2, although at different levels. These cell lines with various genetic backgrounds were treated with DS-3201 or G-CSF 24 hours prior to their exposure of Ven/HMA. A dual inhibitor of EZH1/2, or G-CSF, in combination with Ven/HMA significantly amplified AML cell death compared to Ven/HMA alone treated counterparts. In a clinical phase 1 trial of DS-3201 in AML, EZH1/2 inhibition promoted cell cycle progression. The proliferative fraction of leukemic cells was assessed by measuring Ki67/DNA in sequential samples obtained from DS-3201 treated patients. Baseline Ki67 positivity of LSC was 11.20%, and the maximized average increased to 59.3% and to over 90% in one patient (Fig 1), validating the concept that EZH1/2 inhibition can indeed recruit leukemia stem cells effectively into cell cycle. Further, a primary sample from a R/R AML patient (resistant to DNR/Ara-C 7+3, Ven/HMA, and Ipilimumab/nivolumab) was ex vivo primed for 5 days with combination of DS-3201 and G-CSF, then exposed to AraC/DNR based treatment. Concomitant treatment of G-CSF and EZH1/2 inhibition increased LSC proliferation and subsequently enhanced AraC/DNR induced apoptosis. Conclusion: we here demonstrate that pharmacological inhibition of EZH1/2 in a clinical trial with DS-3201 resulted in massive recruitment of quiescent AML LSC into the cell cycle. In vitro, EZH1/2 inhibition and G-CSF both enhanced Ven/HMA-induced leukemia cell apoptosis. Experiments are ongoing to test the hypothesis that EZH1/2 inhibition combined with G-CSF receptor activation may sensitize resistant primary AML LSC to apoptosis induction by chemotherapy and/or Bcl-2 inhibition. If successful, this concept could further enhance the activity of FLAG-Ida chemotherapy, which was developed a generation ago along the same concept, and of BH-3 mimetic, apoptosis targeting therapies.
Dos Santos: Daiichi Sankyo, Inc.: Current Employment. Slosberg:Daiichi Sankyo, Inc.: Current Employment. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.
| v2 |
2019-11-22T00:44:54.234Z | 2019-11-13T00:00:00.000Z | 209246920 | s2ag/train | Genetic and Genomic Characterisation of Older Adults with Acute Lymphoblastic Leukemia Treated on the UKALL14 and UKALL60+ Clinical Trials
Acute lymphoblastic leukemia (ALL) is characterised by recurrent chromosomal abnormalities and genomic microdeletions. Although the incidence of adult ALL increases with age, very few studies have specifically examined the genetic aberrations in adults aged ≥60 years.
The objectives of the study were to define the frequency of recurrent chromosomal abnormalities and characterise the copy number profile of ALL in older adults.
All patients from UKALL14 and UKALL60+ clinical trials aged ≥60 years at diagnosis of ALL were considered in the study. Cytogenetic and fluorescence in situ hybridisation (FISH) results at diagnosis were used to classify patients in 1 of 5 genetic subgroups - BCR-ABL1, TCF3-PBX1, MLL/KMT2A rearranged (KMT2Ar), low hypodiploidy/near triploidy (HoTr) and high hyperdiploidy (HeH). T-ALL patients were considered separately. B-cell precursor (BCP) ALL patients lacking a primary chromosomal abnormality (B-other ALL - including normal, failed and complex karyotypes, and other non-recurrent chromosomal abnormalities), were selected for extended FISH screening to identify ABL-class fusions, JAK-STAT activating rearrangements and other primary translocations using dual colour break apart probes for ABL1, ABL2, PDGFRB/CSF1R, CRLF2, JAK2, IGH@, ZNF384 and MEF2D.
Separately, single nucleotide polymorphism (SNP) arrays were performed to identify copy number abnormalities (CNAs). Multiplex ligation-dependent probe amplification (MLPA) was used to confirm CNAs in 9 specific genes/regions (EBF1, IKZF1, CDKN2A/B, JAK2, PAX5, ETV6, BTG1, RB1, and PAR1).
207 patients aged ≥60 years at diagnosis were identified from UKALL14 (n=91) and UKALL60+ (n=116). Median age was 64 years (range 60-83) and 50% were male. Cytogenetic data at diagnosis were available for 86% (n=178) of patients. Frequencies of individual genetic subgroups are shown in figure (A). Extended FISH screening of B-other ALL cases identified rearrangements in CRLF2 in 5% (8/146), ZNF384 in 2% (3/137) and MEF2D in <1% (1/136) of the cohort. IGH@ translocations were found in 9% (13/148, including 6 IGH-CRLF2). No variant ABL1 (0/168), ABL2 (0/148), PDGFRB/CSF1R (0/151) or JAK2 (0/149) rearrangements were detected.
SNP arrays were performed on 83 patient samples using Illumina CytoSNP 850k (n=52) or Affymetrix Cytoscan HD (n=31) arrays. Recurrent whole chromosome and whole arm abnormalities seen in >3 cases are shown in figure (B) (HeH and HoTr cases (n=10) excluded). Recurrent deletions were identified affecting IKZF1 in 52% (n=43), CDKN2A/B in 45% (n=37), PAX5 in 39% (n=32), RB1 in 22% (n=18), ETV6 in 21% (n=17), EBF1 in 19% (n=16), BTG1 in 12% (n=10), CD200/BTLA in 16% (n=13) and ATP10A in 13% (n=11). The frequency of individual deletions varied by genetic subtypes (Figure (C)). Recurrent novel and less-well described intragenic microdeletions were also seen in COL11A1 (n=11, 13%), MEF2C (n=8, 10%), MBNL1 (n=7, 8%), PTEN (n=6, 7%), NF1 (n=4, 5%), LEMD3 (n=5, 6%), and KDM6A (n=4, 5%). These deletions will need to be validated by a second technique.
In this large cohort of older adults with ALL, we confirm that over a quarter of patients harbour BCR-ABL1. HoTr ALL is rare in younger patients but was the second most common specific chromosomal abnormality and good risk genetic subgroups were very uncommon. Additionally, we confirm the rarity of T-cell ALL in older adults (<5% of all cases). Within B-other ALL, CRLF2 rearrangements were the most common kinase activating abnormality, present in 5% of all patients, with IGH@ the translocation partner in 6/8 cases. ABL-class fusions were completely absent in this cohort of older patients, differing from published studies (Roberts et. al. JCO 2017). IKZF1 and CDKN2A/B deletions were seen in 52% and 45% of patients respectively. Importantly, these are frequently included in high risk copy number profiles such as IKZF1 plus (Stanulla et. al. JCO 2018), albeit not validated in older patients. A number of novel intragenic microdeletions, including tumour suppressor genes unreported in BCP-ALL, were identified and will require validation in a larger cohort. Collectively, these data further confirm the high risk of ALL in older adults. These patients appear genetically distinct to younger adults and the primary genetic abnormality remains unidentified in significant numbers, underlying the need for further genomic studies to elucidate the mutational landscape of ALL in older adults.
Menne: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. McMillan:Sandoz: Honoraria; Gilead: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; BMS: Honoraria; Pfizer: Honoraria, Research Funding; MSD: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Snowden:Kiadis: Membership on an entity's Board of Directors or advisory committees; Mallinckrodt: Honoraria; Janssen: Honoraria; IDMC: Honoraria; Jazz: Honoraria; Gilead: Honoraria. Papaemmanuil:Celgene: Research Funding. Rowntree:Novartis: Consultancy. Fielding:Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.
| v2 |
2018-04-03T03:50:45.156Z | 1971-04-01T00:00:00.000Z | 36721840 | s2ag/train | Experimental studies of essential hemospermia with special reference to the fibrinolytic activity.
The fibrinolytic activity of the allergic seminal vesiculitis of rabbits induced by the complete adjuvant method using egg albumin was studied by the topographical and the fibrin plate method. A remarkable increase of plasminogen activator was observed in the mucous layer having the allergic reactions. A similar result was also obtained by the estimation of the tissue activator activity. Consequently, the plasminogen activator of the seminal vesicle secretion significantly increased. In addition, the determination of the streptokinase-activated fibrinolytic activity revealed a remarkable increase of proactivator in both the vesicle tissue and secretion. There was no increase of fibrinolytic activity in the blood. The inhibitory effect of trans-AMCHA upon these enhanced fibrinolytic activities was sufficiently obtained following the local infusion into the seminal vesicle. From the standpoint of the plasmin system, the relationship between essential hemospermia and allergic seminal vesiculitis as well as the hemostatic efficacy of the plasmin inhibitor were discussed. Introduction Hemospermia has been defined as a syndrome in which the blood component is found in the seminal fluid. Twenty-four cases with hemospermia were statistically collected in our department, which occupied about 0.3 % of the male outpatients during the years from 1955 to 1964" With the knowledge about male sterility gradually increasing, there has been an increase of semen examinations in the urological department. Consequently, the discovery of hemospermia is gradually increasing. Because of this syndrome, fear of sterility causes psycological anxiety, especially effecting the young. This, therefore, is one of the very important reasons for a urologist to make a study on its etiology. Since the etiology of hemospermia was first reported by Rapine) in 1859, several studies have been made. Organic hemospermia has been classified as one having clear clinical features, whereas essential hemospermia one clinical features of which are not clearly known. The latter is more prominent than the former. A few researchers have made clinical and experimental study of essential hemospermia. According to their studies, it was considered that the allergic reaction in the seminal vesicles is related with essential hemospermia. These concepts have been generally accepted. Along with an advance in 254 Kozaka : Hemospermia • Fibrinolytic Activity study of the fibrinolytic enzyme system, fibrinolysis has been confirmed as a very important subject in relation to urological diseases, especially concerning those of the kidney and prostate. In the author's department, the studies of the fibrinolytic* enzyme in the prostatic tumors have been made by Kuroda, Hisazumi and Korai') (1960). They have performed in remarkable detail the study of the tissue activator of plasminogen in the prostatic tumors. According to the studies by Kuroda et al.4-8), Hisazumi and Iwasa7) (1965) and Hisazumi (1968)8), it is known that local fibrinolysis plays a very important role in postoperative bleeding into the prostatic cavity formed after prostatectomy, in comparison with general fibrinolysis. In addition, they have emphasized that local fibrinolysis often results in the bleeding of the genitourinary organs and others. Furthermore, Hisazumi and Fukushima8) (1965), and Hisazumii°) (1969) stated that, in the cases of hemospermia, the fibrinolytic activity of the seminal fluid of these patients showed a significantly higher level than that of normal men. They also suggested that the enhanced state of fibrinolytic activity in the seminal vesicles might be caused by an allergic reaction in the vesicles. The purpose of the present investigation is to elucidate the relationships of the hemospermia with the allergic reaction in the seminal vesicles by means of the experimental study on fibrinolytic enzyme system. Review of References Since Rapin (1859) reported on hemospermia, there have been many works on the etiology of this syndrome. Ricord" believed it was caused by bleeding from the testis or epididymis. Nelaton") related it to bleeding caused by urethral injury. Ulzmanni" also related it to bleeding caused by injury of the prostatic urethra. These are now accepted as explanations of hemospermia, but not as causes. Some researchers studied the bleeding of the prostatic gland, but in. recent years there has been renewed interest in hemorrhagic lesions in the seminal. vesicles. Guelloit") classified this, according to the site of the bleeding, into false and true hemospermia. In the former the urethra was regarded as the principal source of bleeding and in the latter, the seminal. vesicles. According to the opinion of Huggins and McDonald") (1945), in cases of prostatic bleeding the semen revealed uniformly mingled blood clots, whereas in seminal vesicle bleeding it appeared to be uniformly mixed turbid pink. They have, furthermore, tried to classify it as acute or chronic hemospermia in relation to the symptoms. Momose") (1961) and Endo") (1963) have etiologically classified hemospermia into organic and essential entities. Yata18 (1963) regarded essential hemospermia as being due to a functional disturbance of the seminal vesicles. Concerning inflammatory diseases, much attention has been paid to non-specific, tuberculous, and syphilitic inflammation. Nelken") (1910), Parker") (1942), Eisendrath and Polnik2" emphasized the possibility of genital tuberculosis as an etiologic factor, but Lydston22) (1894) and Huggins disputed this. In Japan, Inada") (1949> reported that hemospermia often appeared as an early symptom of tuberculous prostatitis. Sporer and Oppenheimer") (1957) expressed the same opinion. Some cases of hemospermia caused by tuberculous seminal . vesiculitis were reported by Parker") and Namiki25 (1960). In the latter's report, Kozaka:Hemospermia・FibrinolyticActivity thecaseshowedcalcificationoftheseminal vesiclesoriginatirlgfro皿tuberculousinfiammation. Tomikawa26)(1939)observedthepresence ofredbloodcellsintheseminalvesicle fiuidobtainedbycatheterizationtotheeja。 culatoryductsofpatientswithtuberculous epididymitis. Kuroda27〕(ユ949)examinedthesemenof 24patientssufferingfromgenitaltuberculosis,buttherewasnohemospermia. Ichikawaeta1.28)(1944)performedavesiculectomyonpatientswithtuberculous seminalvesiculitis,butthesespecimens offerednoevidencetosupPortthepresence ofhemospermia.ThirtypatientswithhemospermiatreatedbyEndo,110fwhom hadapast-historyofpulmonarytubercu10sis,sh6wedaverylowincidenceofhemospermiacausedbygenitaltuberculosis.A caseofhemospermiareportedbyArakawa eta1.29)(1944)showedsyphiliticulceration andagummaintheseminalvesicles. Nelkenalsopointedouttheimportantrelationshipbetweensyphilisandhemospermia. Manycasesofhemospermiacausedbynonspeci且cseminalvesiculitisaswellasafew casesofnon-specificprostatitisorposterior urethritishavebeenreported. Tom量kawaexamined51specimensobtainedfromthecannulationoftheejaculatory ductsandfoundgspecimenscontainingred bloodcellsofwhich3casessufferedfrom chronicgonorrheaand3chronicgonorrhea aρcompaniedbyprostatitis.Nakao30)(1950) examining4patientswithhemospermia found3caseswithvesiculitisasanetiologicaldisease.Ochiaieta1.81}(1959)removedtheseminalvesiclesfrom2patients withhemospermiaunderthepresumptive diagnosisofchronicseminalvesiculitis, andfoundnospecialhistologica1且ndings abletoexplainhemospermia.Kusunoki32〕 255 (1947),Shimoe33)(1959),Kanazawaeta1.34h (1960),Nagataeta1.35)(1961)andMomose eta1,reportedtheirowncasesofhemospermiacausedbydiverticulumofthe seminalvesicles,andconcludedthisdisease mighteasilybediagnosedbyseminalvesi-・ culography.Althoughthediagnosisofdiverticulumoftheseminalvesiclesiscom_ parativelyeasy,thatofseminalvesicle cystisnotsoand,unfortunately,most frequentlyitaccompanieshemospermia.In Europe,Stewarteta1.36)(1949)encounter. edonecaseoftheseminalvesiclescyst、 withhemospermiaandobservedthecyst. fullofblood.InJapan,Ishigarni37}(1953), Nakamuraeta1.38)(1955),andMomoseet a1.reportedthesimilarcases.Magidand エヨ[ejtrnanick39)(1957)encountered2cases.. ofhemospermiawithdirectcomlnunication betweenthepelvicveinplexusandthe vesicularcavity..Endo,byinjectingindig(> carmineandEvansblueintothesemina1. vesicles,confirmedthetransmissionof thesedyesintothebloodbuttherewas noevidenceofhemospermiainconnec. tionwiththeabove-metionedcommunications. Theetiologyoforganichemospermiahas beenthoughttober耳ostlythediseaseof theseminalvesiclesandthisconceptis widelyacceptednowadays.PaulandCohn40} (1907)observedthatthesubmucosaofthe seminalvesiclesisquitevascularandtends toableedingcondition。LydstonandLea-・ der41)(1958)agダeedthis.Masunaga42)」 (1968)observedvesselspenetratingverticallyfromthemusclelayertothesubmucouslayer.Thesevesselswerealwaysin aconditionofbeingpressedbythevesicularHuid;andinthecaseofbladderneck disease,theelaculatoryductwasdefomled, resultingintheelevatedseminalvesicle pressurewhichcausestheruptureofthe 256 Kozaka=Hemospermia・FibrinolyticActivity vessels.Concerningotherorganicfactors, Parkerpointedoutthesignificanceofspermatoceleasacauseofhemospermia.On thecontrary,Ishigami43}(1957)couldnot .findanyrelationshipbetweenthesediseases,andalowincidenceoftheircoexistencewasstressed.Omorieta1.44〕 (1953)andKamimuraeta1.45}(1954)re'portedacaseofhemospermiaassociated withsperminvasioncausedbyinjuryof 'theepididym量sandassulnedanetiologyof thehemospermiabasedontheinflammation andnecrosisoftheepididymisorthe increaseofthepermeabilityofthevessels bythespermhyaluronidase. Ontheotherhand,functionalfactors,as Yatahadpreviouslymentioned,suchasa11ergy,sexualneurosis,sexualexcess,overmasturbationandhemorrhagicdiathesis werealsodiscussed(Table1).Lydston 'wrotethatsexualexcitationwasthemain reasonforthecongestionofthemucosaof TablelEtiologicalClassificationofHemospermia(byYata,B.,1963) 1)Hemospermiaduetoorganicdisturbances (Seminaltract) 1)Anatomicalandmorphological abnomalities a)Pathologicaldilatationoftheseminal vesiclesandthevasdeferens b)Directcomm | v2 |
2021-11-25T16:07:14.771Z | 2021-11-05T00:00:00.000Z | 244560880 | s2ag/train | Ibrutinib Plus Rituximab Is Superior to FCR in Previously Untreated CLL: Results of the Phase III NCRI FLAIR Trial
Introduction:
The most effective chemoimmunotherapy (CIT) in previously untreated CLL is the combination of fludarabine, cyclophosphamide and rituximab (FCR). Ibrutinib (I), the first irreversible inhibitor of Bruton's tyrosine kinase approved for CLL, has improved outcomes in numerous clinical trials compared to different CIT.
Methods:
FLAIR (ISRCTN01844152) is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to the IWCLL 2008 guidelines. Patients over 75 years or with >20% 17p-deleted cells were excluded. Participants were randomised on a 1:1 basis to receive 6 cycles of FCR (oral fludarabine 24mg/m 2/day for 5 days, oral cyclophosphamide 150mg/m 2/day for 5 days with IV rituximab [375 mg/m 2 on day 1/2 of cycle 1; 500 mg/m 2 on day 1 of cycles 2-6]) every 28-days or IR (Ibrutinib [420mg/day] plus rituximab [6 doses as for FCR]) given for up to 6 years with stratification by disease stage, age, gender and centre. The primary endpoint was to assess whether IR was superior to FCR in terms of investigator-assessed PFS. Secondary endpoints included overall survival,; attainment of undetectable MRD; response to therapy; safety and toxicity; health-related quality of life and cost-effectiveness. A formal interim analysis was planned when 191 events were observed in both arms or 109 events in the FCR arm alone with a p-value of 0.005 leading to reporting of the trial. Here we report the results of this planned interim analysis.
Results:
A total of 771 patients were randomised (385 to FCR and 386 to IR) from 113 UK Centres between 9/19/2014 and 7/19/2018. The data was locked on 5/24/2021. 73.3% were male, median age was 62 years (33.6% >65yo) and 45.1% were Binet Stage C. IGHV data was available for 728 (94.4%) patients with 53.2% IGHV unmutated (≥98% homology to germline), 40.5% IGHV mutated and 6.3% Subset 2. Hierarchical FISH testing revealed 0.4% 17p del, 15.4% 11q del, 12.3% trisomy 12, 29.7% normal and 35% 13q del; with 7.1% failed. The arms were well-balanced for disease variables with no significance differences. Median follow-up was 52.7 months. IR had a superior PFS compared to FCR (Median PFS not reached for IR versus 67 months for FCR; HR: 0.44; p<0.001; see Figure). The PFS was significantly better for IR in patients with IGHV unmutated CLL (HR: 0.41; p<0.001), but not for patients with IGHV mutated CLL at this follow-up (HR: 0.66; p=0.179). There was no difference in overall survival between the two arms (HR: 1.01; p=0.956) with a total of 29 deaths in FCR arm (including 4 from CLL, 3 Richter's [RT], 3 AML/MDS, 3 COVID-19 and 2 cardiac/sudden) and 30 in the IR arm (including 3 CLL, 1 RT, 0 AML/MDS, 3 COVID-19 and 8 cardiac/sudden). Second line treatment was initiated for 59 patients after FCR (including 38 BTKi, 7 venetoclax+R [venR], 4 BendamustineR [BR] and 3 CHOP-R [RT]) and 21 after IR (including 7 FCR, 5 venR, 1 BR, 1 CHOP-R [RT], 1 ABVD [Hodgkin's]). Overall, 88.1% of patients have received targeted therapies for CLL progression after FCR. The overall survival with FCR in FLAIR is significantly improved compared to FCR in previous NCRI trials (ADMIRE and ARCTIC) which had the same inclusion criteria, the same Centres and an identical FCR schedule, but were conducted prior to widespread availability of targeted therapies in the relapse (recruited between 2009 and 2012). The 4 year overall survival for FCR in FLAIR was 94.5% compared to 84.2% for FCR between 2009 and 2012. SAEs were reported in 53.7% of patients on FCR and 53.4% on IR. Notable differences for SAEs by organ class for FCR vs IR: infections in 33.6% of patients vs 27.1%; blood and lymphatic in 19.8% vs 10.7%; and cardiac in 1.1% vs 8.3%. With current follow-up, there were 10 sudden or cardiac deaths: 8 IR and 2 FCR. Further analysis indicated that 7 of the 8 cardiac or sudden deaths in the IR arm had a history of hypertension or cardiac disease (further detailed in additional abstract; Munir et al.). Neither of the sudden deaths in the FCR arm had a prior cardiac or hypertensive history or were on cardiac or anti-hypertensive treatment. There were 6 cases of secondary MDS/AML in the FCR arm and 1 in the IR arm.
Conclusion:
Ibrutinib plus rituximab resulted in a superior PFS compared to FCR. There was no difference in overall survival, most likely due to effective second-line targeted therapy in patients progressing after FCR.
Figure 1 Figure 1.
Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; SOBI: Honoraria; BeiGene: Honoraria; AstraZeneca: Honoraria. Bloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria. Broom: AbbVie: Honoraria; AstraZeneca: Honoraria; Janssen-Cilag Ltd: Honoraria; Takeda UK Ltd: Honoraria; Celgene Ltd: Honoraria; Gilead: Honoraria. Furtado: Abbvie: Other: Conference support. Morley: Kite: Honoraria; Janssen: Honoraria; AbbVie; Takeda: Other: Conference support; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Paneesha: Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria. Howard: Roche: Current Employment. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Patten: NOVARTIS: Honoraria; ROCHE: Research Funding; JANSSEN: Honoraria; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding. Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria.
| v2 |
2017-04-14T15:15:35.522Z | 2008-01-01T00:00:00.000Z | 17403570 | s2ag/train | Eradication of OvarianTumor Xenografts by Locoregional Administration ofTargeted Immunotherapy
Purpose: Oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN) are potent activators of innate and adaptive immunity. Recognition of CpG-ODN is mediated byToll-like receptor 9 expressed by immune cells, endothelial and epithelial cells, and fibroblasts.We examined the antitumor effect of CpG-ODN and the role of administration route on human ovarian cancers growing in the peritoneal cavity of nude mice. Experimental Design:Mice implanted i.p. withhumanovarian carcinoma cells were treated i.p., s.c., or i.v. and assessed for survival and tumor-free incidence. Peritoneal washingswere analyzed for keratinocyte chemokine production and for functional and phenotypic profiles as indicators of the cell types involved inmediating the antitumor effects. Results: IGROV-1-bearing mice treated i.p. survived significantly longer than those treated i.v. or s.c. (P = 0.0005), andnearly half of them (8 of17)were tumor-free by the endof the experiment, a rate never achieved using a variety of chemotherapeutic drugs. High rates of tumor-free mice were observed in three other ovarian tumor xenografts treated i.p. Compared with peritoneal washings ofmice treated s.c. or i.v., those frommice treated i.p. showed the highest level of serum and tissue keratinocyte chemokine, the highest number of natural killer cells and neutrophils, and the highest antiproliferative activity in vitro. Conclusions: The superior antitumor effect obtained by locoregional administration of CpGODNin i.p. tumor-bearingmicewith a limited adaptive immune response points to the importance of innate effector cells amplification at the site of tumor growth and suggests the promise of i.p. CpG-ODN in clinical trials for ovarian cancer. Oligodeoxynucleotides containing dinucleotides with unmethylated CpG motifs (CpG-ODN) are strong activators of both innate and adaptive immune systems (1, 2). Recognition of CpG-ODN is mediated by Toll-like receptor 9 (TLR9), a member of the TLR family, which is critically important in detecting microbial pathogens. TLRs, initially identified on cells of the immune system, are also expressed by nonprofessional immune cells such as endothelial cells, fibroblasts, and epithelial cells (3, 4). Both bone marrow and non-bone marrow-derived cells are thought to be involved in the response induced by TLR agonists. Successes in preclinical studies using CpG-ODN and early indications of its safe use in humans have led to considerable interest in the clinical development of these agents in the treatment of cancer patients (1, 5). Preclinical studies (6–8) have shown superior antitumor effects after intratumor administration of CpG-ODN; thus far, a mechanistic explanation of the route-dependent effects remains to be elucidated. The critical role ascribed to the adaptive immunity in CpGODN antitumor effects have led to clinical trials conducted using systemic administrations (9–11). In clinical practice, ovarian cancer is among the few tumor types suitable for intratumor treatment, because its growth is mostly confined to the peritoneal cavity. In such patients, locoregional delivery of therapeutic agents may be a suitable option. Ovarian cancer is the fifth most frequent cancer, accounting for about 6% of all cancer death in females. Progress in the treatment of the disease has been made in recent years, with the current 5-year survival rate around 45% (12). Cytoreductive surgery and systemic combination chemotherapy with a platinum drug and a taxane represent the standard of care for ovarian cancer patients (13). The role of immunotherapy for ovarian cancer patients has been addressed in an early clinical trial (14), but to our knowledge the efficacy of CpG-ODN against ovarian tumors has not been addressed clinically. Here, we examined the effects of CpG-ODN on human ovarian cancers in the peritoneal cavity of nude mice and the role of the administration route in determining these effects. The results indicate the superior antitumor activity after i.p. administration compared with other routes of delivery, with increased mouse survival time and tumor-free rates. Analyses of the cellular and immunologic bases of this effect point to the Cancer Therapy: Preclinical Authors’Affiliations: Preclinical Chemotherapy and Pharmacology Unit and Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori; Institute of Pathology, University of Milan, Italy Received 2/19/08; revised 5/8/08; accepted 5/13/08. Grant support: Associazione Italiana per la Ricerca sul Cancro (Milan, Italy). The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Graziella Pratesi, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-2-23902626; Fax: 39-223902692; E-mail: [email protected]. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-0445 www.aacrjournals.org Clin Cancer Res 2008;14(17) September1, 2008 5512 Research. on April 14, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from crucial role of innate effector cells amplification at the site of tumor growth. Materials andMethods Mice. All experiments were carried out using 8to 10-week-old female Swiss nude mice (Charles River). Mice were maintained in laminar flow rooms at constant temperature and humidity, with food and water given ad libitum . Experiments were approved by the Ethics Committee for Animal Experimentation of the Istituto Nazionale Tumori of Milan according to institutional guidelines. Oligodeoxynucleotides. Purified, phosphorothioated ODN1826 (5¶-TCCATGACGTTCCTGACGTT-3¶) containing CpG motifs and control ODN2243 lacking a CpG motif were synthesized by ColeyPharmaceutical Group. Phosphorothioate modification was used to reduce susceptibility of the oligodeoxynucleotide to DNase digestion, thereby significantly prolonging its in vivo half-life. CpG-ODN was administered at a dose of 20 Ag/mouse in 0.2 mL saline based on a dose-response curve assessing the effects on keratinocyte chemokine (KC) production (15). Tumors. IGROV-1 (16), SK-OV-3 (17), OVCAR-5 (18), and OvCa432 (19) human ovarian carcinoma cells were used in the study. The IGROV-1 tumor was adapted to grow i.p. and maintained by serial i.p. passage of ascitic cells into healthy mice as described (20). For experiments here, 2.5 10 ascitic cells in 0.2 mL saline were injected i.p. into mice. For experiments with SK-OV-3, OVCAR-5, and OvCa432 tumors, 10 exponentially growing cells from culture, suspended in 0.4 mL of saline, were inoculated i.p. In three of the four tumor systems, hemorrhagic ascites with diffuse peritoneal carcinomatosis develops and the animals eventually die. In OvCa432-bearing mice, only 75% developed peritoneal tumors and no mouse died for tumor | v2 |
2014-10-01T00:00:00.000Z | 2003-01-01T00:00:00.000Z | 128312270 | s2ag/train | A Study on Investigation of Crustal Deformation and Block Kinematics Along the Eastern Sector of the NAF by GPS Measurements
ABSTRACT Figure 1: Tectonics of Turkey Figure 2: Study Area Including Active Fault Lines This study constitutes a part of integrated project that has been carried out jointly by Kandilli Observatory and Earthquake Research Institute (KOERI) and TUBITAK-MAM to investigate crustal deformation and block kinematics by Global Positioning System (GPS) measurements in and around the eastern sector of the North Anatolian Fault (NAF) Zone. The integrated project is also include investigation of seismicity and earthquake potential. Additionally, the Radon gas emissions will also be monitored on-line, near realtime along active fault zones in an attempt to predict earthquakes. The region is an ideal choice to carry out the above mentioned investigations, because of the northward movement of the Arabian Plate, the Erzincan-Karliova region is squeezed, crushed, and expelled westward along the NAF and East Anatolian Fault Zones. The active fault pattern indicates that maximum crustal shortening and crustal deformation in Turkey takes place in this region. RECONNAISSANCE and PLANNING RECONNAISSANCE and PLANNING RESULTS OF THE PROCESSING RESULTS OF THE PROCESSING OBSERVATIONS OBSERVATIONS Figure 5: Observation Team Figure 4: Study Area Including GPS Stations and Provinces Figure 3: Establishment of GPS Stations Figure 6: GPS Observations Despite this, the Yedisu segment of the NAF was identifed as a seismic gap and it has not been broken entirely since the 1784 earthquake. This region is the tectonically most active region in Turkey as far as the major earthquake occurences are concerned and it is capable of generating major earthquakes in every 3-4 years. It is quite obvious that following the 1992 Erzincan and 2003 Pülümur Earthquakes the Coulomb stress loading on the Yedisu segment of the NAF have been increased significantly and the region needs to be monitored vigilantly with the full armament of geophysical techniques such as seismic (network), geodetic (GPS, InSAR), and geochemical (Radon emissions) techniques. First period GPS measurements were performed at sixteen GPS stations in the area. This presentation reports the steps of the study and evaluation of first period GPS data. Study area covers 250x100 km square in size and 7 administrative provinces. In order to select the approximate locations of GPS stations 394 air photographs at 1:60,000 scale and 28 air photographs at 1:35.000 scale were evaluated in the office. After this study, 10-day field reconnaissance were realized, in the working area. 14 new stations were established and 2 existing geodetic points were used. These points will be measured three times in eight month intervals through the study. LOGGING ELEVATION MASK: +10o LOGGING INTERVAL: 15.0 SEC MINIMUM NUM SVs: 1 Time-Dependent Motions from GPS Measurements The GPS data will be processed following standard procedures using the GAMIT/GLOBK GPS processing software (Herring, 2000; King and Bock, 1998). At first, doubly differenced GPS phase observations from each day is used to estimate station coordinates, the zenith delay and the gradients of the atmosphere at each station, and orbital and Earth orientation parameters (EOPs) by applying loose a priori constrains to all parameters. A reliable set of International GPS Service (IGS) stations is included within the analysis to establish a link between regional and global networks. In the second step, the loosely constrained estimates of station coordinates, orbits, EOPs and their covariance from each day is used as quasi-observations in a Kalman filter to estimate a consistent set of daily coordinates. In this step, we combine for each day the quasi-observations from our regional analysis with the quasi-observations of a global analysis of IGS data performed by Scripps Orbit and Permanent Array Center (SOPAC). The reference frame is constrained on each day using a reliable set of global IGS stations. Positions of the fiducial IGS stations is constrained to ITRF97 coordinates. Further details about the processing method are described in McClusky et al., 2000. Figure 7: Point Error Ellipses References Ozener H., et al. (2003). Investigation of Crustal Deformation and Block Kinematics along the Eastern Sector of the NAF by GPS Measurements-Seismicity and Assesment of Earthquake Potantial. TubitakYDABAG, 103Y043-Project proposal. McClusky S., et al. (2000). Global positioning System constraints on plate kinematics and dynamics in the eastern Mediterranean and Caucasus. J. Geophys. Res., 105, 5695-5719. Herring, T.A. (2000). GLOBK: Global Kalman Filter VLBI and GPS analysis program Version 10.0, Massachusetts Institute of Technology, Cambridge, USA. King, R.W., and Y. Bock, (1998). Documentation for the GAMIT analysis software, release 9.7, Massachusetts Institute of Technology, Cambridge. First period GPS measurements were performed at sixteen GPS stations. Six teams with two people each were constituted for GPS measurement. Trimble 4000 SSI and 4000 SSE receivers were used. 10-hour/day observation was realized at each station. Acknowledgements This research is being supported mainly by TUBITAK-YDABAG grant 103Y043 and in part by Bogaziçi UniversityKOERI. The authors thank to Prof.Dr. Onur Gürkan for his support, advices and for helpful comments. Furthermore the authors would like to thank all assistant personnel, especially, Surveying Engineer Mahmut O. Korkmaz, Kerem Halıcıoğlu, Özgür Avcı, and Onur Süslü for their technical support in the fieldwork studies. 39:36'48.27783" N 39:09'49.78834" E KMAH 39:04'27.28587" N 39:13'01.50944" E HZAT 39:26'53.50004" N 40:48'11.61069" E BYML 39:49'27.90776" N 39:31'27.19729" E KCMZ 39:18'13.11916" N 40:59'55.13258" E KARL 39:12'54.55634" N 40:30'53.15565" E ATAP 39:02'21.26754" N 40:19'46.73406" E USVT 39:10'54.59565" N 40:43'59.83404" E KRPR 39:32'15.12569" N 39:57'24.26118" E KTAS 39:01'34.84168" N 38:55'51.53160" E CMGK 39:18'37.05440" N 38:38'40.25541" E DBAS 39:20'58.70751" N 39:15'30.01622" E SRTS 38:57'31.71410" N 41:03'24.55833" E SOLH 39:10'41.67959" N 38:15'51.39728" E DIVR 38:56'57.46474" N 40:06'17.85665" E KLKY 39:25'47.73321" N 40:02'18.02929" E BLYM LATITUDE LONGITUDE STATION ID Table 1: Coordinates of Points In order to check the quality of measurements Trimble Geomatics Office software was used for the preliminary evaluation of GPS data. Broadcast ephemeris were used for post-processing. Figure 7 represents the point error ellipses of some stations. Point position errors vary between 2-3 mm. | v2 |
2020-12-14T20:14:32.252Z | 2020-11-05T00:00:00.000Z | 228892400 | s2ag/train | EBV-Positive Primary CNS Lymphomas in Older Patients: Incidence, Characteristics, Tumor Pathology, and Outcomes across a Large Multicenter Cohort
Background
Primary CNS lymphoma (PCNSL) is a rare non-Hodgkin lymphoma that is often associated with immunosuppressed states. The Epstein-Barr Virus (EBV) may play a role in tumor pathogenicity in some cases. The objective of this study was to examine the patient characteristics, tumor pathology, and survival outcomes associated with EBV tumor status in patients with PCNSL.
Methods
This was a retrospective subset analysis from 17 academic medical centers that included 439 patients of ages 60 years and above with PCNSL (David K et al. ASH 2020). The associations between EBV status and clinical or demographical variables were tested by Fisher's exact test, Wilcoxon rank-sum test, or CMH trend test. Kaplan-Meier estimator was used to estimate survival probability. Survival difference between groups was tested by log-rank test for statistical significance. Confidence interval of survival rate was calculated using Greenwood's formula.
Results
A total of 247 patients with available EBV status were included in this analysis. Median age was 71 (range 60-84) and 44.5% were male. Notably, none of the patients were HIV-positive. Twenty-five patients (10.1%) had EBV positive tumors as detected by EBER (EBV-encoded RNA) in-situ hybridization or LMP1 immunohistochemistry (IHC), 17 of which were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD) and 8 of which were not PTLD. All EBV-positive non-PTLDs were diffuse large B-cell lymphoma. Three (15%) SOT-related PTLDs were EBV-negative.
Patient characteristics analyzed included age at diagnosis, sex, ECOG performance status, history of prior or concurrent malignancies, history of solid organ transplant or autoimmune disease, history of allogeneic stem cell transplant, and immunosuppressive treatment. Of these, only a history of solid organ transplant or autoimmune disease (P<0.0001) and immunosuppressive treatment (P<0.0001) were highly correlated with EBV-positivity; there were no other patient factors associated with EBV status. For patients with EBV-positive SOT-related PTLD, the most common immunosuppressive medications were mycophenolate (n=13), calcineurin inhibitors (n=11), and prednisone (n=9). Only 1 of the EBV-positive non-PTLD cases had a history of autoimmune disease and was on mycophenolate and hydroxychloroquine.
Tumor characteristics analyzed included expression of C-MYC, BCL2, CD5, cell of origin markers (BCL6, MUM1, CD10), and CD20 through IHC, C-MYC and BCL2 translocation through FISH, histology, and involvement of brain parenchyma, CSF, spinal cord, and eyes. EBV-positive tumors were associated with low C-MYC (p=0.047) and BCL6 (p=0.0006) expression on immunohistochemistry, but not other factors. There were no significant differences in tumor characteristics between those with EBV-positive PTLD and EBV-positive non-PTLD.
Among patients with PTLD, 30% (n=6) did not receive primary chemotherapy, and the most common treatment regimens were high-dose methotrexate (HD-MTX) with or without rituximab (n=5) and rituximab alone (n=3). However, there was no significant difference in outcomes among PTLD patients who received chemotherapy or those who did not. Among EBV-positive non-PTLD patients, only 12.5% (n=1) did not receive primary chemotherapy and the most common treatment regimens were methotrexate/rituximab/temozolomide (n=3) and HD-MTX with or without rituximab (n=3).
There was no difference in overall or progression free survival between patients with EBV-positive and EBV-negative tumors, or in outcomes among SOT-related PTLD patients regardless of EBV status. However, patients with EBV-positive non-PTLD PCNSL had better overall survival compared to patients with EBV-positive PTLD and EBV-negative tumors (p=0.033, Figure).
Conclusions
In this large observational study of older patients with PCNSL, the incidence of EBV positive tumors was overall low and was most commonly associated with SOT-related PTLD. Mycophenolate mofetil was the most common immunosuppressive medication. In those without PTLD, there were no patient or tumor factors that were associated with EBV status. Unexpectedly, non-PTLD EBV-positive PCNSL had superior outcomes to EBV-positive PTLD and EBV-negative PCNSL. Future studies of EBV-positive non-PTLDs are warranted to further evaluate the potential impact of EBV latency and the immune response on the tumor microenvironment.
Reddy: BMS: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; KITE Pharma: Consultancy. Bachanova:Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; WEX: Consultancy, Other: travel; Cortice Bio: Consultancy, Other: travel; Boston Biomedical: Consultancy; COTA: Other; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau. Spurgeon:Gilead: Research Funding; Genentech: Research Funding; Cardinal Health: Honoraria; Bristol-Myers Squibb: Research Funding; VelosBio: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy; Beigene: Research Funding; Verastem: Research Funding; Genmab: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Takeda: Research Funding; BeiGene: Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Smith:Janssen: Consultancy; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Consultancy; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding. Rubenstein:Kymera: Research Funding. Kahl:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy. Evens:Abbvie: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Cellectar: Consultancy; Beigene: Consultancy; Bayer: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy.
| v2 |
2021-11-25T16:15:58.386Z | 2021-11-05T00:00:00.000Z | 244540250 | s2ag/train | Global Phase 3, Randomized, Placebo-Controlled Trial with Open-Label Extension Evaluating the Oral CXCR4 Antagonist Mavorixafor in Patients with WHIM Syndrome (4WHIM): Trial Design and Enrollment
Background: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is a rare primary immunodeficiency associated with broad cytopenia, including neutropenia. It is caused by gain-of-function mutations in C XCR4, leading to dysregulated immune cell trafficking with retention of neutrophils, lymphocytes, and monocytes in the bone marrow and in some cases, hypogammaglobulinemia. As a result, patients with WHIM syndrome have recurrent bacterial and viral infections, and unusual susceptibility to human papillomavirus infection predisposing individuals to recalcitrant warts and malignancy (McDermott D, et al. Immunol Rev. 2019;91-102). Therapeutic options are limited and do not address the underlying pathogenic mechanism of WHIM syndrome. The investigational oral CXCR4 antagonist mavorixafor directly targets the underlying cause of disease and has been shown to increase absolute neutrophil, lymphocyte, and monocyte counts, and to decrease annualized infection rate, and reduce cutaneous wart burden in a phase 2 trial of adults with WHIM syndrome (NCT03005327; Dale D, et al. Blood. 2020;136: 2994-3003). Findings from an ongoing long-term extension of this study support a sustained clinical benefit of long-term mavorixafor treatment in patients with WHIM syndrome. Here, we describe the design of a global phase 3 registrational trial evaluating the safety and efficacy of mavorixafor in WHIM syndrome in participants aged ≥12 years while reporting on preliminary baseline characteristics of the enrolled population.
Methods: This phase 3 trial (4WHIM; NCT03995108) is a randomized, double-blind, placebo-controlled study with open-label extension (OLE) and planned enrollment of 18 to 28 patients from sites in Asia, Australia, Europe, Israel, and the United States. Patients aged ≥12 years with a confirmed CXCR4 mutation consistent with WHIM syndrome phenotype and a screening absolute neutrophil count (ANC) ≤400 cells/µL without clinical evidence of active systemic infection are eligible for enrollment. Patients are randomized 1:1 to receive mavorixafor (400 mg in adults, and adolescents weighing >50 kg; 200 mg in adolescents weighing ≤50 kg) or matching placebo once daily for a total of 52 weeks (≥9 patients per group). Patients who complete the randomized period or are granted early release due to recurrent infections requiring treatment (≤2 requiring hospitalization or 4 requiring intravenous antibiotic or granulocyte colony-stimulating factor) are eligible to enroll in the OLE and receive mavorixafor until commercial availability or study termination. The primary end point is the number of hours above ANC threshold of 500 cells/µL over a 24-hour period, assessed prior to treatment, and 4 times (every 3 months) over the 52-week randomized period. Secondary end points include infection rates adjudicated by a blinded, independent committee, change from baseline in cutaneous warts also with blinded assessment, number of hours above absolute lymphocyte count (ALC) of 1000 cells/µL over a 24-hour period, and patient-reported outcomes such as work/school absence and quality of life assessment using age-appropriate questionnaires.
Patient Demographics and Characteristics: As of July 15 2021, the first 18 patients have enrolled from 10 countries and 15 sites. Of these, 56% are pediatric patients, 56% are males, 56% of the patients have warts, 94% have nonsense and 6% have frameshift CXCR4 mutations. All patients had severe neutropenia (ANC ≤400 cells/μL) and majority had significant lymphopenia (ALC ≤1000 cells/μL).
Conclusions: Evidence supporting efficacy of current therapies in WHIM syndrome is lacking, and approved therapies targeting the underlying molecular mechanisms and hence, able to address the full clinical spectrum of this condition, are needed. The 4WHIM study is the first double-blind, placebo-controlled, randomized trial in patients with this syndrome and is an important next step in the clinical development of a novel, orally bioavailable targeted therapy for WHIM syndrome and potentially for other individuals with related cellular immunodeficiencies. This robust study will build on the findings of the phase 2 trial that suggested a clinical benefit of mavorixafor for WHIM syndrome by incorporating a broader, global population of patients observed for a longer period of time. Full phase 3 trial results are anticipated in late 2022.
Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Azar: X4 Pharmaceuticals: Research Funding. Badolato: Angelini: Consultancy; X4 Pharmaceuticals: Consultancy; Janssen: Consultancy; SOBI (IDMC): Other. Bhandari: X4 Pharmaceuticals: Current Employment. Belschner: X4 Pharmaceuticals: Current Employment. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Dickerson: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Hoffman: Zomagen: Research Funding; Novartis: Consultancy, Speakers Bureau; Takeda: Research Funding; Jecure: Research Funding. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kulagin: Roche: Speakers Bureau; Sanofi: Speakers Bureau; Generium: Speakers Bureau; Biocad: Research Funding; Apellis: Research Funding; Alexion: Research Funding; X4 Pharmaceuticals: Research Funding; Novartis: Speakers Bureau; Johnson & Johnson: Speakers Bureau; Pfizer: Speakers Bureau. Langguth: RCPA: Membership on an entity's Board of Directors or advisory committees. MacLeod: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Sharathkumar: Amgen: Research Funding; BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharmaceuticals: Research Funding; NIH Trials of Pediatric VTE: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Shcherbina: X4 Pharmaceuticals: Speakers Bureau. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Vossen: X4 Pharmaceuticals: Other: PI in WHIM Trial; Brothers of St. John: Consultancy; Austrian National Bank: Research Funding; Menarini: Honoraria; Gilead: Honoraria; Astro Pharma: Honoraria.
| v2 |
2021-11-23T06:22:58.174Z | 2021-11-22T00:00:00.000Z | 244509920 | s2ag/train | Vaccines for measles, mumps, rubella, and varicella in children.
BACKGROUND
Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. This is an update of a review published in 2005 and updated in 2012.
OBJECTIVES
To assess the effectiveness, safety, and long- and short-term adverse effects associated with the trivalent vaccine, containing measles, rubella, mumps strains (MMR), or concurrent administration of MMR vaccine and varicella vaccine (MMR+V), or tetravalent vaccine containing measles, rubella, mumps, and varicella strains (MMRV), given to children aged up to 15 years.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase (1974 to 2 May 2019), the WHO International Clinical Trials Registry Platform (2 May 2019), and ClinicalTrials.gov (2 May 2019).
SELECTION CRITERIA
We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS), interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only ecological method (COEM) studies, self-controlled case series (SCCS) studies, person-time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM) studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any dose, preparation or time schedule compared with no intervention or placebo, on healthy children up to 15 years of age.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed the methodological quality of the included studies. We grouped studies for quantitative analysis according to study design, vaccine type (MMR, MMRV, MMR+V), virus strain, and study settings. Outcomes of interest were cases of measles, mumps, rubella, and varicella, and harms. Certainty of evidence of was rated using GRADE.
MAIN RESULTS
We included 138 studies (23,480,668 participants). Fifty-one studies (10,248,159 children) assessed vaccine effectiveness and 87 studies (13,232,509 children) assessed the association between vaccines and a variety of harms. We included 74 new studies to this 2019 version of the review. Effectiveness Vaccine effectiveness in preventing measles was 95% after one dose (relative risk (RR) 0.05, 95% CI 0.02 to 0.13; 7 cohort studies; 12,039 children; moderate certainty evidence) and 96% after two doses (RR 0.04, 95% CI 0.01 to 0.28; 5 cohort studies; 21,604 children; moderate certainty evidence). The effectiveness in preventing cases among household contacts or preventing transmission to others the children were in contact with after one dose was 81% (RR 0.19, 95% CI 0.04 to 0.89; 3 cohort studies; 151 children; low certainty evidence), after two doses 85% (RR 0.15, 95% CI 0.03 to 0.75; 3 cohort studies; 378 children; low certainty evidence), and after three doses was 96% (RR 0.04, 95% CI 0.01 to 0.23; 2 cohort studies; 151 children; low certainty evidence). The effectiveness (at least one dose) in preventing measles after exposure (post-exposure prophylaxis) was 74% (RR 0.26, 95% CI 0.14 to 0.50; 2 cohort studies; 283 children; low certainty evidence). The effectiveness of Jeryl Lynn containing MMR vaccine in preventing mumps was 72% after one dose (RR 0.24, 95% CI 0.08 to 0.76; 6 cohort studies; 9915 children; moderate certainty evidence), 86% after two doses (RR 0.12, 95% CI 0.04 to 0.35; 5 cohort studies; 7792 children; moderate certainty evidence). Effectiveness in preventing cases among household contacts was 74% (RR 0.26, 95% CI 0.13 to 0.49; 3 cohort studies; 1036 children; moderate certainty evidence). Vaccine effectiveness against rubella, using a vaccine with the BRD2 strain which is only used in China, is 89% (RR 0.11, 95% CI 0.03 to 0.42; 1 cohort study; 1621 children; moderate certainty evidence). Vaccine effectiveness against varicella (any severity) after two doses in children aged 11 to 22 months is 95% in a 10 years follow-up (rate ratio (rr) 0.05, 95% CI 0.03 to 0.08; 1 RCT; 2279 children; high certainty evidence). Safety There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (rr 1.30, 95% CI 0.66 to 2.56; low certainty evidence). The analyses provide evidence supporting an association between MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2% to 4% of healthy children at least once before the age of 5. The attributable risk febrile seizures vaccine-induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. The analyses provide evidence supporting an association between MMR vaccination and idiopathic thrombocytopaenic purpura (ITP). However, the risk of ITP after vaccination is smaller than after natural infection with these viruses. Natural infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The attributable risk is estimated about 1 case of ITP per 40,000 administered MMR doses. There is no evidence of an association between MMR immunisation and encephalitis or encephalopathy (rate ratio 0.90, 95% CI 0.50 to 1.61; 2 observational studies; 1,071,088 children; low certainty evidence), and autistic spectrum disorders (rate ratio 0.93, 95% CI 0.85 to 1.01; 2 observational studies; 1,194,764 children; moderate certainty). There is insufficient evidence to determine the association between MMR immunisation and inflammatory bowel disease (odds ratio 1.42, 95% CI 0.93 to 2.16; 3 observational studies; 409 cases and 1416 controls; moderate certainty evidence). Additionally, there is no evidence supporting an association between MMR immunisation and cognitive delay, type 1 diabetes, asthma, dermatitis/eczema, hay fever, leukaemia, multiple sclerosis, gait disturbance, and bacterial or viral infections. AUTHORS' CONCLUSIONS: Existing evidence on the safety and effectiveness of MMR/MMRV vaccines support their use for mass immunisation. Campaigns aimed at global eradication should assess epidemiological and socioeconomic situations of the countries as well as the capacity to achieve high vaccination coverage. More evidence is needed to assess whether the protective effect of MMR/MMRV could wane with time since immunisation. | v2 |
2020-02-20T09:09:34.982Z | 2019-11-13T00:00:00.000Z | 212961120 | s2ag/train | Detectable Circulating Tumor DNA 28 Days after the CD19 CAR T-Cell Therapy, Axicabtagene Ciloleucel, Is Associated with Poor Outcomes in Patients with Diffuse Large B-Cell Lymphoma
Introduction:
The autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel (Axi-cel) improved long-term survival of patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Long-term analysis of the pivotal ZUMA-1 trial indicates a 2-year PFS of ~40% (Locke, Lancet Oncology 2018). Early identification of patients with increased relapse risk may allow for early intervention and improved outcomes. In a pilot study of 6 ZUMA-1 patients, minimal residual disease (MRD) evaluation via a next-generation sequencing MRD assay (Adaptive Biotechnologies, Seattle, WA) to assess for circulating tumor (ct)DNA, mirrored clinical outcome as assessed by PET-CT (Hossain et. al. Leukemia & Lymphoma 2019). Based on these promising results, a multi-institutional prospective study utilizing cell-free MRD assessments to predict outcomes in r/r DLBCL patients after Axi-cel therapy was initiated.
Methods:
To identify tumor clonotype(s), tumor DNA extracted from archival paraffin-embedded tissue underwent PCR amplification of IgH-VDJ, IgH-DJ and IgKappa/Lambda regions using universal consensus primers. CtDNA levels were measured pre-LD, 0, 7, 14, 21, 28, 56, 90, 180, 270, and 365 days following Axi-cel infusion. PET-CT scans were obtained at baseline, Day 28, Month 3, 6, and 12 with response assessed per Lugano criteria. Deauville 1-3 was considered PET-negative. The protocol prespecified that patients with less than Day 28 follow-up be excluded from analysis. Any detectable ctDNA was considered MRD positive.
Results:
Here we report on the pre-planned analysis of the first 50 study patients with at least a Day 28 MRD assessment and 3 months of follow up. An additional 4 patients with at least 3 months of follow-up but who did not have a Day 28 MRD assessment were also included. Baseline characteristics and clinical outcomes of patients were similar to ZUMA-1 and a real-world analysis of 295 patient who received Axi-cel (Nastoupil et al ASH 2018). The median age was 61 years old (range 19-76) (53.7% male, 46.3% female) and 59% of patients received 3 or more prior lines of therapy (range 1-6). After a median follow-up of 7.5 months, the best overall response rate was 87% (47 of 54) and complete response rate was 57% (31 of 54). The median OS was not reached and median PFS was 4.6 months (panel A). At Day 28, 56% (28 of 50) of patients were MRD negative (MRD-neg) and 44% (22 of 50) were MRD positive (MRD-pos). As compared to MRD-pos, MRD-neg correlated with improved median PFS (not reached vs. 2.96 months, p<0.0001) and median OS (not reached vs.7.4 months, p=0.0005) (panels B and C). By PET assessment on Day 28, 46% (25 of 54) of patients were PET-negative (PET-neg) and 54% (28 of 54) were PET-positive (PET-pos). When compared to PET-pos patients, PET-neg patients demonstrated an improved median PFS (not reached vs. 3.1 months, p=0.0007) and median OS (both not reached, p=0.0096). MRD and PET-CT on Day 28 were able to identify patients relapsed by 6 months with similar sensitivity, 71% (95% CI: 48-89%) and 77% (95% CI: 55% to 92%), respectively. However, Day 28 MRD status had improved specificity as compared to Day 28 PET status, 94% (95% CI: 71% to 99%) versus 63% (95% CI: 38% to 83%). Day 28 MRD assessment was particularly helpful in identifying high-risk patients in the Day 28 PET-pos subgroups of patients with a PR (n=20) or SD (n=3) (panel D). This subgroup of patients with MRD-pos (n=13) had an inferior median PFS compared to those who were MRD-neg (n=10) (3.1 months vs. not reached, p=0.0033). Of note, one MRD-neg patient died without disease at 4.5 months. After excluding those (n=4) with progressive disease on Day 28 (all MRD-pos), 72% (16 of 22) of patients were MRD-pos at least 2 months prior to radiographic progression and 86% (19 of 22) were MRD-pos at least 1 month prior to radiographic progression.
Conclusion:
MRD monitoring using high-throughput sequencing of ctDNA has the potentially to make an impact on the clinical management of patients undergoing Axi-cel therapy. Furthermore, ctDNA is an informative tool to compare CAR19 therapies that vary by costimulatory domains or production methods. This technology potentially overcomes fundamental limitations of DLBCL imaging (cost, radiation exposure & limited repetition) and may minimize the need for surveillance PET-CT scans. These results provide a rationale for designing MRD-based risk-adaptive CAR T cell clinical trials.
Figure
Kirsch: Adaptive Biotechnologies: Employment. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Mullins:Adaptive Biotechnologies: Employment. Lee:Adaptive Biotechnologies: Employment, Equity Ownership. Mackall:Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board; Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Miklos:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding.
| v2 |
2020-02-27T09:35:04.138Z | 2019-11-01T00:00:00.000Z | 214029060 | s2ag/train | Phase III PAOLA-1/ENGOT-ov25 trial: olaparib plus bevacizumab as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy plus bevacizumab
Introduction/Background In the Phase III SOLO1 first-line trial, maintenance therapy with the PARP inhibitor olaparib provided a substantial progression-free survival (PFS) benefit to advanced ovarian cancer (OC) patients who have a BRCA1/2 mutation (BRCAm) and are in complete or partial response to first-line chemotherapy (Moore K et al. N Engl J Med 2018). VEGF inhibitor may increase PARP sensitivity, particularly in some OC patients with BRCA wild type (Liu JF et al. Lancet Oncol 2014). PAOLA-1/ENGOT-ov25 (NCT02477644) is the first Phase III trial to evaluate the efficacy and safety of a PARP inhibitor with bevacizumab as first-line maintenance therapy, and in patients regardless of BRCAm status. Methodology PAOLA-1 is a randomized, double-blind, international Phase III trial. Eligible patients had newly diagnosed, advanced (FIGO stage IIIA-IV) high-grade serous or endometrioid ovarian, fallopian tube or peritoneal cancer. Patients had no evidence of disease or were in partial response following first-line platinum-based chemotherapy plus bevacizumab. Bevacizumab was to be given for up to 15 months, including the initial combination with chemotherapy. 806 patients were randomized (2:1) in maintenance therapy to olaparib (300 mg bid) or placebo plus bevacizumab (15 mg/kg, d1, q3w), stratified by first-line treatment outcome and tumour BRCAm status. The primary endpoint is investigator-assessed PFS (modified RECIST v1.1). The 458 PFS events required for the primary analysis to show significance at the two-sided 5% level with an estimated >80% power have been reached in March 2019. Database lock was in July and analyses are ongoing. Results The LBA will report: investigator-assessed PFS, PFS by BRCAm/HRD status, health- related quality of life, and safety and tolerability results. Conclusion PAOLA-1 will demonstrate whether addition of olaparib to bevacizumab maintenance therapy following first-line platinum-based chemotherapy plus bevacizumab provides a clinically meaningful benefit to OC patients. Disclosure P Harter declares honoraria from AstraZeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab and MSD; and consultancy/advisory board fees from AstraZeneca, Roche, Tesaro, Lilly, Clovis, Immunogen and MSD/Merck. Marie Ange Mouret-Reynier declares no conflicts of interest. S Pignata declares honoraria from Roche, AstraZeneca, MSD, Pfizer, Incyte, Novartis, PharmaMar, Clovis and Tesaro; and travel expenses from Roche, AstraZeneca and MSD. Claire Cropet declares no conflicts of interest. A Gonzalez-Martin declares consulting/advisory board fees from Roche, AstraZeneca, Tesaro, Clovis, Pfizer, ImmunoGen, PharmaMar, MSD, Genmad and Novartis; and speaker bureau/expert testimony fees from Roche, AstraZeneca, MSD Tesaro and PharmaMar. Gerhard Bogner declares consulting/advisory board fees from AstraZeneca Tesaro and Roche; and travel expenses from GSK, Roche, Pharmamar, AstraZeneca and Tesaro. K Fujiwara declares honoraria from AstraZeneca, Chugai Roche, Zeria, Taiho, Nihon Kayaku, Kyowahakko Kirin, Janssen and Daiichi Sankyo; consulting/advisory board fees from Pfizer, MSD and Eisai; research funding from AstraZeneca, MSD, Chugai Roche, Eisai and Kaken; and travel expenses from Pfizer. I Vergote declares consulting/advisory board fees from Advaxis, BIOCAD, Eisai, MSD, Roche, Genmab, Roche, PharmaMar, Millenium Pharmaceuticals, Clovis, AstraZeneca, Tesaro, Oncoinvent, ImmunoGen and Sotio; contracted research with Oncoinvent and Genmab; research funding from Amgen, Roche and Stichting tegen Kanker; and Takeda Oncology, PharmaMar, Genmab, Roche, AstraZeneca, Tesaro, Clovis and Immunogen. N Colombo declares honoraria from Roche, AstraZeneca, PharmaMar, Tesaro, Clovis, Pfizer, MSD, BIOCAD and Takeda; consulting/advisory board fees from Roche, AstraZeneca, PharmaMar, Tesaro, Clovis, Pfizer, MSD, BIOCAD, Takeda; and travel expenses from PharmaMar, Tesaro and Roche. J Mäenpää declares honoraria from Roche, AstraZeneca and Tesaro; consultancy/advisory board fees from AstraZeneca, Tesaro, Clovis and MSD; and travel expenses from Roche. Anne Floquet declares consultancy/advisory board fees from GSK, AstraZeneca and Clovis; and travel expenses from Roche, GSK and AstraZeneca. Ahmed El-Balat declares honoraria from AstraZeneca, Roche, Pharmamar, MSD, Tesaro, Clovis; and consultancy/advisory board fees from AstraZeneca and Roche. D Lorusso declares honoraria from Merck; consultancy/advisory board fees from Merck, AstraZeneca, Tesaro, Clovis, Immunogen, PharmaMar and Roche; research funding from Clovis, PharmaMar, Merck and Roche; and travel expenses from Tesaro, Roche and PharmaMar. EM Guerra Alia declares consultancy/advisory board fees from Roche, Clovis and AstraZeneca; and travel expenses from Roche and Baxter. Michel Fabro declares honoraria from Tesaro and AstraZeneca; and consultancy/advisory board fees from Tesaro and AstraZeneca. Barbara Schmalfeldt declares honoraria from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MSD; consultancy/advisory fees from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS; speaker bureau/expert testimony fees from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS; research grant funding from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS and travel expenses from Roche, AstraZeneca, Tesaro, Clovis, Ethicon, MDS. Anne Claire Hardy Blessard declares honoraria from AstraZeneca, Lilly, Novartis, Pfizer, Roche and Tesaro. Ingo Runnebaum declares honoraria from AstraZeneca. I Ray-Coquard declares honoraria from AstraZeneca, Clovis, Tesaro and PharmaMar; consulting/advisory board fees from AstraZeneca, Roche, Clovis, Tesaro, Genmab, PharmaMar, MSD and Pfizer; research funding from MSD; and travel expenses from AstraZeneca and Roche; consulting/advisory board fees from Roche; and travel expenses from Roche, MSD, Tesaro and AstraZeneca. E Pujade-Lauraine declares honoraria from AstraZeneca and Tesaro; consulting/advisory board fees from AstraZeneca, Roche, Clovis, Tesaro, Genmab, Incyte, MSD and Pfizer; research funding from AstraZeneca, Roche and Tesaro; and travel expenses from AstraZeneca, Roche and Tesaro. | v2 |
2019-07-15T22:29:29.963Z | 2019-10-01T00:00:00.000Z | 196580620 | s2ag/train | A Maturation Index Defines Newly Diagnosed Multiple Myeloma Patients with Advanced Immunophenotypic and Molecular Differentiation Profiles Associated with Poor Prognosis
Introduction
The differentiation status plasticity of Multiple Myeloma (MM) plasma cells (PCs) is an adaptive strategy that might confer a specific fitness to tumour cells, enabling their interaction with an evolving microenvironment. Therefore, proliferation rates of MM clones are not constant, and the immunophenotypic profile of the most skilled MM PCs might be the expression of specific genetic and genomic programs, that emerge under the therapeutic pressure and promote tumour development. However, the genomic background that supports any diverse plasma cell differentiation phenotypes has not yet been inferred.
Aim
To correlate the genetic and genomic background with the immunophenotypic profile of MM clones at diagnosis, in order to stratify patients (pts) according to a Maturation Index, and ultimately to evaluate the impact of this stratification on the disease outcome.
Patients and Methods
117 newly diagnosed MM (NDMM) pts, mostly treated up-front with a proteasome inhibitor (PI) -based treatment, were included in the study. For each pts, both neoplastic PCs and CD19+ B cells compartments were characterized by 8-color multi-parameter flow cytometry analysis, combining CD138-PE, CD38-PE-Cy7, CD56-APC-Cy7, CD20-APC, CD19-FITC, CD27-APC, CD45-PerCp, CD28-APC, CD117-FITC, CD28-APC, CD81-APC, IgK-APC and IgL-FITC. In a subgroup of pts, both a SNP array profile for copy number alterations (CNAs) and a 25-genes targeted mutational panel were assessed in CD138+ PCs. A custom ddPCR assay was also employed to evaluate through a 10-Hh gene signature the self-renewal status of PCs.
Results
In order to define a Maturation Index, pts were evaluated at different levels of heterogeneity for: a) differential expression of CD19/CD81 markers; b) level of chromosomal instability (CIN) and point mutations; d) self-renewal status.
Based on the co-expression of CD19 and CD81 markers, pts were stratified in 3 different subgroups, recapitulating a progressive PC maturation process: the most immature, which included pts with CD19+/CD81+ PCs (18/117 = 15%), the intermediate, including CD19-/CD81+ PCs (42/117 = 36%) and the most mature, including CD19-/CD81- PCs (57/117 = 49%). The advanced PC differentiation status characterizing this latter subgroup was further confirmed by the high expression of CD28 and CD44, and the reduced expression of CD20, CD27 and CD45, commonly associated with less mature stages of the disease (p<.05). Accordingly, a reduced CD138-/low/CD19+/CD20-/CD38high plasmablastic population was observed, reflecting a more quiescent immature reservoir pool in these more differentiated PCs (5,1% vs. 0,5%; p<.05).
CIN was defined according both to the total CNAs count and to the number of chromosomes' breakpoints (BPs). Pts with an advanced differentiation status displayed a higher number of total CNAs and BPs (median tot. CNAs = 550 vs. 105, and median BPs nr. = 18.5 vs. 8 in CD19-81- and CD19+81+ pts, respectively, p<.05). Interestingly, 16q deletion (CYLD, WWOX, FANCA) and 17p deletion (TP53) were the most recurrent abnormalities in mature PCs (p<.05). Genomic instability was also confirmed by a higher incidence of clonal pathogenic mutations in critical genes (e.g. NRAS, KRAS, TP53). Interestingly, the application of a 10 Hh-genes signature, resuming the Hedgehog pathway, demonstrated that PCs with more advanced differentiation status displayed a substantial overexpression of all the genes, indicating a more proliferative, aggressive and, possibly, persistent phenotype.
Finally, a more mature PC clone was significantly related to a higher prevalence of unfavourable features at baseline (e.g. ≥ 3 PET lesions, ≥ 100 k/l ratio, ISS III disease stage p<.05), ultimately resulting in shorter progression-free (HR=3.5; CI:1.3-9.4; p= 0.088) and overall survival (median not reached, p = 0.005).
Conclusions
A Maturation Index defined NDMM pts with an advanced differentiation status both at immunophenotypic and molecular level, finding lastly associated with a prevalence of poor prognostic features. Chromosomal instability, together with cellular phenotypic plasticity, represents an important, yet poorly defined, mechanism by which MM clones accelerate their own evolution and survival.
Acknowledgements: AIRC_IG2014-15839, RF-2016-02362532.
Mancuso: Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Zamagni:Sanofi: Honoraria, Other: Advisory Board, Speakers Bureau; Celgene Corporation: Honoraria, Other: Advisory board, Speakers Bureau; Janssen: Honoraria, Other: Advisory board, Speakers Bureau; Amgen: Honoraria, Other: Advisory board, Speakers Bureau; BMS: Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Tacchetti:Oncopeptides: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria. Zinzani:CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
| v2 |
2019-11-22T00:52:14.652Z | 2019-11-13T00:00:00.000Z | 209248860 | s2ag/train | Prognostic Impact of a Composite Genetic Profile Defined By Cytogenetics and Next Generation Sequencing at Diagnosis on Treatment Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia
Introduction: The introduction of next-generation sequencing (NGS) has expedited the discovery of novel genetic lesions in acute myeloid leukemia (AML), thereby allowing better risk stratification with respect to overall survival (OS). We have previously reported that AML patients with PTPN11 and NPM1 mutations had longer OS following chemotherapy, while those carrying mutations in ASXL1, JAK2, RUNX1, TP53 and SRSF2 had a shorter OS (Daher-Reyes,ASH 2018). Little is known, however, regarding the impact of genetic profiles (somatic mutations and cytogenetic abnormalities) at initial AML diagnosis on the treatment outcomes following allogeneic hematopoietic stem cell transplantation (HCT).
Methods & Patients: We enrolled AML patients who had available NGS data at time of initial diagnosis as part of the AGILE project between February 2015 and December 2018, and who subsequently underwent allogeneic HCT. NGS was performed on DNA samples isolated from peripheral blood or bone marrow samples at diagnosis. Analysis was performed using the TruSight Myeloid Sequencing Panel on the MiSeq sequencer (Illumina; San Diego, CA). Transplant outcomes (overall survival (OS), relapse-free survival (RFS), relapse incidence (RI), and non-relapse mortality (NRM)) after HCT were compared according to genetic profiles defined at diagnosis. Survival analysis for OS and RFS was performed using Cox's proportional hazard model, while the Fine-Gray model was used for RI and NRM analyses. Variables considered in the model included CR status prior to HCT (CR1 vs. beyond CR1), de novo AML (vs. secondary/therapy-related AML), induction chemotherapy used (3+7 vs. others), conditioning regimen (myeloablative vs. reduced intensity), WBC, age, donor type, mutation status of commonly mutated genes, and the composite adverse genetic profile (defined as having at least one of monosomal karyotype (MK), TP53 mutation, del(5), complex karyotype (CK), and monosomy 7), given that these 5 features were highly co-occurring, adverse prognostic factors (Figure 1A).
Results: We identified 435 patients in whom frontline NGS was performed, of whom a total of 178 patients (40.9%) received HCT and were included in the final analysis. A total of 598 (median 4, IQR 2-5) mutations were identified in 165 patients (n=165/178, 92.7%). Among 54 genes in the panel, 12 genes were mutated in more than 10% of the cohort, with the most commonly mutated genes being DNMT3A (30.3%), TET2 (25.3%), NPM1 (22.5%), RUNX1 (18.5%), IDH2 (16.9%), FLT3 (15.7%), ASXL1 (12.4%), BCOR (12.4%), CEBPA (11.2%), NRAS (11.2%), IDH1 (10.1%), and SRSF2 (10.1%).
In univariate analysis, the groups with a composite adverse genetic profile (n=30/178, 16.9%) showed decreased OS (HR 2.19 [1.30-3.67]; p=0.003), while patients harbouring spliceosome gene (SF3B1, SRSF2, U2AF1, and ZRSR2) mutations (n=37/178, 20.8%) had longer OS (HR 0.39 [0.18-0.85]; p=0.018), with 2-year OS rates of 24.9% and 57.9%, respectively (p=0.002)) (Figure 1B). The composite adverse genetic profile was also associated with shorter RFS (HR 2.23 [1.34-3.69]; p=0.002), while spliceosome gene mutations were associated with longer RFS (HR 0.42 [0.20-0.88]; p=0.022), with 2-year RFS rates of 23.7% vs. 57.9%, respectively (p=0.001)). The composite adverse genetic profile was also associated with higher RI (HR 2.94 [1.52-5.66]; p=0.001), with 2-year RI rates of 47.2% vs. 17.2%, respectively, for patients with and without adverse genetic features (p=0.002) (Figure 1C). Neither the composite adverse genetic profile, nor spliceosome gene mutations, were associated with NRM, with HR of 1.21 [0.55-2.65], p=0.64) and 0.45 [0.16-1.31], p=0.15, respectively (Figure 1D). Multivariate analyses confirmed that the composite adverse genetic profile and spliceosome gene mutations were independent prognostic factors for OS, RFS, and RI (p=0.004, p=0.002, and p=0.001, respectively) and for OS and RFS (p=0.020 and p=0.022, respectively).
Conclusion: In our cohort, the composite adverse genetic profile (i.e. having at least one of MK, TP53 mutation, del(5), CK and monosomy 7 remained as a poor prognostic factor even after allogeneic HCT. To clarify the role of genetic risk stratification in HCT, further analysis using a larger cohort is warranted. In addition, a comparative analysis between HCT vs no-HCT groups according to the genetic profile, is ongoing in a in a larger patient cohort.
Figure 1
Michelis: CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Celgene: Honoraria; Therakos: Honoraria. Schimmer:Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding. McNamara:Novartis Pharmaceutical Canada Inc.: Consultancy. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gupta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yee:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Minden:Trillium Therapetuics: Other: licensing agreement. Schuh:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2020-12-14T20:14:29.485Z | 2020-11-05T00:00:00.000Z | 228919090 | s2ag/train | Immunologic Predictors for Clinical Responses in Patients with Myelodysplastic Syndromes Treated with Immune Checkpoint Blockade
Backgound Myelodysplastic Syndrome (MDS) is a disorder in hematopoiesis where mutations may alter the epigenetic landscape facilitating leukemogenesis. Such epigenetic alterations may contribute to the immune-dysregulation leading to ineffective anti-tumor immunity required for the immune-surveillance during cancer immune-editing process. Hypomethylating agents (HMAs) such as 5-azacytidine and 5-aza-2' deoxycytidine are standard treatment for patients with high risk MDS. Resistance to HMAs ultimately occurs in most MDS patients leading to treatment failure. The expression of immune checkpoint proteins on leukemia blasts and immune cells from MDS patients during HMA treatment was reportedly increased, and is thought to be one of acquired immune-mechanism of resistance to HMA. Therefore, the combination therapy with HMA and immune checkpoint blockade have been tried to provide additional immune-pressure to shift this equilibrium in tumor microenvironment towards tumor elimination, through the promotion of inflammation, putative neo-antigen presentation, and anti-tumor immune responses in MDS. However, there are limited data on biomarkers for response to facilitate the patient selection and beneficial combinations.
Aims This study investigates whether the immunotherapy (IMT) using immune checkpoint blockade in combination with hypomethylating agent (HMA) can restore anti-tumor T cell responses eradicating leukemic clones, and attempt to determine the immune-related biomarkers to predict effective anti-Tumor immunity in MDS.
Methods Peripheral blood samples from 55 MDS patients who receive IMT (aCTLA and/or aPD1) +/- HMA, and HMA alone were collected at pre- and post-treatments. Comprehensive immunophenotypic analysis by multiparameter flow cytometry, next generation sequencing (NGS)-based TCR sequencing, immune-related gene expression profiling by NanoString Technologies, and NGS-based targeted sequencing were performed.
Results Thirty-seven patients who received IMT+/-HMA, and 18 patients who received with HMA alone were included in the analysis. We further divided 37 patients receiving IMT+/-HMA into responder (n=21) and non-responder (n=16), and 18 patients receiving HMA into responder (n=12) and non-responder (n=6). The patients who received aCTLA-4 blockade +/- HMA (n=28) showed significant increases in activated T cells, central memory T cells, and Treg after C#1 treatment, compared to those who received aPD-1 blockade +/- HMA (n=9) or HMA alone (n=18). When we evaluated the changes of immune cell subsets post treatment in relation to clinical response, a significant increase in central memory CD8+ T cells was associated with clinical responses in patients with IMT+/-HMA but not with HMA alone. Additionally, we found that the increase in clonality after 1 cycle of treatment was shown for responders (p=0.03), in contrast there was no marked change in clonality for non-responders. Next, immune signature in tumor immune-microenvironment (TIME) associated with response during IMT were evaluated. Among the responders, the expression of genes related to processes such as the adaptive immune system, cell adhesion, host-pathogen interaction, lymphocyte activation, and T cell receptor signalling significantly increased after IMT +/- HMA treatment. Lastly, we evaluated whether non-synonymous mutations detected at pre-treatment correlated to the clinical response. Responders among patients with IMT+/- HMA (p=0.0043) but not HMA alone showed a trend toward higher burden of individual mutations than those of non-responders, suggesting the presence of potential neoantigens may drive antigen specific expansion of central memory CD8+ T cells in responders during immunotherapy.
Conclusions The results demonstrated that aCTLA4 but not aPD-1 blockade elicited significant increases in activated T cell, central memory T cell, and Treg frequencies. Significant expansion of central memory CD8+ T cells and clonal expansion of T cells were associated with clinical response in MDS patients who received IMT +/- HMA. In addition, distinct immune microenvironment signature and higher individual mutation burden were observed in responders among MDS patients who received IMT+/-HMA. Further investigation is warranted to determine the immunological and genetic factors critical for effective anti-Tumor immunity in MDS patients during immunotherapy.
Champlin: Takeda: Patents & Royalties; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Omeros: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding. Kantarjian:BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Immunogen: Research Funding; Sanofi: Research Funding; Jazz: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Garcia-Manero:Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding.
| v2 |
2019-03-19T13:06:44.290Z | 2003-10-10T00:00:00.000Z | 82883970 | s2ag/train | Fundamental Bacterial Genetics
1. Introduction To The Cell.The Molecules That Make Up A Cell.The Bacterial Cell: A Quick Overview.How Do Cells Grow?.What Is Genetics?.Summary.2. The Bacterial Dna Molecule.The Structure Of DNA And RNA.Deoxyribonucleosides And Deoxyribonucleotides.DNA Is Only Polymerized 5' To 3'.Double-Stranded Dna.Supercoiling Double-Stranded Dna.Replication Of The Escherichia Coli Chromosome.Constraints That Influence Dna Replication.The Replication Machinery.Dna Polymerases.Dnag Primase.Replication Of Both Strands.Theta Mode Replication.Minimizing Mistakes In Dna Replication.The Dna Replication Machinery As Molecular Tools.Summary.3. Mutations.Phenotype And Genotype.Classes Of Mutations.Point Mutations And Their Consequences.Measuring Mutations: Rate And Frequency.Spontaneous And Induced Mutations.Errors During Dna Replication: Incorporation Errors.Errors Due To Tautomerism.Spontaneous Alteration By Depurination.Spontaneous Alteration By Deamination.Alterations By Spontaneous Genetic Rearrangement.Alterations Caused By Transposition.Induced Mutations.Chemicals That Mimic Normal Dna Bases: Base Analogues.Chemicals That React With Dna Bases: Base Modifiers.Chemicals That Bind Dna Bases: Intercalators.Mutagens That Physically Damage The Dna: Ultraviolet Light And Ionizing.Radiation.Mutator Strains.Reverting Mutations.Suppression.Ames Test.How Have We Exploited Bacterial Mutants.Summary.4. Dna Repair.Lesions That Constitute Dna Damage.Reverse, Excise Or Tolerate?.Mechanisms That Reverse Dna Damage.Photoreactivation.O6-Methylguanine Or O4-Methylthymine Methyltransferase.Mechanisms That Excise Dna Damage.Uvrabc Directed Nucleotide Excision Repair.Muthls Methyl Directed Mismatch Repair.Very Short Patch Repair.Glycosylases.Uracil-N-Glycosylase Coupled With Ap Excision Repair.Deaminated Bases Removed By Dna Glycosylase.Alkylated Bases Removed By Dna Glycosylase.Mutm/Muty: Oxidative Damage.N-Glycosylases Specific For Pyrimidine Dimmers.Mechanisms That Tolerate Dna Damage.Transdimer Synthesis.Post Replication/Recombinational Repair (Prr).Introduction To The Sos Regulon.Summary.5. Recombination:.Homologous Recombination.Models For Homologous Recombination.The Holliday Or Double-Strand Invasion Model Of Recombination.An Alternative To The Holliday Model: The Single Strand Invasion Model Of Meselson And Radding.Further Enzymatic Considerations.Site-Specific Recombination.A Typical Site-Specific Recombinational Event.Bacteriophage l:A Model For Site-Specific Recombination.Other Examples Of Site-Specific Recombination.Illegitimate Recombination.Summary.6. Transposition.The Structure Of Transposons.The Frequency Of Transposition.The Two Types Of Transposition Reactions.The Transposition Machinery.The Transposition Machinery Accessory Proteins Encoded By The Transposon.The Transposition Machinery: Accessory Proteins Encoded By The Host.Non-Replicative Transposition.Replicative Transposition.Does The Formation Of A Cointegrate Predict The Transposition Mechanism?.The Fate Of The Donor Site.Target Immunity.Transposons As Molecular Tools.Summary.7. Bacteriophage.The Structure Of Phage.The Life Cycle Of A Bacteriophage.Lytic-Lysogenic Options.The l Lifecycle.l Adsorption.l Dna Injection.Protecting The l Genome In The Bacterial Cytoplasm.What Happens To The l Genome After It Is Stabilized?.l And The Lytic-Lysogenic Decision.The l Lysogenic Pathway.The l Lytic Pathway.Dna Replication During The l Lytic Pathway.Making l Phage.Getting Out Of The Cell-The l S And R Proteins.Induction Of By The Sos System.Superinfection.Restriction And Modification Of Dna.The Lifecycle Of M13-M13 Adsorption And Injection.Protection Of The M13 Genome.M13 Dna Replication.M13 Phage Production And Release From The Cell.The Lifecycle Of P1.Adsorption, Injection And Protection Of The Genome.P1 Dna Replication And Phage Assembly.The Location Of The P1 Prophage In A Lysogen.P1 Transducing Particles.The Lifecycle Of T4-T4 Adsorption And Injection.T4rii Mutations And The Nature Of The Genetic Code.Summary.8. Transduction.Generalized Transduction Vs Specialized Transduction.P1 As A Model For Generalized Transducing Phage.Packaging The Chromosome.Moving Pieces Of The Chromosome From One Cell To Another.Identifying Transduced Bacteria: Selection Vs Screen.Carrying Out A Transduction.Uses For Transduciton.Two Factor Crosses To Determine Gene Linkage.Mapping The Order Of Genes- Three Factor Crosses.Uses For Transduction-Strain Construction.Uses For Transduction-Localized Mutagenesis.Specialized Transducing Phage.Making Merodiploids With Specialized Transducing Phage.Moving Mutations From Plasmids To Specialized Transducing Phage To The.Chromosome.Summary.9. Natural Plasmids.Origins Of Replication.Plasmid Copy Number.Setting The Copy Number.Plasmid Incompatibility.Plasmid Amplification.Other Genes That Can Be Carried By Plasmids.Plasmids Can Be Circular Or Linear Dna.Broad Host Range Plasmids.Moving Plasmids From Cell To Cell.Summary.10. Conjugation:.The F Factor.The R Factors.The Conjugation Machinery.Transfer Of The Dna.Surface Exclusion.F, Hfr Or F-Prime.Formation Of The Hfr.Transfer Of Dna From An Hfr To Another Cell.Formation Of F-Primes.Transfer Of F-Primes From One Cell To Another.Genetic Uses Of F-Primes.Genetic Uses Of Hfr Strains-Mapping Genes On The E. Coli Chromosome Using Hfr.Crosses.The 50% Rule.Using Several Hfr Strains To Cover The Chromosome.Mobilization Of Non-Conjugatible Plasmids By R And F.Conjugation From Prokaryotes To Eukaryotes.Summary.11. Transformation:.Natural Competency.The Process Of Natural Transformation.The Machinery Of Naturally Transformable Cells.Artificial Transformation.Transformation As A Genetic Tool: Gene Mapping.Transformation As A Molecular Tool.Summary.12. Gene Expression And Regulation.The Players In The Regulation Game.Operons And Regulons.Repression Of The Lac Operon.Activation Of The Lac Operon By Cyclic Amp And The Cap Protein.Regulation Of The Tryptophan Biosynthesis Operon By Attenuation.Regulation Of The Heat Shock Regulon By An Alternative Sigma Factor, Mrna Stability And Proteolysis.Regulation Of The Sos Regulon By Proteolytic Cleavage Of The Repressor.Two Component Regulatory Systems, Signal Transduction And The Cps Regulon.Summary.13. Plasmids, Bacteriophage And Transposons As Tools.What Is A Cloning Vector?.Why Not Use Naturally Occurring Plasmids As Vectors?.The Importance Of Copy Number.An Example Of How A Cloning Vector Works-Pbr322.Multiple Cloning Sites.Determining Which Plasmids Contain An Insert.Expression Vectors.Vectors For Purifying The Cloned Gene Product.Vectors For Localizing The Gene Product.Vectors For Studying Gene Expression.Shuttle Vectors.Artificial Chromosomes.Constructing Phage Vectors.Suicide Vectors.Phage Display Vectors.Combining Phage Vectors And Transposons.Summary.14. DNA Cloning:.Isolating DNA From Cells - Plasmid DNA Isolation.Isolating DNA From Cells - Chromosomal DNA Isolation.Cutting DNA Molecules.Type I Restriction-Modification Systems.Type II Restriction-Modification Systems.Type III Restriction-Modification Systems.Restriction-Modification As A Molecular Tool.Generate Double Stranded Breaks In DNA By Shearing The Dna.Joining DNA Molecules.Manipulating The Ends Of Molecules.Visualizing The Cloning Process.Constructing Libraries Of Clones.DNA Detection - Southern Blotting.DNA Amplification: Polymerase Chain Reaction.Adding Novel Dna Sequences To The Ends Of A Pcr Amplified Sequence.Site Directed Mutagenesis Using Pcr.Cloning And Expressing A Gene.Dna Sequencing Using Dideoxy Sequencing.Dna Sequence Searches.Summary.15. Bioinformatics And Proteomics.Bioinformatics.Strategies For Sequencing Genomes.Bacterial Genomes.Analyzing Genomes.The E. Coli K-12 Genome.Proteomics.Techniques For Examining The Proteome-Sds-Page And 2-Dimensional Sds-Page.Techniques For Examining The Proteome-Microarray Technology.Summary.Glossary.Additional References. | v2 |
2017-10-20T07:56:03.965Z | 2001-01-01T00:00:00.000Z | 31445360 | s2ag/train | Ninth Work Plan , Feeds and Fertilizers Research 4 ( 9 FFR 4 ) Final Report
An on-farm trial was conducted on seven farms in Nueva Ecija, Philippines, to investigate the effect of two onsets of feeding on the growth, yield, and survival of Nile tilapia. There were no significant differences in the performance data (final mean weight, daily weight gain, extrapolated gross fish yield, and survival rate) that were recorded in this study. The only statistically significant difference observed was in the total feed used in the trial. The 45-day onset in feeding produced more gross value of the crop (P205,617 ha-1) compared with the 75-day delay (P197,063 ha-1), but by delaying the start of feeding, the costs were reduced such that the net value of the crop was improved (P124,242 ha-1 in 75-day versus P106,026 ha-1 in 45-day delay). EIGHTEENTH ANNUAL TECHNICAL REPORT 34 total feed used in the trial. The extrapolated total feed used was 8,299 and 6,068 kg ha-1 for 45-day and 75-day delays in feeding, respectively. The growth patterns of tilapia in the two feeding schemes are shown in Figure 1. The simple cost/benefit analysis of this farm trial, taking into consideration the gross sales and the cost of feed, indicated that the 45-day onset in feeding produced more gross value of the crop (P205,617 ha-1) compared with the 75-day delay (P197,063 ha-1), but by delaying the start of feeding, the feed cost was reduced such that the net value of the crop was improved (P124,242 ha-1 in 75-day versus P106,026 ha-1 in 45-day delay; US$1 = P45). Table 2 presents the range of values of the water quality parameters measured at monthly intervals. Water quality parameters appeared to be within the acceptable ranges for tilapia culture and there were no treatment-dependent differences that were observed. This study provides technical guidance to farmers on the efficient feeding practices that will optimize tilapia production. The on-farm trial indicated that a delay in the onset of feeding did not significantly reduce the production of tilapia but significantly reduced the cost of feed by about 37%. It is important, however, that proper pond fertilization be maintained to promote the production of natural foods in the pond. ANTICIPATED BENEFITS A simple technique has been identified which reduces production costs by the equivalent of about $400 per hectare 0 30 60 90 120 150 180 30 45 60 75 90 105 120 135 150 Culture period (d) Early Delayed M e a n b o d y w e ig h t (g ) Figure 1. Mean body weight of Nile tilapia in the early (45 days) and delayed (75 days) feeding onset trials. Table 1. On-farm growth performance of Nile tilapia at two periods of delay before feeding (45 and 75 days) in a 150-day experiment. Table 2. Range of values for water quality parameters measured monthly over a 150-day culture period in ponds fed 45 days (Pond A) and 75 days (Pond B) after stocking of tilapia. Performance Treatment (Feeding Onset) 45 Days 75 Days Final Mean Weight (g fish) 164.7 151.7 Mean Daily Weight Gain (g fishd) 1.09 1.01 Extrapolated Gross Fish Yield (kg ha) 5,140 4,926 Survival (%) 85 87 Total Amount of Feed (kg ha) 8,299 6,068 Farm Pond (A = 45 d) (B = 75 d) Secchi Disk Visibility (cm) DO (mg l) Temperature (C) pH Alkalinity (mg l) Ammonia (mg l) Phosphorus (mg l) A 7–23 4–10 28–31 7.8–8.9 36–95 0.08–0.17 0.18–0.80 1 B 8–28 3–9 28–31 7.6–9.9 42–87 0.03–0.33 0.29–0.56 A 9–59 9–15 31–35 8.6–9.1 112–156 0.12–0.36 0.06–0.85 2 B 14–60 11–16 31–38 8.4–9.6 92–220 0.10–0.30 0.06–0.62 A 15–30 11–12 30–31 8.4–10.3 49–81 0.02–0.26 0.08–0.13 3 B 15–54 8–13 29–31 8.0–10.3 56–93 0.05–0.32 0.07–0.45 A 12–32 9–12 30–32 7.9–9.7 150–162 0.10–0.35 0.27–0.37 4 B 10–22 9–11 29–31 8.0–10.4 115–140 0.03–0.37 0.03–0.30 A 9–65 6–16 29–32 8.0–9.9 127–175 0.05–0.25 0.14–0.68 5 B 11–65 5–14 29–32 8.0–9.5 119–230 0.03–0.35 0.11–0.35 A 8–50 14–20 31–32 7.7–9.6 112–210 0.11–0.28 0.18–0.77 6 B 12–46 14.6–20 31–34 7.7–9.5 86–207 0.05–0.24 0.09–0.63 A 8–40 4–15.4 29–33 8.4–9.7 239–302 0.06–0.22 0.04–0.51 7 B 9–28 5–12 29–33 8.4–9.7 271–345 0.09–0.10 0.10–0.57 FEEDS AND FERTILIZERS RESEARCH 35 Cite as: [Author(s), 2001. Title.] In: A. Gupta, K. McElwee, D. Burke, J. Burright, X. Cummings, and H. Egna (Editors), Eighteenth Annual Technical Report. Pond Dynamics/Aquaculture CRSP, Oregon State University, Corvallis, Oregon, [pp. ___.] during a tilapia grow-out cycle without significantly reducing yields. That is a meaningful amount of money (P2,200) in the Philippines, especially considering the increased profit is the result of reduced effort on the part of the farmers. Following effective dissemination of these results (see “Workshop on the timing of the onset of supplemental feeding of Nile tilapia (Oreochromis niloticus) in ponds,” 9ADR6A and “Production of improved extension materials,” 9ADR6B), it is expected that the technique of providing commercial feeds to tilapia later in the grow-out period will be broadly adopted, resulting in more cost-effective and profitable farming. It is also possible that the time gained by adding a month of very low-maintenance farming will facilitate other farm activities, such as vegetable gardening or other crop diversification, or educational and training activities. ACKNOWLEDGMENTS We wish to acknowledge the support of the farmer-cooperators who willingly made available their pond facilities for this study. | v2 |
2019-03-28T13:34:02.800Z | 2018-11-29T00:00:00.000Z | 86425010 | s2ag/train | Noninvasive Genotyping and Monitoring of Classical Hodgkin Lymphoma
Introduction: Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) have an emerging diagnostic role in multiple malignancies including in lymphomas (Kurtz et al ASH 2017). In classical Hodgkin Lymphoma (cHL), malignant Reed Sternberg (RS) cells are rare, requiring laser capture microdissection from archival tissues or flow sorting from viable tumor cell suspensions for genotyping. We profiled ctDNA in cHL to assess the utility of ctDNA in the noninvasive evaluation of somatic single nucleotide variants (SNVs), somatic copy number alterations (SCNAs), and tumor EBV status.
Methods: A total of 53 subjects with HL (29 with early stage and 24 with advanced disease) were studied encompassing a total of 95 blood and tissue samples (72 from Stanford, 23 from UZ Leuven). Plasma samples were sequenced with CAPP-Seq (Newman et al Nat Biotech 2016), using a panel informed by the genotyping of primary tumor biopsies. The genotypes of cHL patients were compared to that of 189 patients with other B-cell malignancies. Given the thoracic distribution of most cHL, we also compared ctDNA levels to that of 55 lung carcinomas. ctDNA levels were calculated as the product of the cfDNA concentration and the mean allelic fraction of somatic mutations.
Results: The median pretreatment ctDNA level in cHL was 125 hGE/mL (15 - 5277 hGE/mL), corresponding to a median variant allelic fraction (VAF) of 3.2% (0.3 - 13.9%) (Fig 1A). Pretreatment ctDNA burden was greater in cHL cases than in follicular lymphoma (FL) cases (p = 0.002), but was not significantly different from that of diffuse large B-cell lymphoma (DLBCL) (p = 0.26). Plasma genotyping in cHL and DLBCL also identified similar numbers of SNVs, recovering a median of 108 mutations in cHL and 117 mutations in DLBCL (p = 0.53). In samples with available diagnostic PET/CT, pre-treatment ctDNA levels in cHL were significantly correlated with total metabolic tumor volume (MTV) (Spearman ρ = 0.615, p = 0.006) (Fig 1B), but not with diagnostic PET/CT SUVmax, stage, bulky status (>10 cm), B-symptoms, or presence of extranodal disease. Surprisingly, despite the lower tumor purity of RS cells in cHL tumor masses than that of malignant B-cells in DLBCL, the relationship between ctDNA and PET/CT estimates of disease burden in cHL was highly similar to that of DLBCL. Specifically, cHL and DLBCL were statistically indistinguishable for the ratio between ctDNA levels and MTV (mean ctDNA/MTV of 2.1 vs 1.5 hGE/mL per cm3 tumor, p = 0.38), and both were significantly higher than that of non small cell lung carcinoma (NSCLC) (p < 0.0001) (Fig 1C). In patients with available mid-treatment cfDNA (n = 10), we monitored ctDNA concentrations and observed that circulating tumor burden falls rapidly, with a third of our patients reaching undetectable levels within the first month after start of therapy.
PD-L1 copy number gains, previously shown to be prognostic for survival in cHL treated with checkpoint inhibitors, were observed in 42% of cHL patients with ctDNA VAFs above our SCNA limit of detection (1%) and were genotyped significantly more frequently than in other non-PMBCL B-cell malignancies (42% vs 18%, p = 0.005) (Fig 1D). Coding SNVs in the most commonly mutated genes involved STAT6 (24%), SOCS1 (20%), GNA13 (20%), TNFAIP3 (18%), and B2M (16%) while noncoding SNVs in IGK and IGH were more abundant in cHL and DLBCL respectively (Fig 1E). EBV tumor cell presence has previously been shown to be prognostic in cHL (Keegan et al JCO 2005). Prior to therapy, EBV cfDNA constituted a significantly larger fraction of total cfDNA in patients confirmed by EBER ISH to have EBV+ cHL than in either EBER-negative cHL patients or healthy controls (p < 0.0001) (Fig 1F).
Conclusions: Levels of ctDNA in cHL are higher than might be expected based on tumor purity, with pre-treatment levels similar to DLBCL and higher than FL. ctDNA allows for reliable noninvasive genotyping of cHL at diagnosis, encompassing coding and non-coding SNVs and additional clinically significant factors such as tumor EBV status and SCNAs. Additional cases are currently being profiled and expanded analyses of genotyping and monitoring will also be presented at the meeting.
Dührsen: Celgene: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Research Funding; Gilead: Consultancy, Honoraria. Hüttmann:Roche: Other: Travel expenses; Celgene: Other: Travel expenses. Gaidano:Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Morphosys: Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Advani:Regeneron: Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Infinity: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Agensys: Research Funding; Forty Seven Inc.: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Merck: Research Funding.
| v2 |
2022-12-18T16:03:22.545Z | 2022-10-01T00:00:00.000Z | 254808640 | s2ag/train | 2022-RA-1020-ESGO Family history in BRCA mutation carriers affected by breast and ovarian cancer and its role in identifying subjects at high risk
2022-RA-983-ESGO Table 1 Methodology The objective of this monocentric prospective study was to analyze the prevalence of AIN2–3 among women treated for CIN2–3. Exclusion criteria were: age <25 years, previous HPV vaccination, immunosuppression, HIV infection and a history of anorectal cancer. All patients enrolled in the study underwent anal cytology and anal high-risk HPV-DNA testing (aHPV-DNA). If one or both tests were positive a high-resolution anoscopy with biopsy of suspicious lesions was performed. All women also completed a questionnaire on a sexual habit. Results A total of 100 women were enrolled between 2019 and 2021. Among these, eight patients had a concomitant or past diagnosis of anogenital warts, while one patient had a previous diagnosis of VaIN-HSIL. Anal Pap smears were positive for low-grade lesions in three patients, while 73 women tested positive for aHPV-DNA. Histological examination revealed the presence of AIN2–3 lesions in four patients, who subsequently underwent excisional treatment. Although 50% of aHPV-DNA positive women reported having anal intercourse, as many as 45% of these declared they used condoms. Conclusion Women with CIN2–3 are at high-risk of developing AIN2–3, although to date no recommendations regarding prevention and treatment of AIN in this group of patients are available. Barrier methods aren’t always effective to prevent anal HPV infection, probably due to the fact that the cervix is a reservoir of the infection. 2022-RA-1020-ESGO FAMILY HISTORY IN BRCA MUTATION CARRIERS AFFECTED BY BREAST AND OVARIAN CANCER AND ITS ROLE IN IDENTIFYING SUBJECTS AT HIGH RISK Serena Negri, Elena de Ponti, Federica Paola Sina, Elena Sala, Cristina Dell’Oro, Gaia Roversi, Sara Lazzarin, Martina Delle Marchette, Alessandra Inzoli, Claudia Toso, Simona Fumagalli, Ornella Campanella, Joanne Kotsopoulos, Robert Fruscio. Clinic of Obstetrics and Gynaecology, Department of Medicine and Surgery, University of MilanoBicocca, Milano, Italy; Department of Physical Medicine, ASST Monza, San Gerardo Hospital, Monza, Italy; UOC Gynecologic Surgery, ASST Monza, San Gerardo Hospital, Monza, Italy; UO Medical Genetics, ASST Monza, San Gerardo Hospital, Monza, Italy; UOC Gestione Sanitaria delle Convenzioni, ATS Brianza, Lecco, Italy; President of aBRCAdabra ONLUS, Italian advocacy BRCA genes mutation, Italy; Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada 10.1136/ijgc-2022-ESGO.812 Introduction/Background BRCA1 and BRCA2 mutations are the most common cause of hereditary breast and ovarian cancer, and are also associated with an increased risk of prostate and pancreatic cancer.Many guidelines have been provided over time to identify BRCA mutation carriers, and they are usually based on a suggestive personal and family history (FH) of cancer. Addressing affected patients to genetic counseling can lead to therapeutic benefits, however identifying healthy high risk individuals before they develop cancer could give them the opportunity to access appropriate surveillance and risk-reducing treatments. Methodology We applied the family history (FH) criteria proposed by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) and the Italian Association of Medical Oncology (AIOM) guidelines to the FH of 157 women who found out to be BRCA mutations carriers after a diagnosis of breast or ovarian cancer. Results A FH of BRCA-related cancer was found in almost 85% of women. NCCN and AIOM FH criteria would have detected 63.6% and 52.2% of patients respectively before tumor diagnosis (p<0,05). The most frequent criteria were a FH of ovarian cancer and of breast cancer diagnosed <45 years old. 65% of the women who died from progression of Abstracts A378 Int J Gynecol Cancer 2022;32(Suppl 2):A1–A504 on D ecem er 4, 2022 by gest. P rocted by coright. http/ijgc.bm jcom / nt J G ynecol C acer: frst pulished as 10.11ijgc-2022-E S G O .12 on 20 O cber 222. D ow nladed fom disease would have been eligible for testing based on their FH. Conclusion Family history should always be investigated and specific sets of criteria should be included in guidelines independently from a personal history of cancer. 2022-RA-1032-ESGO EVALUATION OF INTRAOPERATIVE HPV TEST AS AN EARLY MARKER OF RESIDUAL DISEASE AFTER HSIL SURGICAL TREATMENT. A PROSPECTIVE MULTICENTER STUDY. PRELIMINARY RESULTS Melissa Bradbury, Ursula Acosta, Alfonso Quesada, Jose A Lopez-Fernandez, Jose Quilez, Cristina Centeno, Antonio Gil, Multicenter VPH IOP Team. Gynecology, Hospital Vall d’Hebron. Barcelona SPAIN, Barcelona, Spain; Gynecology, Hospital Nuestra Señora de la Candelaria, Tenerife, Spain; Gynecology, Hospital General Alicante, Alicante, Spain; Gynecolgy, Hospital de Basurto, Bilbao, Spain 10.1136/ijgc-2022-ESGO.813 Introduction/Background Objective To evaluate if the intraoperative human papillomavirus (IOP-HPV) test has the same prognostic value as the HPV test performed 6 months after treatment of high-grade squamous intraepithelial Lesion (HSIL) to predict treatment failure. Methodology Design Prospective multicenter cohort studySetting: 22 Referral Hospitals in Spain.Population: 1824 women treated for cervical HSIL by Loop Electrosurgical Excision between May 2020 and December 2021 After LEEP an HPV test was performed immediately after excision using a Cobas (83%) or other genotyping test. Subsequently, pacients were followed with citology and HPV test, 6, 12 and 24 months after treatment. The IOP-HPV test was compared with HPV test 6 months after procedure and with surgical margins in order to detect residual disease. Results We described results of the first 992 cases with the 6 month co-test performed. IOP HPV test was feasible (valid result 98,5%). IOP-HPV was positive in 40%, while only 25% at 6 month test. We observed association between the IOP and 6 month HPV test (ChiSquare p= 0.0001), IOP HPV positivity and abnormal citology at 6 months (p=0.063), and positive IOP HPV test and positive surgical margins. (p=0.0001) Conclusion Preliminary results show that IOP HPV test could be a satisfactory prognostic factor of cervical HSIL treatment result. 2022-RA-1049-ESGO PATIENTS WITH TP53 MUTATION FOLLOWED UP IN A HEREDITARY GYNAECOLOGICAL CANCER UNIT Amanda Veiga-Fernández, Ainoa Sáez Prat, Juan Manuel Pina Moreno, Laura Pérez Burrel, Mercedes Sánchez Rodríguez, Rocío Aracil Rodríguez, Isabel Echavarria Díaz-Guardamino, Patricia Rincón Olbes, Elsa Mendizábal Vicente, Santiago Lizarraga Bonelli. Obstetrics and Gynecology, Gregorio Marañon University General Hospital, Madrid, Spain; Medical Oncology, Gregorio Marañon University General Hospital, | v2 |
2018-01-24T17:25:33.048Z | 2017-02-01T00:00:00.000Z | 38551250 | s2ag/train | P625 Ustekinumab use in Crohn's disease: effectiveness of dose escalation.
s of the 12th Congress of ECCO – European Crohn’s and Colitis Organisation S401 ing data on response of perianal fistulas with UST. However, larger studies are required to confirm these findings. P627 Surrogate markers of mucosal healing in Crohn’s disease patients in clinical remission under biological/immunomodulator treatment S. Siakavellas*, A. Kostas, C. Kosmidis, M. Gizis, G. Papatheodoridis, G. Bamias National & Kapodistrian University of Athens, Academic Dpt. of Gastroenterology, Athens, Greece Background: Mucosal healing is a desired endpoint in both clinical trials and “real-life” practice as it has been associated with better outcomes in patients with IBD. Lower GI endoscopy is required to determine the presence or absence of mucosal healing. Our aim was to assess specific biomarkers that could accurately predict (either alone or in combination) the presence of mucosal healing in Crohn’s disease (CD) patients under long-term anti-TNF and/or immunomodulator treatment. Methods: Eligible patients were those with CD who were on clinical remission for at least 6 months under stable treatment with anti-TNF and/or immunomodulators. Prior to endoscopy all patients were subjected to thorough workup every two months with recordings of Harvey-Bradshaw index score and selected laboratory tests that included fecal calprotectin and serological inflammatory markers. After the end of this 6 month period, colonoscopy was performed and mucosal healing was determined as present [complete (no inflammatory lesions) or partial (minimal inflammatory lesions)] or absent. The predictive value of several clinical and laboratory markers for the presence of mucosal healing was investigated. Results: Twenty-three patients have been recruited so far (Male=9, Age: 40.8±14.3, 19–70, mean ± SD, range, in years). Fourteen patients (60.8%) achieved mucosal healing as evidenced by lower gastrointestinal endoscopy. Patients in the “no healing” group had significantly higher fecal calprotectin values when compared to patients with mucosal healing at 2 months prior to endoscopy [“no healing” group 554 μg/gr, 235–1800 (median, interquartile range) vs. mucosal healing group 83, 33–330.5, p=0.012), 4 months prior to endoscopy (“no healing”, 600, 338–600 vs. mucosal healing 134, 22.5–272, p=0.009), as well as at 6 months prior to endoscopy respectively (“no healing”, 265.0, 142–482.5 vs. mucosal healing 64, 13.8–199, p=0.039). No significant differences between the two groups were observed regarding CRP levels. Moreover, higher amylase values were found in the “no healing group” in comparison to the healed mucosa group at 6 months prior to endoscopy (91.1 IU/L ± 24.8 vs. 63.1±27.2, mean ± SD, p=0.02). Finally, smokers had less often mucosal healing (p<0.0001) and higher CRP and fecal calprotectin values as well, than non-smokers. Conclusions: Fecal calprotectin is a better predictor of mucosal healing than CRP in patients with CD in clinical remission. Its use in clinical practice may improve patient management by allowing the identification of patients at higher risk for disease flare, who may require closer follow up and earlier endoscopy. Funding: The present work has been funded by a grant from the Hellenic Society of Gastroenterology to Dr. Bamias. P628 Anti-TNF therapy in refractory pouchitis and Crohn’s disease-like complications of the pouch after ileal pouch-anal anastomosis following colectomy for ulcerative colitis: a systematic review and meta-analysis M. Huguet1, B. Pereira2, M. Goutte1,3, F. Goutorbe1,4, C. Allimant1, M. Reymond1, G. Bommelaer1,3, A. Buisson*1,3 1University Hospital Estaing, Gastroenterology Department, Clermont-Ferrand, France; 2University Hospital, Biostatistics Unit, DRCI, Clermont-Ferrand, France; 3UMR 1071 Inserm/Université d’Auvergne; USC-INRA 2018, Microbes, Intestine, Inflammation and Susceptibility of the host, Clermont-Ferrand, France; 4Hospital of Bayonne, Gastroenterology Department, Bayonne, France Background: Pouchitis and secondary Crohn’s disease (CD)-like complication of the pouch are the most common complications after ileal pouch-anal anastomosis following colectomy for ulcerative colitis. Data about the effectiveness of anti-TNF agents in these two entities remains sparse. We aimed to perform a systematic review and meta-analysis to evaluate the efficacy of anti-TNF therapy in differentiating patients with chronic refractory pouchitis and CD-like complications. Methods: Systematic literature search was performed in MEDLINE and from international meetings abstracts. The search process, selection of manuscripts, and data extraction were performed independently by two physicians according to PRISMA statements. Prevalence and 95% confidence interval (CI) were estimated using random-effects models assuming between and within study variability. Statistical heterogeneity between results was assessed by examining forest plots, CIand using I2 and sensitivity analyses were conducted. CD-like complications of the pouch were defined as the presence of non-anastomotic fistula and/or non-anastomotic stenosis and/or prepouch ileitis. Chronic refractory pouchitis was defined as inflammation limited to the pouch. The short term and the long term responses were evaluated at 8 weeks and 12 months, respectively. Results: We identified 21 articles and three abstracts including 313 patients treated either with infliximab (IFX) (n=194) or adalimumab (ADA) (n=119) for inflammatory complications of the pouch. The rate of complete response (CR) after anti-TNF induction therapy for inflammatory complications of the pouch was 0.51 (95% CI [0.39–0.64]; I2=0.56). The rate of short-term CR was 0.57 (95% CI [0.38–0.75]; I2=0.36) for IFX-treated patients compared to 0.38 (95% CI [0.08–0.72]; I2=0.50) for ADA-treated patients (p=0.20). The long-term rate of CR in patients treated with anti-TNF therapy was 0.52 (95% CI [0.39–0.65]; I2=0.59), with 0.59 (95% CI [0.45– 0.72]; I2=0.30) for IFX-treated patients compared to 0.30 (95% CI [0.15–0.46]; I2=0.00) for ADA-treated patients (p=0.19). The rate of CR after anti-TNF induction therapy seemed to be higher for CD-like complications of the pouch 0.64 (95% CI [0.5–0.77]; I2=0.18), compared to refractory pouchitis 0.10 (95% CI [0.08– 0.35]; I2=0.00) (p=0.06). The rate of long-term CR in patients treated with anti-TNF was 0.57 (95% CI [0.43–0.71]; I2=0.32) for CD-like complications of the pouch compared to refractory pouchitis 0.37 (95% CI [0.14–0.62]; I2=0.47) (p=0.57). Conclusions: Despite wide heterogeneity of the data, anti-TNF agents have a clear trend to have higher and faster efficacy in CD-like complications of the pouch compared to refractory pouchitis, highlighting the need to differentiate these two entities in clinical practice. Downloaded from https://academic.oup.com/ecco-jcc/article-abstract/11/suppl_1/S400/2961569 by guest on 27 July 2018 | v2 |
2019-11-07T14:51:56.018Z | 2019-08-20T00:00:00.000Z | 209375430 | s2ag/train | Preparation of Glycolether Lignin from Sugi (Cryptomeria japonica D. Don) Woodmeal by Acid-Catalyzed Solvolysis and Preparation of Heat-Resistant Polyester from the Glycolether Lignin
Preparation of glycolether lignin from Sugi (Cryptomeria japonica D. Don) woodmeal by acid-catalyzed solvolysis in 2-phenoxyethanol has been performed. The glycolether lignin had the hydroxyl content of 0.677 mmol/g and average molecular weight of 2.5×103. The glycolether lignin showed good solubility to various common organic solvents, such as methanol, ethanol, acetone, 2-butanone and chloroform. Crosslinked glycolether lignin, obtained by esterification with adipoyl chloride in acetone, showed thermal stability up to 230 °C. Key-words: Glycolether lignin, Acid-catalyzed solvolysis, Polyesters Note J. Jpn. Soc. Colour Mater., 92〔8〕,220–224(2019) 220 © 2019 Journal of the Japan Society of Colour Material -8solvents, and moderate affinity to cellulosic polysaccharides and lignins. On the other hand, hydroxy groups of these solvents are not dissociative enough to cause solvolysis of lignins solely by the solvents themselves. Therefore, catalytic amounts of inorganic acids, such as sulfuric acid, or organic sulfonic acids are required for the preparation. In the present paper, we have investigated the solubilized state of lignin condensates in 2-PhEtOH or EGMBE (referred to as glycolether lignins in the following sections) prepared by using catalytic amount of dodecylbenzene sulfonic acid. Furthermore, we have prepared aromatic polyesters from the lignin condensates by esterification with various dicarboxylic acid chlorides. We also report the thermal properties of the glycolether lignin polyesters. 2.Materials and methods 2.1 Preparation of Glycolether Lignin Condensate In a 300-mL double-necked flask equipped with thermometer and condenser placed on magnetic stirrer, 10 g of 65 mesh-passed wood meal of Sugi (Cryptomeria japonica D. Don), 10 g of 2-PhEtOH, 85 g of EGMBE, and 0.663 g (2 mmol) of dodecylbenzenesulfonic acid were mixed at 160 °C for 2 h. After cooled to the ambient temperature, the solvolysis product was collected by suction filtration by using No.2 filter paper. Solid reside on the Buffner funnel was washed with diethyleneglycol monoethyl ether (DEGMEE) and 2-butanone (100 ml each). The filtrate of reaction mixture, mixed with the wash liquid, was condensed at 120 °C for 3 h to obtain 47 g of the glycolether lignin condensate. 2.2 Characterization of Glycolether Lignin Glycolether lignin was firstly assessed for the solubility in various common organic solvents. Based on the results of solubility test, characterization of glycolether lignin in the solvated state was performed by the following methods: FTIR analysis, liquid film method on KBr with the resolution of 4 cm-1 by using Horiba FT-720 spectrometer (Horiba Corporation, Kyoto, Japan); molecular weight distribution by gel permeation chromatography by using HLC-8020 chromatograph (Tosoh Corporation, Tokyo, Japan) equipped with refractive index detector and GMHHR-M column (7.8 mm i.d.×300 mm) calibrated by polystyrene standards, to which chloroform was eluted with the flow rate of 0.8 ml/min; 1H NMR analysis (Avance DPX400, Bruker Biospin, Billerica, MA, USA, solvent: CDCl3). 2.3 Fractionation of glycolether lignin condensate Glycolether lignin condensate (47 g) was mixed with 200 ml of 1-butanol / hexane = 1/1 (v/v) and kept at 4 °C overnight. Supernatant and precipitate were separated by centrifugation (9,800×g, 4 °C, for 5 min). Supernatant was vacuum-condensed by rotary evaporator. Precipitate was washed with 1-butanol and vacuum-dried. Yield of the supernatant and precipitate was 43.5 g and 2.6 g, respectively. 2.4 Esterification of Glycolether lignin with diacid chlorides To 0.2 g of Glycolether lignin condensate dissolved in 0.3 ml of acetone, dicarboxylic acid chlorides with the corresponding molarity to hydroxy groups in glycolether lignin condensate (0.15 g of adipoyl chloride, 0.28 g of sebacoyl chloride, or 0.15 g of terephthaloyl chloride) and the corresponding amount of triethylamine were added and mixed at 4 °C. Esterification product, precipitate in acetone, was washed by acetone, methanol, and distilled water. Afterwards, the esterification product was centrifuged (9,800×g, 4 °C, for 5 min). After the supernatant was decanted, precipitated esterification product was vacuum dried at 50 °C for 1 day. Yield of the product was 0.124 g (62.2%). Characterization of the esterification product was performed by FT-IR (Horiba FT-720), observation of phase transition behaviour by hotstage-equipped optical microscopy (Nikon ECLIPSE 50i POL polarized optical microscope, Nikon Corporation, Tokyo, Japan), equipped with Linkam 10013L hotstage (Linkam Scientific Instruments, Tadworth, UK), heating rate of 10 K/min, and thermal degradability by differential scanning calorimetry (DSC, DSC-8230, Rigaku Corporation, Tokyo, Japan). 3.Results and discussion 3.1 Properties of Glycolether Lignin Condensate The obtained glycolether lignin condensate had an appearance of dark-brownish tar-like liquid. Glycolether lignin condensate was fully soluble in methanol, ethanol, acetone, 2-butanone and chloroform, partially soluble in ethyl acetate, but insoluble in hexane toluene, 1-butanol, and 2-propanol. Hydroxyl content of glycolether lignin condensate, estimated by titration of released acetic acid after acetylation, was 38 mg/g (0.677 mmol OH/g). 3.2 Molecular weight Distribution of Glycolether Lignin Condensate and Its Fractions Fig. 1 shows elution profiles of glycolether lignin condensate and its fractions. Each elution profiles are mainly composed of two regions. While the region 1 contains broad elution peak, the region 2 contains sharp peaks with positive or negative polarities. The broad peak in the region 1 originates from the polymeric components in the condensate. The negative peaks in the region 2 (the components with relatively smaller refractive indices than chloroform) are attributed to solvent species in the reaction medium. Therefore, the regions 1 and 2 are mainly composed of glycolether lignin and residual solvents, respectively. While condensate and soluble fraction are mainly composed of the 221 Preparation of Glycolether Lignin from Sugi (Cryptomeria japonica D. Don) Woodmeal by Acid-Catalyzed Solvolysis and Preparation of Heat-Resistant Polyester from the Glycolether Lignin | v2 |
2018-04-03T04:38:13.109Z | 2015-07-15T00:00:00.000Z | 39803680 | s2ag/train | Intraalveolar Catecholamines and the Human Lung Microbiome.
To the Editor:
Respiratory infections are responsible for tremendous mortality and morbidity worldwide (1). The advent of culture-independent techniques of bacterial identification and the discovery of the lung microbiome have prompted reconsideration of existing models of pneumonia pathogenesis (2, 3). Multiple studies have demonstrated an in vitro association between catecholamines and growth of select bacteria, including prominent members of the lung microbiome, including Pseudomonas aeruginosa and Streptococcus pneumoniae (4–6). A positive-feedback loop involving alveolar inflammation, intraalveolar catecholamines, and the selective growth promotion of pathogens has been posited as a novel mechanism of pneumonia pathogenesis (2, 4, 6). However, no study has measured intraalveolar catecholamines or determined their association with changes in the lung microbiome.
Using 40 clinically obtained bronchoalveolar lavage (BAL) specimens from lung transplant recipients, we compared intraalveolar catecholamine concentrations with the composition of the bacterial lung microbiome. Twenty-two specimens were obtained during bronchoscopies for an acute clinical indication (cough, sputum production, abnormal chest imaging, or worsened lung function), and 18 were performed on asymptomatic patients for posttransplant surveillance. No subjects were taking inhaled β-agonists at the time of bronchoscopy. All patients were receiving both systemic immunosuppression and Pneumocystis jirovecii prophylaxis at the time of bronchoscopy; additional antibiotic exposure in both groups has been previously reported (7). Patient characteristics, methods of bronchoscopy, DNA isolation and amplification, pyrosequencing, and analysis have previously been published (7, 8). Catecholamines were quantified using 2-CAT (A-N) Research ELISA (Rocky Mountain Diagnostics, Colorado Springs, CO). We measured associations between catecholamine levels and lung microbiota using linear regression. In permutation testing (permutational multivariate analysis of variance) of community composition (adonis function in vegan), we analyzed alveolar catecholamine levels as log-adjusted continuous environmental variables.
Norepinephrine was detected in 26 (65%) specimens (range, 2.6–105.0 pg/ml), and epinephrine was detected in 33 (83%) specimens (range, 0.8–40.7 pg/ml). Five (13%) specimens had no detectable norepinephrine or epinephrine; all five were obtained from asymptomatic patients undergoing surveillance bronchoscopy. Symptomatic patients had higher total alveolar catecholamines than patients undergoing surveillance bronchoscopy (P = 0.01). Intraalveolar catecholamine levels were significantly associated with culture-independent indices of acute infection, including total bacterial burden and BAL neutrophilia (Table 1).
Table 1.
Regression Analysis of Bronchoalveolar Lavage Bacterial Microbiome Features versus Intraalveolar Catecholamine Concentration
Increased intraalveolar catecholamine concentrations were strongly associated with decreased community diversity in the bacterial lung microbiome, a feature of pneumonia (8). As measured by the Shannon diversity index, diversity was negatively correlated with norepinephrine and epinephrine concentrations (P ≤ 0.05 for each) and combined catecholamine concentration (P = 0.009). The emergence of a single dominant bacterial species, as measured by maximum operational taxonomic unit (OTU) percentage (the highest relative abundance of a single community member in a bacterial community), was significantly associated with greater intraalveolar concentrations of norepinephrine (P = 0.003), epinephrine (P = 0.014), and total catecholamines (P = 0.0006) (Figure 1). Thus, intraalveolar catecholamines, both norepinephrine and epinephrine, are associated with collapse of community diversity to domination by a single bacterial species.
Figure 1.
Increased intraalveolar catecholamines in conditions of low lung microbiome diversity. High concentrations of epinephrine, norepinephrine, and total catecholamines are associated with emergence of a single dominant bacterial species. Maximum OTU percentage ...
We then asked whether the community membership of the bacterial lung microbiome was associated with concentrations of intraalveolar catecholamines. As tested by adonis (permutational multivariate analysis of variance), the community membership of BAL specimens was significantly associated with differences in total catecholamine levels (P = 0.010). Specifically, high-catecholamine specimens were relatively enriched with P. aeruginosa, which was present in low abundance in low- and moderate-catecholamine specimens. Conversely, a prominent nonaeruginosa pseudomonad, Pseudomonas fluorescens, was enriched in low-catecholamine specimens and absent from high-catecholamine specimens (Table 1). Its relative abundance was negatively associated with intraalveolar norepinephrine and total catecholamine concentrations (P ≤ 0.01 for each). These associations remained significant when adjusted for indices of acute infection (Shannon diversity index and total bacterial DNA, P ≤ 0.05 for each). Thus, community membership of the bacterial lung microbiome is significantly associated with intraalveolar catecholamine concentrations.
This study is the first to report an association between increased intraalveolar catecholamines and both indices of acute infection and emergence of specific microbiome community members as a dominant species. Our results support the in vivo plausibility of a previously postulated (2, 4, 6) positive feedback loop that propels the inflammation and bacterial growth of acute pneumonia: select bacterial growth provokes alveolar inflammation, resulting in increased intraalveolar catecholamines, which in turn further provoke selective bacterial growth among catecholamine-responsive species. P. aeruginosa was the community member most enriched in high-catecholamine conditions; this finding is consistent with past in vitro demonstrations that P. aeruginosa growth is dose-dependently promoted by various catecholamines (4, 5). P. aeruginosa is the most commonly isolated respiratory pathogen in a variety of clinical settings, including ventilator-associated pneumonia; thus, our findings may have broad mechanistic implications in the pathogenesis of respiratory infections. Interestingly, we found a strong and independent negative association between intraalveolar catecholamines and P. fluorescens, which we have shown to be a prominent, nonpathogenic inhabitant of the human lung microbiome (7, 9). The mechanism and significance of this negative association is undetermined. We also observed a strong correlation between intraalveolar catecholamine levels and the abundance of alveolar neutrophils; this finding is consistent with experimental evidence that neutrophils generate catecholamines and contribute to alveolar inflammatory injury (10).
Catecholamines, both endogenous and exogenous, are prominent in the pathogenesis and treatment of respiratory disease and critical illness. This is the first report of an association between endogenous catecholamines and features of the bacterial lung microbiome. To our knowledge, nothing is known about the effects of exogenous catecholamines, adrenergic agonists, or adrenergic antagonists on the bacterial lung microbiome. Our results suggest that further study is warranted to determine whether microbe–host interactions via catecholamines contribute to the pathogenesis of respiratory infections. | v2 |
2019-11-22T00:53:42.210Z | 2019-11-13T00:00:00.000Z | 209267480 | s2ag/train | Dynamics of Activated CD8+ T-cells and Decreased Osteoclasts in the Tumor Microenvironment are Associated with Clinical Efficacy of Anti-PD-L1 and Anti-CD38 Combination Treatment in Relapsed or Refractory Multiple Myeloma
Introduction: Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway is insufficient to induce clinical response in relapsed or refractory (R/R) multiple myeloma (MM). We postulated that combining atezolizumab (A; anti-PD-L1) with daratumumab (D; anti-CD38), which targets myeloma cells and has immunomodulatory activity, may alter the tumor microenvironment (TME) to favor cytotoxic T-cell activation and clinical activity. To assess the immunologic efficacy of this combination, we studied changes in CD8+ T cells in D-naïve and D-refractory pts from a Phase Ib study (GO29695; NCT02431208).
Methods: Flow cytometry was performed using longitudinal peripheral blood (PB) and bone marrow aspirates (BMA) to characterize CD8+ cytotoxic T cells using 8 color flow panels. RNA sequencing (RNAseq) and dual-plex immunohistochemistry (IHC) (CD138/CD8, CD8/Ki-67, CD138/osteoclast) were performed using longitudinal CD138+ fraction and bone biopsies, respectively. For IHC, CD138+ cell masses of >5000μm2 were defined as tumor clusters. Osteoclasts were enumerated based on TRAP positivity and morphology. Table 1 shows on-treatment changes in Cohorts D1-D3. Table 2 shows baseline data in Cohorts A, B, D1-D3, and E. The median (bootstrap 95% CI) is used to describe the data.
Results: 9/36 (25%) pts in cohorts D1-3 showed clinical efficacy (partial response or better); all were D-naïve. We studied CD8+ T-cell activation and proliferation (%CD8+HLA-DR+Ki-67+), the pharmacodynamic marker for A (Herbst et al. Nature 2014), in PB. All D-naive pts showed on-treatment increase in %CD8+HLA-DR+Ki-67+ cells in the periphery (C1D15-C2D1) compared to baseline, which was not observed in D-refractory pts (Table 1). In BMA, the increase in %CD8+HLA-DR+Ki-67+ (C2D15-C4D1) was observed in D-naïve pts with clinical response to A-D (sensitive), but not in non-responders (resistant) or D-refractory pts (all resistant), suggesting that sensitive pts have an immune-supportive TME. Preliminary IHC staining also showed an increase in CD8+Ki-67+ T cells in two responders after treatment. Gene enrichment analysis (RNAseq data, n=20) showed upregulation of an innate immune response signature, which appeared to be driven by a 'macrophage activation' gene signature post-treatment, in the CD138+ fraction of responders. To understand the mechanisms regulating sensitivity to treatment, we studied the spatial localization of CD8+ T cells with respect to CD138+ tumor cells by IHC. A higher density of CD8+ T cells within tumor clusters was seen at baseline in sensitive versus resistant pts, but this was not observed outside of tumor clusters (Table 1). In addition, the number of osteoclasts in the tumor region was higher in resistant pts, suggesting that these cells may contribute to the inhibition of T-cell function as reported(An et al. Blood 2016). This hypothesis was further supported by higher osteoclast numbers in D-refractory pts at baseline (Table 2), for whom an on-treatment increase in %CD8+HLA-DR+Ki-67+ cells was not observed in PB or BMA. Interestingly, higher median fluorescence intensity of PD-1 on CD8+ T-effector cells and on CD8+ T-effector memory cells was observed at baseline in D-naïve relative to D-refractory pts, while the level of PD-L1 expression on tumor cells was similar. An increase in activated proliferating T cells (%CD8+HLA-DR+Ki-67+) observed after treatment in D-naïve responders suggests that high PD-1 expression in this subset is not a marker of CD8+ T-cell exhaustion, but of functional capability.
Conclusions: Clinical efficacy of A-D therapy in R/R MM pts is associated with higher CD8+ cell density in tumor clusters and lower osteoclast numbers in the tumor region at baseline, and an on-treatment increase in activated CD8+ T-cell populations in the bone marrow. The lack of a D-monotherapy arm in this study makes it difficult to assess the individual contribution of A to T-cell activation. The data presented, albeit a small number of samples from a Phase Ib study, support the hypothesis that the TME, including CD8+ T cells, tumor cells, and cells of myeloid lineage such as osteoclasts, has significant impact on the immunologic and clinical efficacy of combination therapy. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential for long-term disease control.
Raval: Roche: Employment, Equity Ownership. Cho:Agenus: Research Funding; Genentech: Honoraria, Research Funding; Takeda: Research Funding; BMS: Consultancy; The Multiple Myeloma Research Foundation: Employment; Celgene: Honoraria, Research Funding; GSK: Consultancy. Green:Genentech Inc.: Employment. Wassner Fritsch:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ma:Genentech: Employment. Chang:Roche Canada: Employment. Yan:F. Hoffmann-La Roche Ltd, Mississauga, Canada: Employment. Kockx:HistoGeneX: Equity Ownership. Shen:Genentech, Inc.: Employment. Huw:Roche/ Genentech: Employment, Equity Ownership. Balestiere:Genentech: Employment. Lipkind:Roche/Genentech: Employment. Huang:F. Hoffmann-La Roche Ltd: Employment. Byrtek:Genentech: Employment; Roche: Equity Ownership. Colburn:Genentech: Employment; Roche: Equity Ownership. Wong:Celgene Corporation: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Fortis: Research Funding; Juno: Research Funding. Venstrom:F. Hoffmann-La Roche Ltd: Employment. Adamkewicz:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment.
Atezolizumab (atezo) is a programmed death-ligand 1 (PD-L1) blocking antibody. In the United States, atezo is approved for treatment of pts with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy (chemo) and whose tumors express PDââ‚â'¬Ã'ÂL1, or are not eligible for any platinumââ‚â'¬Ã'Âcontaining chemo regardless of PDââ‚â'¬Ã'ÂL1 status, or have disease progression during or following any platinum-containing chemo, or within 12 months of neoadjuvant or adjuvant chemo. Atezo is also approved: in combination with bevacizumab, paclitaxel and carboplatin for first-line treatment of pts with metastatic non-squamous non-small-cell lung carcinoma (NSCLC) with no EGFR or ALK genomic tumor aberrations, and for pts with metastatic NSCLC who have disease progression during or following platinum-containing chemo; in combination with paclitaxel protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1; and in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer. Atezo is not approved for treatment of pts with multiple myeloma.
| v2 |
2018-04-03T00:20:39.319Z | 2003-01-03T00:00:00.000Z | 10993540 | s2ag/train | 1,2-Migration of the thio group in allenyl sulfides: efficient synthesis of 3-thio-substituted furans and pyrroles.
The 1,2-migration of the thio group is an important chemical transformation that is extensively used in carbohydrate chemistry for stereoselective Mitsunobu-type substitution at the anomeric center [Eq. (1)].[1] There are also reports on employment of a 1,2-shift of the thio group in the synthesis of heterocycles [Eq. (2)][1a,b] Known 1,2-migrations of the thio group can be classified as one of two types: 1) An SN2-type attack of the lone pair of electrons of the sulfur atom at the adjacent sp3 center in A produces the thiiranium intermediate B, which after subsequent nucleophile-assisted ring opening affords C, a product of 1,2-migration of the thio group [Eq. (1)].[1] 2) The migration is triggered by attack of the sulfur atom at the sp2 carbon atom of the iminium[2a,b] or imine[2c] moiety of D to form the thiiranium species E. The latter either produces sulfide F through nucleophilic attack[2c] or gives the thioenamine G as a result of a deprotonation/ring-opening process [R1 = H, Eq. (2)].[2a,b] In all cases the migrations of the thio group proceeded from an sp3 center to either another sp3 [Eq. (1)][1] or to an sp2 [Eq. (2)][2] carbon center. To the best of our knowledge, there are no reports of 1,2-migration of the thio group from an olefinic carbon atom.
Herein we wish to report a novel 1,2-migration of the thio group from an sp2 carbon atom in allenyl sulfides. This unprecedented migration allowed the development of an
(1)
(2)
efficient method for the synthesis of 3-thio-substituted furans and pyrroles.
During the investigation of the scope of the recently found Cu-catalyzed transformation of alkynyl ketones and alkynyl imines into 2,5-disubstituted furans[3] and pyrroles,[4] we discovered that heating ketopropargyl sulfide 1 in N,N-dimethylacetamide (DMA) in the presence of CuI (10 mol%) not only gave the targeted 2,5-disubstituted furan 2, but also a small amount of the unexpected 2,4-disubstituted furan 3 [Eq. (3)]. It was hypothesized that first, propargyl–allenyl isomerization[5] produces an allenic intermediate 4 (Scheme 1).
(3)
Scheme 1
Different routes for the cyclization of the ketopropargyl sulfide 1 to give either furan 2 or 3. Based on this mechanistic proposal, the reaction of ketopropargyl sulfides in which Hb of 4 is replaced with any other nonmigrating group should exclusively ...
Next, the allenyl sulfide 4, according to the “standard” cycloisomerization scenario (Scheme 1, path a)[3] produces the major reaction product, furan 2.[3] It was proposed that alternatively, an intramolecular nucleophilic attack of the lone pair of electrons of the sulfur atom at the central carbon atom of the allene can transform it into the aromatic thiirenium zwitterion 5.[6] The latter, either via AdN-E (5→6) or through a direct SN2-Vin-type[7] process, affords the minor isomeric furan 3 (Scheme 1, path b). Although the role of the copper catalyst in this reaction is not completely understood, there are some indications that it facilitates propargyl–allenyl isomerization,[3, 4,8] and in some cases it is also required for further transformations [Eq. (4)], probably as a result of the stabilization of carbanionic intermediates.[8] It occurred to us that if the above mechanistic proposal is correct, then replacement of Hb in allene 4 with any other nonmigrating group should enforce selective migration of the thio group to produce 2,4-disubstituted furan 3 exclusively (path b). To examine this proposal, thioallenes 7a,b were prepared by independent methods and subjected to the cycloisomerization conditions described above [Eq. (4)]. Remarkably, it was found that thioallenyl phenyl ketone 7a, even in the absence of CuI, underwent quantitative thermal transformation to 8a. In contrast, attempts to perform analogous thermal cycloisomerization of thioallenyl alkyl ketone 7b resulted in total decomposition of the starting material, whereas 82% of 8b was isolated when the reaction was performed at room temperature in the presence of CuI (5 mol%) [Eq. (4)].
(4)
Naturally, we next attempted a selective migrative cycloisomerization of substituted propargyl sulfides, undoubtedly superior precursors when compared with allenyl sulfides from a synthetic point of view. Accordingly, a series of alkyl-substituted propargyl sulfides 9 were synthesized and subjected to the cycloisomerization reaction [Eq. (5)].
We were very pleased to find that thiopropargyl aldehyde 9c underwent smooth and selective cycloisomerization, producing 2-butyl-3-phenylsulfanyl-furan (8c) in 71% yield as a single reaction product (Table 1, entry 1). Cycloisomerization of thiopropargyl ketones 9a,d,e proceeded provided the trisubstituted furans 8a,d,e in very good yields (Table 1, entries 2–4).[9] Cycloisomerization of phenylsulfanyl propargyl ketones possessing alkenyl (9 f), ester (9g), and protected alcohol (9h) functionalities in the side chain proceeded readily to afford the corresponding trisubstituted furans 8 f–h in good to very high yields (Table 1, entries 5–7). The alkyl sulfanyl group migrated with an efficiency comparable to that of its phenylsulfanyl analogue to give the corresponding furan 8i in 72% yield (Table 1, entry 8).
Table 1
Cu-catalyzed synthesis of 3-substituted furans and pyrroles.
Inspired by the successful synthesis of trisubstituted furans, the cycloisomerization of thiopropargyl imines was then investigated. It was found that thiopropargyl imines 9j–o in the presence of
(5)
CuI underwent a similar transformation to give the corresponding 3-thio-substituted pyrroles 8j–o in very good yields (Table 1, entries 9–14).[10] Again, the dodecyl sulfanyl group (Table 1, entry 10) migrated comparably to the phenyl sulfanyl analogue (Table 1, entry 9) and the THP-protected alcohol functionality was tolerated (Table 1, entry 14). It is worth mentioning that all synthesized pyrroles have removable groups at the nitrogen atom, for example, the tert-butyl (8j,k, Table 1, entries 9, 10),[11] trityl (8 l, Table 1, entry 11),[12] and 3-ethylbutyryl[4, 13] (8m–o, Table 1, entries 12–14) groups, and thus can be easily functionalized further at the nitrogen site.[14]
In conclusion, a novel 1,2-migration of the thio group in thioallenyl ketones and thioallenyl imines was discovered. An efficient method for the synthesis of di- and trisubstituted furans and trisubstituted pyrroles that possess an aryl sulfanyl or alkyl sulfanyl substituent at C3 has been developed. | v2 |
2021-06-23T22:38:13.565Z | 2018-01-01T00:00:00.000Z | 235619790 | s2ag/train | Geochemistry and Risk Assessment in Surface Sediments of the Brass River, Bayelsa State, Niger Delta Region, South-South,
This paper deals with the physico-chemical parameters and some heavy metals in sediment samples of the Brass River, Bayelsa State, Nigeria. Physico-chemical parameters and heavy metals such as pH, chloride, sulphate, magnesium, potassium, sodium, copper, chromium, zinc, cadmium, lead, manganese, iron and nickel were analyzed. In this present study, all heavy metals investigated showed low concentration of the Brass River. This means that there is a low source of pollution arriving to the Brass River. Potential ecological risk index assessment of heavy metals and comparison with DPR / FEPA standards was employed to infer anthropogenic input from natural input. The heavy metals concentration and potential ecological risk were evaluated systematically using geoaccumulation index (Igeo) and potential ecological risk index (RI). The results showed that the geoaccumulation index placed Brass River under practically unpolluted (Igeo < 0). Furthermore, the potential ecological risk index of both single and multi-element placed the Brass River under the category of low ecological risk (E i r < 40).and RI<150) respectively. In general, the ranking of heavy metals in surficial sediment samples of the Brass River in terms of potential ecological risk coefficient (E i r) was as follows: Cu > Pb > Ni > Zn. Compared to the heavy metals permissible limit in DPR/FEPA standards copper, chromium, zinc, cadmium, lead, manganese, iron and nickel showed lower concentration, possibly indicating that the origin of these heavy metals is lithogenic. © 2018 Elixir All rights reserved. Elixir Appl. Chem. 117 (2018) 50531-50535 Applied Chemistry Available online at www.elixirpublishers.com (Elixir International Journal) Leizou et al./ Elixir Appl. Chem. 117 (2018) 50531-50535 50532 standards and similar environments to know the extent of deterioration. 2.0 MATERIALS AND METHODS 2.1 STUDY AREA The Brass River is a natural river geographically located in Bayelsa state, Niger Delta region, Nigeria. Twon-Brass is a community on Brass Island in the Nun River estuary of Southern Bayelsa State, Nigeria, in the Brass Local Government Area. The river lies between the coordinates of latitude 04o 19‟ 1‟‟ North and longitude 06o 14‟ 34‟‟ East. Brass River is a distributary and it also flows into the Atlantic Ocean. Figure 1. Map of Brass River showing sampling locations. 2.2.1 SAMPLING AND ANALYSIS Sediment samples were collected using a bottom grab sampler (Hydro-Bios) from four stations: upstream, middle reach, mouth and downstream along the Brass River system. Sediments were then immediately transferred into plastic bags and refrigerated and transported to the laboratory. In order to get a representative sample for each station, several sub-samples were collected and mixed together. At the laboratory, the samples were air-dried, pulverized and sieved through a 2mm mesh to remove dirt and other debris, then stored in closed plastic containers for digestion and analysis. The air-dried, sieved sediment samples were used to perform the following physico-chemical analysis: pH, electrical conductivity, chloride, sulfate, magnesium, potassium and sodium content according to standard techniques (Jackson, 1973 ;Singare et al., 2011). Furthermore, the dried sediment samples were digested in a mixture of concentrated nitric acid (HNO3), concentrated hydrochloric acid (HCl) and 27.5% hydrogen peroxide (H2O2) according to the standard USEPA method 3050B for the analysis of heavy metals and major ions (USEPA, 1996; Amadi et al., 2012; Leizou et al., 2016). The resulting solutions were subjected to elemental analysis using an atomic absorption spectrometer (ANALYST 400 PerkinElmer AAS),in compliance with manufacturer‟s instructions and specifications. 3.0 RESULTS AND DISCUSSION Table 1 Summaries the concentrations of physicochemical parameters and heavy metals in (range, minimum, maximum, mean ± standard deviation) except pH; others are expressed as milligram / Kilogram (mg/Kg) of dried sediments of the Brass River, Bayelsa State, South-South, Nigeria. The Concentration of pH, Cl-, SO4 2, Mg, K, and Na in sediment ranged from 2.36-5.29, 2459-12678, 425-8776, 0.03-1.04, 1.63-27.63 and 6.44-125.50 with mean values of 4.03±1.25, 6.85E3±4278.24, 4.93E3±4043.14, 0.68±0.45, 19.37±12.01 and 87.26±54.47 respectively. Vincent-Akpu et al., 2015 reported that the sediments of Bodo Creek, Niger Delta, Nigeria exhibit fluctuating pH values that ranged from 5.7 to 8.0, that is, from acidic to alkaline. pH is a simple parameter but is extremely important, since most of the chemical reactions in aquatic environment are controlled by any change in its value. Anything either highly acidic or alkaline would kill marine life (Singare et al., 2011). The data in this study suggested low concentration of heavy metals in surface sediments of the Brass River. The concentration (mg/kg) of heavy metals: copper, zinc, iron and lead in sediments ranged from 0.65 – 1.07, 0.11-0.30, 4.93128.91 and 0.02-0.03 with mean value of 0.83±0.18, 0.21±0.10, 79.49±52.94 and 0.02±0.01 respectively. The highest value for copper (1.07 mg/kg), was recorded in the sediment from downstream and was closely followed by sediment from mouth (0.82 mg/kg). The lowest value was recorded in the sediment from upstream (0.65 mg/kg) (Table 1). Klassen (1996) grouped metals into four categories: a) major toxic metals with multiple side effects, b) essential metals with potential for toxicity, c) metals related to medical therapy, and d) minor toxic metals. Copper and zinc are essential elements with potential for toxicity and both exhibit an oxidation state of 2+. Copper is widely used in electrical wiring, roofing, various alloys, pigments, cooking utensils, piping and in the chemical industry. Copper is present in amunitions, alloys (brass, bronze) and coatings. Copper compounds are used as or in fungicides, algicides, insecticides and wood preservatives and in electroplating, azo dye manufacture, engraving, lithography, petroleum refining and pyrotechnics. Copper compounds can be added to fertilizers and animal feeds as a nutrient to support plant and animal growth. Copper compounds are also used as food additives (Abbasi et al., 1998; Eaton, 2005; WHO, 2004). In addition, copper salts are used in water supply systems to Table 1. Summary of physico-chemical parameters and heavy metals in sediment Variables Range Min. Max. Sum Mean Std Error Std Dev. Variance pH 2.93 2.36 5.29 16.12 4.03 .63 1.25 1.57 Chloride 1.02E4 2459.0 | v2 |
2021-09-28T15:35:25.254Z | 2021-07-21T00:00:00.000Z | 241661310 | s2ag/train | Planetary Terrestrial Analogues Library (PTAL): online database platform and spectroscopic tools
<p><strong>The PTAL Project: </strong>Mars2020/Perseverance <sup>1</sup> and ExoMars/Rosalind Franklin <sup>2</sup> rovers will look for traces of present or past life on Mars. To do so, the spectroscopic systems included in their analytical payloads will investigate the geochemistry and mineralogy of Martian rocks and soils to detect geological samples that could potentially host biomarkers. In order to optimize the scientific exploitation of planetary spectroscopic analysis, the PTAL project will provide the scientific community with a novel library of terrestrial analogue materials that have been selected based on their similarity to well-known Martian geological contexts. Funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement Nº 687302, the PTAL online platform will be released to public in October 2021. As further detailed by Werner et al. during this conference, the core of the database are the spectroscopic data collected by means of multiple Raman (University of Valladolid, UVa, Spain), NIR (University of Paris-Sud, UP-Sud, France) and LIBS (French National Centre for Scientific Research, IRAP, France) systems. Spectroscopic results are additionally supported by X-ray diffractograms and thin section observations (University of Oslo, Uio, Norway) to provide an exhaustive geochemical and mineralogical characterization of the samples. The whole set of data, collected by means of both commercial systems and prototypes/flight spares (FS) of analytical instruments validated for Mars exploration (RLS-Sim, MicrOmega-FS, ChemCam-FS), will be available to the public thanks to a dedicated online platform, which main characteristics are detailed below.</p><p><strong>The online PTAL platform:</strong></p><p>The PTAL database will be accessible to public through the following URL: http://erica.uva.es/PTAL/. After login (credentials will be provided by the PTAL consortium upon request), future users will have access to the whole set of diffractometric and spectroscopic data collected from a total of 102 analogue materials. On one side, clicking on the sample name, the metadata associated to the selected terrestrial analogues are provided (e.g., Sample Name and Lithology, Sampling Campaign and coordinates) together with high quality pictures of the terrestrial analogue sample. On the other side, by clicking on “analytical summary”, the PTAL platform displays the list of NIR, LIBS, Raman and XRD analyses associated to the selected terrestrial analogue, together with a table summarizing and comparing the main results gathered from each technique (Figure 1).</p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gepj.07b339aa6ba067966481261/sdaolpUECMynit/1202CSPE&app=m&a=0&c=c4c50add229d920c4b4f3e5b5bb7dc6e&ct=x&pn=gepj.elif&d=1" alt=""></p><p><em>Figure 1: Screenshots collected from the PTAL online database: a) list of samples, b) summary result of a selected analogue, and c) online visualization of a selected Raman spectrum.</em></p><p>At this stage, all NIR, XRD, Raman and LIBS data have been successfully uploaded to the PTAL database <sup>3–5</sup>. In detail, the PTAL database provides access to 102 diffractograms (1 per sample), 102 LIBS spectra, 102 NIR spectra collected by means of the commercial spectrometer, and 102 NIR data cubes obtained through the MicrOmega system (of them composed of 62500 spectra collected at steps of 20µm in a field of view of 5x5mm). Regarding Raman results, only the spectra providing the highest mineralogical information were uploaded to the PTAL database. As such, the number of Raman spectra was reduced from over 4500 to 577 (an average of 5-6 spectra per sample). 245 of them were collected by means of the RLS-Sim, while the remaining 332 were obtained with a commercial spectrometer. All data can be either visualized online or downloaded for further data comparison and processing. In this framework, it must be underlined the PTAL platform also gives access to a dedicated software for data treatment. Named SpectPro, the details of this downloadable software are detailed below.</p><p><strong>The SpectPro software:</strong></p><p>Developed in the framework of the ExoMars mission <sup>6</sup>, the PTAL version of the SpectPro software could be downloaded from the PTAL webpage (download section) for both windows and MacOs operating systems. Through the SpectPro software, PTAL users will be able to run individual and multi-spectra operations such as labelling, trimming, shifting, normalization, baseline correction (see Figure 2).</p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gepj.465546ba6ba060176481261/sdaolpUECMynit/1202CSPE&app=m&a=0&c=7e8c748d53ca13358d27d217bfea3ca6&ct=x&pn=gepj.elif&d=1" alt=""></p><p><em>Figure 2: Screenshot of PTAL/SpectPro, in which the main functionalities and characteristics of the software are highlighted.</em></p><p>Among the main functionalities, the software also features a general-purpose spectrum calculator to perform lineal combinations, product and derivative of spectra, among others. The software team has been working to facilitate a direct access from SpectPro to the PTAL database, using the same credentials for access to the PTAL web interface. This connection will boost the capability of the scientist working in a planetary mission (but not only) to perform a fast and comprehensive characterization and identification of the mineral phases present in a sample by comparing the data obtained from the sample with the extensive spectral information included in the PTAL database. This will be possible by profiting from the navigation pane included in SpectPro. In addition, using the peak detection capabilities of SpectPro, it will be possible to perform sample identification based on the acquired spectra.</p><p><strong>Acknowledgments: </strong>This work is financed through the European Research Council in the H2020- COMPET-2015 programme (grant 687302).</p><p><strong>References: </strong><sup>1 </sup>Farley, K. A. <em>et al</em>. <em>Space Sci. Rev.</em> 216, 142 (2020); <sup>2 </sup>Vago, J. L. <em>et al</em>. <em>Astrobiology</em> 17, 471–510 (2017); <sup>3</sup> Lantz, C. <em>et al</em>. <em>Planet. Space Sci.</em> 189, 104989 (2020); <sup>4 </sup>Loizeau, D. <em>et al.</em> <em>Planet. Space Sci.</em> 193, 105087 (2020); <sup>5</sup> Veneranda, M. <em>et al</em>. <em>J. Raman Spectrosc.</em> 1–19 (2019) doi:10.1002/jrs.5652; <sup>6 </sup>Lopez-Reyes G. <em>et al.</em> <em>European Planetary Science Congress 2018</em> vol. 12 1–2 (2018).</p><p><strong> </strong></p> | v2 |
2017-09-01T08:30:33.204Z | 2003-01-01T00:00:00.000Z | 19794020 | s2ag/train | Distribution of UDPglucuronosyltransferase in rat tissue ( tissue distribution / intracellular distribution / immunocytochemistry ) JAYANTA
UDPglucuronosyltransferase [UDPglucuronate 13-D-glucuronosyltransferase (acceptor-unspecific), EC 2.4.1.17] is a group of enzymes with distinct but partially overlapping substrate specificity. A rabbit antiserum raised against one purified rat liver UDPglycuronosyltransferase isoform was specific for UDPglucuronosyltransferase and recognized all transferase isoforms by immunodiffusion or immunotransblot analysis. The transferase activity toward all substrates was immunoabsorbed from solubilized rat liver microsomes by IgG purified from the antiserum. The purified IgG was used for immunocytochemical localization of UDPglucuronosyltransferase in rat liver, jejunum, kidney, and adrenal gland. In the liver, UDPglucuronosyltransferase was present exclusively in hepatocytes and was uniformly distributed within all zones of the hepatic lobule. In the jejunum, the transferase was present exclusively in the epithelial cells and showed a progressive increase in concentration from the crypt to the villar tip. In the kidney, the greatest concentration of the transferase was observed in the epithelial cells of the proximal convoluted tubule. Adrenal medullary cells showed intense immunocytochemical staining; the zona glomerulosa and the zona reticularis of the adrenal cortex were more intensely stained than the zona fasciculata. By light microscopy, UDPglucuronosyltransferase was found in the endoplasmic reticulum and nuclear envelope of all the four organs; this was confirmed in the hepatocyte by electron microscopy. The transferase was not observed in mitochondria, Golgi apparatus, lysosomes, peroxisomes, and plasma membrane, even after 3to 4-fold induction of various substrate-specific UDPglucuronosyltransferase activities. UDPglucuronosyltransferase (UDPglucuronate ,B-Dglucuronosyltransferase, EC 2.4.1.17) is a group of membrane-bound enzymes that catalyze the transfer of glucuronic acid from uridine diphosphoglucuronic acid to a variety of metabolites, drugs, toxins, carcinogens, and other xenobiotics. The resulting glucuronides are generally less biologically active and more polar than the aglycone substrates, and they are readily excreted in bile and urine. Glucuronidation is an important pathway of detoxication (1); tissue and intracellular location of UDPglucuronosyltransferase may be important in the chemical defense against these toxins. We have previously isolated six UDPglucuronosyltransferase isoforms with distinct but partially overlapping substrate specificity from solubilized rat liver microsomes (2). A rabbit antiserum raised against one purified isoform was specific for UDPglucuronosyltransferase and recognized all isoforms of the enzyme. Using purified IgG from this antiserum, we have determined the tissue and intracellular location of UDPglucuronosyltransferase in rat liver, kidney, jejunal mucosa, and adrenal gland; this was correlated with the tissue distribution of the enzyme activity toward various substrates. MATERIALS AND METHODS Male Wistar rats (200-250 g) were purchased from Charles River Breeding Laboratories. Clofibrate was purchased from Ayerst Laboratories (New York); 3-methylcholanthrene was a gift of W. G. Levine. Horseradish peroxidase-conjugated staphylococcal protein A (pA-HRP) was purchased from E-Y Laboratories (San Mateo, CA). Assay of UDPglucuronosyltransferase Activity. Enzyme activity in tissue homogenates toward bilirubin (3), 4nitrophenol (4, 5), testosterone (6), androsterone (6), f3estradiol (6), and estrone (7) was assayed in the presence of 4mM glucaro-1,4-lactone (7) after activation with digitonin (2 mg/ml). For purified preparations, phosphatidylcholine liposomes (0.1 mg/ml) were added (5, 6). Purification of UDPglucuronosyltransferase Isoforms. Six UDPglucuronosyltransferase isoforms were purified from Emulgen 911-solubilized rat liver microsomes (5) by a combination of chromatofocusing (pH 9.4-6.0), affinity chromatography, and gel-permeation high-pressure liquid chromatography as described (2, 6). Preparation and Characterization of Antisera. An antiserum was raised in rabbits against purified UDPglucuronosyltransferase isoform III as described (5). IgG purified from the antiserum by affinity chromatography (8) was tested by double immunodiffusion (9) against solubilized rat liver microsomes or pure transferase isoforms (2) and by immunotransblot analysis against liver homogenates (50 ,ug of protein), microsomes (25 ,ug of protein), or purified transferase isoforms (1-2 ,g of protein) after electrophoresis on 10% NaDodSO4/polyacrylamide slabs (10). To evaluate the recognition of the functional forms of UDPglucuronosyltransferase by the antiserum, solubilized rat liver microsomal proteins (5 mg in 0.5 ml) were gently stirred with the specific IgG or IgG from nonimmunized rabbit serum (2 mg in 0.5 ml of 0.1 M Tris HCl, pH 7.4) or saline at 4°C for 16 hr. The immune complexes were removed after gentle mixing (8 hr at 4°C) with 0.5 ml of staphylococcal protein A-Sepharose slurry (binding capacity, 10 mg of rabbit IgG), followed by centrifugation (10,000 x g for 1 min). The protein ASepharose beads were washed twice with 0.5 ml of 0.1 M Tris-HCl containing 50 mM KCl; the supernatants were pooled and UDPglucuronosyltransferase activity for 4nitrophenol, 1-naphthol, 4-methylumbelliferone, testosterone, 13-estradiol, estrone, androsterone, and bilirubin was assayed. Enzyme Induction. Rats were injected with clofibrate (300 mg/kg, s.c.) for 7 days, or with 3-methylcholanthrene (40 mg per kg of body weight in olive oil, i.p.) once 4 days prior to sacrifice; UDPglucuronosyltransferase activity for 4-nitrophenol, testosterone, ,-estradiol, androsterone, estrone, and bilirubin in liver homogenates was assayed. Immunocytochemical and Microscopic Procedures. Tissues were fixed and processed as described (11). Nonfrozen sections were exposed to the anti-rat UDPglucuronosyltransferase (rabbit) IgG (0.07-0.7 mg per ml of phosphatebuffered saline); nonimmune rabbit IgG was used as control. Vibratome sections were prepared and examined by light and 2990 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. Proc. Natl. Acad. Sci. USA 82 (1985) 2991 | v2 |
2017-04-05T16:37:08.408Z | 2006-01-01T00:00:00.000Z | 6565970 | s2ag/train | N 1-( 3-Cyclohexylbutanoyl )-N 2-[ 3-( 1 H-imidazol-4-yl ) propyl ] guanidine ( UR-AK 57 ) , a Potent Partial Agonist for the Human Histamine H 1-and H 2-Receptors
Both the histamine H1-receptor (H1R) and H2-receptor (H2R) exhibit pronounced species selectivity in their pharmacological properties; i.e., bulky agonists possess higher potencies and efficacies at guinea pig (gp) than at the corresponding human (h) receptor isoforms. In this study, we examined the effects of N-acylated imidazolylpropylguanidines substituted with a single phenyl or cyclohexyl substituent on H1R and H2R species isoforms expressed in Sf9 insect cells. N-(3-Cyclohexylbutanoyl)-N-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-AK57) turned out to be the most potent hH2R agonist identified so far (EC50 of 23 nM in the GTPase assay at the hH2R-Gs fusion protein expressed in Sf9 insect cells). UR-AK57 was almost a full-hH2R agonist and only slightly less potent and efficacious than at gpH2R-Gs . Several N -acylated imidazolylpropylguanidines showed similar potency at hH2R and gpH2R. Most unexpectedly, UR-AK57 exhibited moderately strong partial hH1R agonism with a potency similar to that of histamine, whereas at gpH1R, UR-AK57 was only a very weak partial agonist. Structure/activity relationship studies revealed that both the alkanoyl chain connecting the aromatic or alicyclic substituent with the guanidine moiety and the nature of the carbocycle (cyclohexyl versus phenyl ring) critically determine the pharmacological properties of this class of compounds. Collectively, our data show that gpH1R and gpH2R do not necessarily exhibit preference for bulky agonists compared with hH1R and hH2R, respectively, and that UR-AK57 is a promising starting point for the development of both potent and efficacious hH1R and hH2R agonists. Histamine (HIS) (1) (see Fig. 1) is a neurotransmitter and autacoid and acts through H1-, H2-, H3-, and H4-receptors (H1R–H4R) (Hill et al., 1997; Hough, 2001; Bakker et al., 2002). The H1R couples to Gq-proteins to mediate phospholipase C activation and plays a role in the regulation of alertness and as mediator of type 1 allergic reactions (Hill et al., 1997; Bakker et al., 2002). The H2R couples to Gs-proteins to mediate adenylyl cyclase activation and regulates H secretion in gastric parietal cells, cardiac contractility, and various myeloid cell functions (Klinker et al., 1996; Hill et al., 1997; Bakker et al., 2002). It has been difficult to establish relevant native test systems for the analysis of the human H1R (hH1R) and human H2R (hH2R), because there are unexplained pharmacological differences in the properties of hH1R and hH2R in native cells relative to standard guinea pig test organs (Burde et al., 1990; Seifert et al., 1994; Klinker et al., 1996). To facilitate the comparison of histamine receptors under identical experimental conditions, we established expression systems for the H1R and H2R in Sf9 insect cells (Kelley et al., 2001; Houston et al., 2002). Sf9 cells express the H1R and H2R at high levels and can be cultured in large quantities. GPCR/Gprotein coupling in Sf9 membranes is monitored with high sensitivity using the steady-state GTPase assay. This assay This work was supported by the National Institutes of Health COBRE Award 1 P20 RR15563 and matching support from the State of Kansas and the University of Kansas (to R.S. and Q.-Z.Y.) and the Graduate Training Program (Graduiertenkolleg GRK 760, “Medicinal Chemistry: Molecular Recognition— Ligand-Receptor Interactions”) of the Deutsche Forschungsgemeinschaft (to R.S., S.E., and A.B.). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.106.102897. ABBREVIATIONS: HIS, histamine; UR-AK57, N-(3-cyclohexylbutanoyl)-N-[3-(1H-imidazol-4-yl)propyl]guanidine; AIPG, N-acylated imidazolylpropylguanidine; GPCR, G-protein-coupled receptor; gpH1R, guinea pig histamine H1-receptor; gpH2R, guinea pig histamine H2-receptor; gpH2R-Gs S, fusion protein of the guinea pig histamine H2-receptor and the short splice variant of Gs ; hH1R, human histamine H1-receptor; hH2R, human histamine H2-receptor; hH2R-Gs S, fusion protein of the human histamine H2-receptor and the short splice variant of Gs ; HIS, histamine; RGS, regulator of G-protein signaling; TM, transmembrane domain. 0022-3565/06/3173-1262–1268$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 317, No. 3 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 102897/3117058 JPET 317:1262–1268, 2006 Printed in U.S.A. 1262 at A PE T Jornals on A ril 5, 2017 jpet.asjournals.org D ow nladed from assesses GPCR/G-protein coupling at a proximal point of the signaling cascade, avoiding potential bias introduced by assessing more downstream events such as effector activation or changes in gene expression. For the H1R, coupling of the GPCR to insect cell Gq-proteins is determined, and the GTPase signal is amplified by RGS proteins (Houston et al., 2002; Seifert et al., 2003). For the H2R, fusion proteins of GPCR and mammalian Gs proteins ensure defined 1:1 stoichiometry of the coupling partners and their efficient interaction (Seifert et al., 1999; Kelley et al., 2001). By measuring GTP hydrolysis, potencies and efficacies of H2R agonists are assessed in an expression level-independent manner (Seifert et al., 1999; Kelley et al., 2001; WenzelSeifert et al., 2001). Both H1R and H2R agonists are important pharmacological tools for studying the role of the H1R and H2R, respectively, in (patho)physiological processes (Bakker et al., 2002; Dove et al., 2004; Pertz et al., 2004). H1R agonists are divided into three classes: 1) small agonists derived from HIS, such as 2-methylhistamine and 2-(2-thiazolyl)ethanamine, 2) HIS derivatives with a bulkier aromatic substituent at position 2 of the imidazole ring, such as 2-(3-bromophenyl)histamine, and 3) the histaprodifens (Bakker et al., 2002; Pertz et al., 2004). Unfortunately, bulky H1R agonists exhibit considerably lower potency and efficacy at the hH1R than at the guinea pig H1R (gpH1R), limiting their usefulness as tools for studying the hH1R (Seifert et al., 2003). The molecular basis for the differences in pharmacological properties between hH1R and gpH1R has recently been elucidated (Bruysters et al., 2005). A further complication is that, at concentrations in the range of 10 M to 1 mM, 2-phenylhistamines may activate G-proteins directly, i.e., in a receptor-independent manner (Seifert et al., 1994; Hagelüken et al., 1995; Klinker et al., | v2 |
2020-10-06T13:33:24.498Z | 2020-09-29T00:00:00.000Z | 222168450 | s2ag/train | Pine bark (Pinus spp.) extract for treating chronic disorders.
BACKGROUND
Pine bark (Pinus spp.) extract is rich in bioflavonoids, predominantly proanthocyanidins, which are antioxidants. Commercially-available extract supplements are marketed for preventing or treating various chronic conditions associated with oxidative stress. This is an update of a previously published review.
OBJECTIVES
To assess the efficacy and safety of pine bark extract supplements for treating chronic disorders.
SEARCH METHODS
We searched three databases and three trial registries; latest search: 30 September 2019. We contacted the manufacturers of pine bark extracts to identify additional studies and hand-searched bibliographies of included studies.
SELECTION CRITERIA
Randomised controlled trials (RCTs) evaluating pine bark extract supplements in adults or children with any chronic disorder.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trial eligibility, extracted data and assessed risk of bias. Where possible, we pooled data in meta-analyses. We used GRADE to evaluate the certainty of evidence. Primary outcomes were participant- and investigator-reported clinical outcomes directly related to each disorder and all-cause mortality. We also assessed adverse events and biomarkers of oxidative stress.
MAIN RESULTS
This review included 27 RCTs (22 parallel and five cross-over designs; 1641 participants) evaluating pine bark extract supplements across 10 chronic disorders: asthma (two studies; 86 participants); attention deficit hyperactivity disorder (ADHD) (one study; 61 participants), cardiovascular disease (CVD) and risk factors (seven studies; 338 participants), chronic venous insufficiency (CVI) (two studies; 60 participants), diabetes mellitus (DM) (six studies; 339 participants), erectile dysfunction (three studies; 277 participants), female sexual dysfunction (one study; 83 participants), osteoarthritis (three studies; 293 participants), osteopenia (one study; 44 participants) and traumatic brain injury (one study; 60 participants). Two studies exclusively recruited children; the remainder recruited adults. Trials lasted between four weeks and six months. Placebo was the control in 24 studies. Overall risk of bias was low for four, high for one and unclear for 22 studies. In adults with asthma, we do not know whether pine bark extract increases change in forced expiratory volume in one second (FEV1) % predicted/forced vital capacity (FVC) (mean difference (MD) 7.70, 95% confidence interval (CI) 3.19 to 12.21; one study; 44 participants; very low-certainty evidence), increases change in FEV1 % predicted (MD 7.00, 95% CI 0.10 to 13.90; one study; 44 participants; very low-certainty evidence), improves asthma symptoms (risk ratio (RR) 1.85, 95% CI 1.32 to 2.58; one study; 60 participants; very low-certainty evidence) or increases the number of people able to stop using albuterol inhalers (RR 6.00, 95% CI 1.97 to 18.25; one study; 60 participants; very low-certainty evidence). In children with ADHD, we do not know whether pine bark extract decreases inattention and hyperactivity assessed by parent- and teacher-rating scales (narrative synthesis; one study; 57 participants; very low-certainty evidence) or increases the change in visual-motoric coordination and concentration (MD 3.37, 95% CI 2.41 to 4.33; one study; 57 participants; very low-certainty evidence). In participants with CVD, we do not know whether pine bark extract decreases diastolic blood pressure (MD -3.00 mm Hg, 95% CI -4.51 to -1.49; one study; 61 participants; very low-certainty evidence); increases HDL cholesterol (MD 0.05 mmol/L, 95% CI -0.01 to 0.11; one study; 61 participants; very low-certainty evidence) or decreases LDL cholesterol (MD -0.03 mmol/L, 95% CI -0.05 to 0.00; one study; 61 participants; very low-certainty evidence). In participants with CVI, we do not know whether pine bark extract decreases pain scores (MD -0.59, 95% CI -1.02 to -0.16; one study; 40 participants; very low-certainty evidence), increases the disappearance of pain (RR 25.0, 95% CI 1.58 to 395.48; one study; 40 participants; very low-certainty evidence) or increases physician-judged treatment efficacy (RR 4.75, 95% CI 1.97 to 11.48; 1 study; 40 participants; very low-certainty evidence). In type 2 DM, we do not know whether pine bark extract leads to a greater reduction in fasting blood glucose (MD 1.0 mmol/L, 95% CI 0.91 to 1.09; one study; 48 participants;very low-certainty evidence) or decreases HbA1c (MD -0.90 %, 95% CI -1.78 to -0.02; 1 study; 48 participants; very low-certainty evidence). In a mixed group of participants with type 1 and type 2 DM we do not know whether pine bark extract decreases HbA1c (MD -0.20 %, 95% CI -1.83 to 1.43; one study; 67 participants; very low-certainty evidence). In men with erectile dysfunction, we do not know whether pine bark extract supplements increase International Index of Erectile Function-5 scores (not pooled; two studies; 147 participants; very low-certainty evidence). In women with sexual dysfunction, we do not know whether pine bark extract increases satisfaction as measured by the Female Sexual Function Index (MD 5.10, 95% CI 3.49 to 6.71; one study; 75 participants; very low-certainty evidence) or leads to a greater reduction of pain scores (MD 4.30, 95% CI 2.69 to 5.91; one study; 75 participants; very low-certainty evidence). In adults with osteoarthritis of the knee, we do not know whether pine bark extract decreases composite Western Ontario and McMaster Universities Osteoarthritis Index scores (MD -730.00, 95% CI -1011.95 to -448.05; one study; 37 participants; very low-certainty evidence) or the use of non-steroidal anti-inflammatory medication (MD -18.30, 95% CI -25.14 to -11.46; one study; 35 participants; very low-certainty evidence). We do not know whether pine bark extract increases bone alkaline phosphatase in post-menopausal women with osteopenia (MD 1.16 ug/L, 95% CI -2.37 to 4.69; one study; 40 participants; very low-certainty evidence). In individuals with traumatic brain injury, we do not know whether pine bark extract decreases cognitive failure scores (MD -2.24, 95% CI -11.17 to 6.69; one study; 56 participants; very low-certainty evidence) or post-concussion symptoms (MD -0.76, 95% CI -5.39 to 3.87; one study; 56 participants; very low-certainty evidence). For most comparisons, studies did not report outcomes of hospital admissions or serious adverse events.
AUTHORS' CONCLUSIONS
Small sample sizes, limited numbers of RCTs per condition, variation in outcome measures, and poor reporting of the included RCTs mean no definitive conclusions regarding the efficacy or safety of pine bark extract supplements are possible. | v2 |
2017-11-19T11:27:18.407Z | 2003-01-01T00:00:00.000Z | 29926560 | s2ag/train | Mechanism of inhibition of growth of 3 T 3L 1 fibroblasts and their differentiation to adipocytes by dehydroepiandrosterone and related steroids : Role of glucose-6-phosphate dehydrogenase ( pentose phosphate pathway / 6-phosphogluconate / liposomes / epiandrosterone / 16 a-bromoepiandrosterone )
Dehydroepiandrosterone (DHEA) and certain structural analogues block the differentiation of 3T3-L1 mouse embryo fibroblasts to adipocytes. These steroids also are potent uncompetitive inhibitors of mammalian glucose-6-phosphate dehydrogenases (G6PDs). We provide direct evidence that treatment ofthe 3T3-L1 cells withDHEA and its analogues results in intracellular inhibition of G6PD, which is associated with the block of differentiation: (i) Levels of 6-phosphogluconate and other products of the pentose phosphate pathway are decreased; (ii) the magnitude of these decreases depends on the potency of steroids as inhibitors of G6PD and on concentration and duration of exposure, and it is accompanied by a proportionate block of differentiation; (iu) in cells exposed to 16a-bromoepiandrosterone (a more potent inhibitor of G6PD than DHEA) at concentrations that block differentiation, introduction of exogenous 6-phosphogluconate in liposomes raises the levels of 6-phosphogluconate and other products of the pentose phosphate pathway and partially relieves the steroid block of cell growth and differentiation. Dehydroepiandrosterone (DHEA) is a weakly androgenic and weakly estrogenic steroid that is present in human plasma and urine and is especially abundant as its sulfate (DHEAS) (1, 2). Concentrations of DHEA and DHEAS decline continuously with age (3, 4), and low levels ofDHEA and/or DHEAS have been associated with the presence or risk of developing cancer and with increased mortality from cardiovascular disease (5-7). Hence, it is an intriguing possibility that DHEA may exercise hitherto unrecognized regulatory functions, and that some diseases associated with aging may result from a relative deficiency of DHEA or related steroids. These speculations are bolstered by animal experiments. In rodents, administration ofDHEA decreases the incidence of spontaneous and carcinogen-induced tumors, retards atherosclerosis, slows weight gain without affecting food intake, ameliorates autoimmune disease, and increases life span (8-10). The mechanisms by which DHEA exerts these actions are unclear. An unusual property of DHEA and several closely related steroids is their potent uncompetitive inhibition of mammalian glucose-6-phosphate dehydrogenases (G6PDs) (11-13). Uncompetitive inhibition, in which the inhibitor binds only to the enzyme-substrate complex, is extremely rare. Inhibition results in proportionate decreases in Km and Vm., values and may have profound effects on the flux and levels of intermediates in a multienzyme pathway (13). The possible relationship between inhibition of G6PD and the mechanism of action ofDHEA is the subject of this report. The unequivocal demonstration that inhibition of an enzyme is responsible for a biological effect observed in vivo is often difficult. We have used cultures of the 3T3-L1 clone of mouse embryo fibroblasts to obviate some of the complexities encountered with intact animals. Confluent 3T3-L1 monolayers rapidly differentiate into adipocytes when exposed to an appropriate differentiation mixture, and glycerol3-phosphate dehydrogenase levels provide a simple measure of the extent of differentiation (14, 15). DHEA and related steroidal inhibitors ofG6PD block this differentiation process (16, 17). We provide strong evidence in this paper that depression of pentose phosphate levels by steroids contributes to block of differentiation. Thus, intracellular levels of 6-phosphogluconate (6PG) and other intermediates of the pentose phosphate pathway are depressed by steroid treatment, and introduction of 6PG by means of liposomes into such cells restores these levels and reverses the block of differentiation. MATERIALS AND METHODS Materials. All reagents were from Sigma. Lipids were from Avanti Polar Lipids. The sources of all other materials have been described (16). Standard Protocol for Differentiation of 3T3-L1 Cells. Cultures were grown as monolayers on plastic dishes (usually 10-cm diameter) in Dulbecco's modified Eagle's medium containing 10% calf serum (15). Cells were plated at a density of 1.4 x 103 cells per cm2 and maintained at 370C in a humidified atmosphere of 10% C02/90% air. The medium was replaced on days 3, 5, 7, 9, and 11. To induce differentiation, the medium on day 7 contained 10% fetal calf serum, insulin (10,ug/ml), dexanmethasone (1.0 ,uM), and 1-methyl3-isobutylxanthine (0.5 mM), and on days 9 and 11 the medium contained 10% fetal calf serum and insulin (10 ,ug/inl). Additions ofblocking steroids [in ethanol or dimethyl sulfoxide; 0.1% (vol/vol)] were made simultaneously with the differentiation mixture on day 7 (16, 17). The cells were always harvested on day 12. The cell layers were washed three times with cold phosphate-buffered saline (PBS; 150 mM NaCl/10 mM sodium/potassium phosphate, pH 7.4) and then incubated at 25°C for 5 min with small volumes of 100 mM triethanolamine hydrochloride (pH 7.4) containing digitonin (0.8 mg/ml). The supernatant fluids obtained after centrifugation at 20,000 x g for 40 min at 40C were assayed for glycerol-3-phosphate dehydrogenase (16) and for protein concentration (18). Preparation of Liposomes. Unilamellar anionic liposomes were prepared either by vaporization of petroleum ether solutions (19) or by high-pressure filtration through a 2-,um Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; 6PG, 6-phosphogluconate; DHEA, dehydroepiandrosterone (3/3-hydroxy5-androsten-17-one); DHEAS, dehydroepiandrosterone-3-sulfate; EA, epiandrosterone (3p8-hydroxy-5a-androstan-17-one); BrEA, 16a-bromo-3,8-hydroxy-5a-androstan-17-one. 3852 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. Proc. Natl. Acad. Sci. USA 86 (1989) 3853 polycarbonate filter with the use of an "extruder" (Lipex Biomembranes, Vancouver, BC, Canada) (20) of lipid mixtures containing phosphatidylcholine, dicetylphosphate, and cholesterol (molar ratio, 7:2:1). The aqueous phase to be trapped was either PBS or 10-50mM 6PG in PBS. Liposomes were sonicated for 5 min at 4°C with the microtip ofa Branson sonifier at a setting of 5 and 70% power output. Liposomes were concentrated and the untrapped 6PG was removed by filtration through a C-30 Centricon cartridge (Amicon; 30,000 MW cutoff) at 5000 x g. The concentration of 6PG trapped in the liposomes was determined enzymatically (21) in the presence of 0.1% Triton X-100. In a typical experiment, 5% of the 6PG contained initially in the aqueous medium was entrapped by the liposomes. Measurement of Phosphorylated Intermediates. Perchloric acid extracts of cell monolayers (22) were treated with activated charcoal and filtered through Millipore HV 0.45-,um filters to reduce the background fluorescence. Phosphorylated intermediates were assayed enzymatically (21, 23). | v2 |
2019-06-21T23:05:36.918Z | 2019-06-20T00:00:00.000Z | 195187590 | s2ag/train | Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn's disease.
BACKGROUND
Crohn's disease (CD) is a chronic inflammatory disorder that can involve any part of the gastrointestinal tract. 5-Aminosalicylates (5-ASAs) are locally acting, anti-inflammatory compounds that reduce inflammation of the colonic mucosa with release profiles that vary among various commercially available formulations. This updated Cochrane review summarizes current evidence on the use of 5-ASA formulations for maintenance of surgically-induced remission in CD.
OBJECTIVES
To assess the efficacy and safety of 5-ASA agents for the maintenance of surgically-induced remission in CD.
SEARCH METHODS
We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register from inception to 16 July 2018. We also searched references, conference abstracts, and trials registers.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that included participants with CD in remission following surgery and compared 5-ASAs to no treatment, placebo or any other active intervention with duration of at least three months were considered for inclusion.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. The primary outcome was clinical relapse. Secondary outcomes included endoscopic recurrence, radiologic and surgical relapse, adverse events, serious adverse events and withdrawal due to adverse events.
MAIN RESULTS
Fourteen RCTs (1867 participants) were included in the review. Participants (15 to 70 years) were recruited from gastroenterology hospitals and medical clinics in Europe and North America and followed up between 3 and 72 months. The risk of bias was assessed as 'low' in one study, 'unclear' in seven and as 'high' in six.At 12 months, 36% (20/55) of participants in the 5-ASA group experienced clinical relapse compared to 51% (28/55) in the no treatment control group (RR 0.71, 95% CI 0.46 to 1.10; low certainty evidence). Moderate certainty evidence suggests that 5-ASAs are more effective for preventing clinical relapse than placebo. During a follow-up period of 12 to 72 months, 36% (131/361) of 5-ASA participants relapsed compared to 43% (160/369) of placebo participants (RR 0.83, 95% CI 0.72 to 0.96; I² = 0%; moderate certainty evidence). At 12 months, 17% (17/101) of the 4 g/day mesalamine group relapsed compared to 26% (27/105) of the 2.4 g/day group (RR 0.65, 95% CI 0.38 to 1.13; moderate certainty evidence). There was no evidence of a difference in clinical relapse rates when 5-ASA compounds were compared to purine antimetabolites. At 24 months, 61% (103/170) of mesalamine participants relapsed compared to 67% (119/177) of azathioprine participants (RR 0.90, 95% CI 0.76 to 1.07; I² = 28%; low certainty evidence). During 24 months, 50% (9/18) of 5-ASA participants had clinical relapse compared to 13% (2/16) of adalimumab participants (RR 4.0, 95% CI 1.01 to 15.84; low certainty evidence). The effects of sulphasalazine compared to placebo on clinical relapse rate is uncertain. After 18 to 36 months, 66% (95/143) of participants treated with sulphasalazine relapsed compared to 71% (110/155) in the placebo group (RR 0.88, 95% CI 0.56 to 1.38; I² = 38%; low certainty evidence).The effect of 5-ASA drugs on safety was uncertain. During 24 months follow-up, 4% (2/55) of 5-ASA participants experienced adverse events compared to none (0/55) in the no treatment control group (RR 5.00, 95% CI 0.25 to 101.81; very low certainty evidence). An equal proportion of 5-ASA participants (10%; 23/241) and placebo (9%; 20/225) groups experienced an adverse event during a follow-up of 3 to 72 months (RR 1.07, 95% CI 0.60 to 1.91; I² = 0%; low certainty evidence). Adverse event rates were similar in the 5-ASA and purine analogues groups. However, serious adverse events and withdrawals due to adverse events were more common in participants who received purine analogues than 5-ASA. At 52 weeks to 24 months, 52% (107/207) of 5-ASA participants had an adverse event compared to 47% (102/218) of purine analogue participants (RR 1.11, 95% CI 0.97 to 1.27, I² = 0%; low certainty evidence). Four per cent (6/152) of 5-ASA participants had a serious adverse event compared to 17% (27/159) of purine analogue participants (RR 0.30, 95% CI 0.11 to 0.80; very low certainty evidence). Eight per cent (17/207) of 5-ASA participants withdrew due to an adverse event compared to 19% (42/218) of purine analogue participants (RR 0.48, 95% CI 0.28 to 0.83; low certainty evidence). Adverse event rates were similar in high and low dose mesalamine participants. After 12 months, 2% (2/101) of 4 g/day mesalamine participants had an adverse event compared to 2% (2/105) of 2.4 g/day participants (RR 1.04, 95% CI 0.15 to 7.24; low certainty evidence). The proportion of participants who experienced adverse events over a 24 month follow-up in the mesalamine group was 78% (14/18) compared to 69% (11/16) of adalimumab participants (RR 1.13, 95% CI 0.75 to 1.71; very low certainty evidence). None (0/32) of the sulphasalazine participants had an adverse event at 18 months follow-up compared to 3% (1/34) of the placebo group (RR 0.35, 95% CI 0.01 to 8.38; very low certainty evidence). Commonly reported adverse events in the included studies were diarrhoea, nausea, increased liver function tests, pancreatitis, and abdominal pain.
AUTHORS' CONCLUSIONS
5-ASA preparations are superior to placebo for the maintenance of surgically-induced clinical remission in patients with CD (moderate certainty). The number needed to treat to prevent one relapse was 13 patients. The evidence for endoscopic remission is uncertain. The sulphasalazine class of 5-ASA agents failed to demonstrate superiority against placebo, 5-ASAs failed to demonstrate superiority compared to no treatment (very low and low certainty). The efficacy of two different doses of the same 5-ASA and the efficacy of 5-ASA compared to purine antimetabolites (azathioprine or 6-mercaptopurine) in maintaining surgically-induced remission of CD remains unclear. However, purine analogues lead to more serious adverse events and discontinuation due to adverse events. There is a low certainty that 5-ASA is inferior for maintaining surgically-induced remission of CD compared to biologics (anti TNF-ɑ). 5-ASA formulations appear to be safe with no difference in the occurrence of adverse events or withdrawal when compared with placebo, no treatment or biologics. | v2 |
2021-11-26T16:04:20.067Z | 2021-11-05T00:00:00.000Z | 244654310 | s2ag/train | PB2313: DARATUMUMAB AS A TREATMENT FOR ADULT IMMUNE THROMBOCYTOPENIA: A PHASE II STUDY WITH SAFETY RUN-IN (THE DART STUDY)
Background: Immune thrombocytopenia (ITP) is characterized by antibody-mediated platelet destruction and impaired platelet production. Residual long-lived autoreactive plasma cells may be a source of treatment resistance in autoimmune cytopenias. Antiplatelet-specific plasma cells have been detected in the spleen of the rituximab refractory ITP patients. These cells can also migrate and reside in bone marrow as long-lived plasma cells.
Daratumumab, an anti-CD38 antibody, targets plasma cells and is approved for the treatment of multiple myeloma. Daratumumab has been successfully used to treat refractory autoimmune cytopenias in children and a few cases of post-transplant autoimmune cytopenias and refractory SLE in adults.
We hypothesized that long-lived autoreactive plasma cells may be the source of treatment failure in some ITP patients. Based on that, we initiated a multicenter, open-label, dose-escalating phase II study with a safety run-in to evaluate the safety and efficacy of daratumumab in patients with ITP (NCT04703621). The first 3 patients were included in the safety run-in during Jan - May 2021.
Study design and methods:
Main inclusion criteria include age ≥18, primary ITP with a platelet count of ≤30X109/L, failure of corticosteroid therapy, and at least one second-line therapy including rituximab and/or TPO-RA.
Main exclusion criteria include active bleeding, secondary ITP, concomitant autoimmune hemolytic anemia.
Twenty-one patients will be included in the study. The safety run-in phase includes 3 patients who receive 4 weekly subcutaneous daratumumab injections followed by a 4-week observational period. Enrollment of the next patient in this phase occurs after the previous patient has completed treatment and an observational period. In cohort 1, 9 patients will receive 8 weekly injections. If the response rate is <100% and no severe adverse events appear, the subsequent 9 patients will receive 8 weekly daratumumab injections followed by 2 injections administered every other week. Standard premedication before all daratumumab injections consists of antihistamine, corticosteroid (methylprednisolone 100 mg or equivalent before the 1 st daratumumab injection and 60 mg or equivalent before subsequent injections), and paracetamol.
Rescue ITP medications are allowed during the first 8 weeks of the study. Steroid or TPO-RA (eltrombopag or romiplostim) dosing must remain stable during the 2 weeks preceding the inclusion. Dose escalation is not allowed during the study.
The primary endpoint is a platelet count >50x10 9/L in 2 measurements 12 weeks after treatment initiation for cohort 1, and 16 weeks for cohort 2, without rescue therapy after week 8. Safety will be assessed by the incidence and severity of adverse events. Secondary endpoints will include the number of weeks with platelet count >50x10 9/L between the end of treatment and end of study without rescue therapy or dose increments of corticosteroids. Time to treatment failure (TTF) is defined as time to first platelet count <30x10 9/L or administration of any platelet elevating therapy after achieving response.
Exploratory endpoints include: role of anti-GPIIb/IIIa and Ib antibodies; serial characterization of various subsets of immunocompetent cells in the bone marrow and blood; measurement of HRQoL and fatigue
Statistics: The primary outcome (treatment response) will be reported separately for each cohort and the entire study population, expressed by absolute numbers and rates with the corresponding 95% confidence interval. Daratumumab treatment will be considered "successful" if we observe a response rate of 30% or higher.
Current enrollment status: As of July 10, 2021, 2 sites are open. Two patients have completed the safety run-in; one is close. One/two responded to treatment at week 12. Platelet response in all 3 patients is shown in Figure 1. No serious or grade 3 adverse events were reported. Cohort 1 will start in August 2021.
Figure 1 Figure 1.
Tsykunova: Ablynx: Consultancy; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sobi: Consultancy; Sanofi: Consultancy. Holme: bayer, Octapharma, Pfizer: Other: support to institution, Research Funding; Bayer, Novo Nordisk, Octapharma, Pfizer, Roche, Takeda, Sobi: Consultancy, Honoraria. Tran: Astra Zeneca: Consultancy; Novartis, Janssen, Abbvie, Takeda, CSL Bering: Consultancy. Tvedt: Ablynx,Alexion, Novartis: Membership on an entity's Board of Directors or advisory committees. Michel: Amgen,Novartis,UCB,Argenx,Rigel: Honoraria. Frederiksen: Novartis: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Alexion: Research Funding; Gilead: Research Funding. Bussel: CSL: Other: DSMB; UCB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Principia/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; UptoDate: Honoraria; RallyBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova/Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Momenta/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuter: Rubius: Current equity holder in publicly-traded company; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Principia, Protalex, Protalix, Rigel: Consultancy, Other: grant support and consulting fees; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ), UCB: Research Funding; Platelet Disorder Support Association: Membership on an entity's Board of Directors or advisory committees; Up-to-Date: Patents & Royalties: Up-To-Date. Ghanima: Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, Sanofi: Honoraria; Bayer, BMS/Pfizer: Research Funding; Amgen, Novartis, Pfizer, Principia Biopharma Inc- a Sanofi Company, Sanofi, SOBI, Griffols, UCB, Argenx: Consultancy.
| v2 |
2020-11-05T09:05:47.771Z | 2020-11-05T00:00:00.000Z | 228842520 | s2ag/train | Orca-T, a Precision Treg-Engineered Donor Product, Prevents Acute Gvhd with Less Immunosuppression in an Early Multicenter Experience with Myeloablative HLA-Matched Transplants
BACKGROUND
GVHD remains a frequent and serious complication of HSCT despite the decades-long use of standard immunosuppression, such as tacrolimus and methotrexate, as prophylaxis against GVHD. Preclinical models have shown that the timed infusion of donor-derived high-purity CD4+CD25+FOXP3+ regulatory T cells (Treg) preceding adoptive transfer of conventional T cells (Tcon) prevents GVHD and maintains anti-cancer immunity without the need of pharmacologic agents. Early clinical trials using purified Treg-engineered graft showed safety and feasibility, but more extensive clinical studies are needed to test scalability and efficacy. Orca-T is an industry-manufactured, precision-engineered CD34-selected, Treg-engineered graft made in a central GMP laboratory and distributed to multiple centers in the U.S. We present our early patient experience with Orca-T in an ongoing single center phase 2 trial and a multicenter Phase Ib trial and report a pre-planned evaluation of patients randomized to receive Orca-T plus single-agent GVHD prophylaxis (PPX) or Orca-T and no PPX.
METHODS
51 patients with high risk or active hematologic malignancies undergoing myeloablative conditioning were enrolled on two trials: a single-center Phase I/II (n=40, NCT01660607) and a multicenter Phase Ib (n=11; NCT04013685) study. Patients received CD34-selected cells infused with highly purified Treg (target dose: 3.0 x 106 cells/kg) followed 2 days later by the infusion of Tcon (3.0 x 106 cells/kg). Initial GMP manufacturing was demonstrated at Stanford (n=9 grafts; 2016 - 2019) and then transferred to Orca Bio in 2019 for scaled production.
We evaluated the 34 patients beyond dose escalation since July 2016 who received Orca-T grafts from either matched related (n=25) or unrelated (n=9) donors and single agent GVHD PPX with either tacrolimus (n=28) or sirolimus (n=6). For comparative analysis, we identified a contemporaneous SOC cohort at Stanford (n=138) with both matched related (n=79) and unrelated (n=59) transplant recipients who received unmanipulated PBSC products (median f/u 546 days) and methotrexate plus tacrolimus.
In April 2019, enrollment on a phase 2, stage 1 pre-planned subgroup of 24 patients were randomized to test whether all GVHD PPX could be removed: Orca-T plus either single-agent PPX (Arm 1, n=12) or no PPX (Arm2, n=12).
RESULTS
The Orca-T drug products were manufactured reliably with high Treg purity (93.8% +/- 3.1%) and a dose of 2.6 +/- 0.4 x 106 per kg (equivalent between arms and trials). Central lab turn-around times were 25.3 +/- 3.0 hours and all vein-to-vein times were less than 72 hrs (Table 1). For trial participants, there were no manufacturing failures, engraftment failures or treatment related mortality. Orca-T patients vs. SOC showed earlier neutrophil (median of 11 days vs. 14 days, p<0.0001 by Mann-Whitney U) and platelet engraftment (11 vs 17 days, p<0.0001) and a shorter hospital stay (15 vs 19 days, p=0.0002).
Patients across 4 clinical sites received Orca-T plus single agent GVHD PPX (n=34; median f/u 261 days) had an acute GVHD grade 2-4 incidence of 0% as compared to 33% in the SoC cohort (n=138, p=0.0018 by Log-rank Mantel-Cox test, Fig. 1). The rate of moderate to severe chronic GVHD for Orca-T patients was 4% vs. 44% in the SoC cohort (p=0.016).
In a preliminary subset of evaluable Orca- T patients, GVHD & relapse free survival (GRFS) at one year was higher for Orca-T patients vs SoC (69% versus 33%, p=0.006) while relapse and overall survival did not appear to differ. We observed no differences in infectious complications.
In patients randomized to PPX vs. no PPX, the incidence of aGVHD grade 2-4 was 0% in Arm 1 and 58% in Arm 2 (p <0.0001, Log-rank Mantel-Cox test), with 17% of these events being Grade 3-4. All GVHD in Arm 2 responded to steroids with no GVHD-related deaths.
CONCLUSIONS
Manufacture of high precision Orca-T Treg-engineered donor products were successfully scaled in a central GMP with reliable distribution to centers. Patients who received Orca-T and single agent PPX had no grade 2 or greater acute GVHD acute and very little chronic GVHD when compared to SOC. Patients randomized to Orca-T and no PPX showed an increased incidence of acute GVHD vs. those with Orca-T and single agent PPX. Engineered Treg grafts show promise to improve GFRS and other transplant outcomes. Orca-T has been granted RMAT status by the FDA and evaluation continues in an ongoing multicenter clinical trial.
Meyer: Orca Bio: Research Funding. Moroz:Orca Bio: Research Funding. Miklos:Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Muffly:Servier: Research Funding; Adaptive: Research Funding; Amgen: Consultancy. Rezvani:Pharmacyclics: Research Funding. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Fernhoff:Orca Bio: Current Employment, Current equity holder in private company. Putnam:Orca Bio: Current Employment, Current equity holder in private company. McClellan:Orca Bio: Current Employment, Current equity holder in private company. Shaw:Orca Bio: Consultancy. McGuirk:Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Bellicum Pharmaceutical: Research Funding; Gamida Cell: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pluristem Ltd: Research Funding. Abedi:BMS, Gilead Sciences: Research Funding; AbbVie, BMS, Gilead Sciences, Seattle Genetics, Takeda: Speakers Bureau. Negrin:Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; KUUR Therapeutics: Consultancy; Biosource: Current equity holder in private company; UpToDate: Honoraria; Amgen: Consultancy; BioEclipse Therapeutics: Current equity holder in private company.
| v2 |
2020-11-05T09:05:59.182Z | 2020-11-05T00:00:00.000Z | 228906870 | s2ag/train | A Molecular-Based Response Prediction Model to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndrome and Severe Thrombocytopenia
*UP, LA contributed equally
Introduction
A significant proportion of lower risk (LR)-MDS patients present with thrombocytopenia, being associated with shortened survival and higher risk of progression to acute myeloid leukemia (AML). Treatment options for patients with LR-MDS and severe thrombocytopenia remain limited apart from transfusion support. Romiplostim (ROM), a thrombopoietin receptor agonist (TPO-RA) has shown safety and efficacy dependent on endogenous TPO levels as well as platelet transfusion history in a poorly defined subset of LR-MDS patients (Giagounidis et al. Cancer 2014, Sekeres et al. BJH 2014).
Methods
The multicenter phase 2 EUROPE trial investigated potential biomarkers of response (e.g. TPO levels, molecular markers) to single agent ROM in LR-MDS patients with severe thrombocytopenia. Patients were eligible if platelet counts were ≤30 G/L or ≤50 G/L in case of bleeding history. The primary efficacy endpoint was the rate of hematologic improvement of platelets (HI-P, according to IWG 2006 criteria) lasting for at least 8 weeks after 16 weeks of ROM (750µg SC qw) treatment. At the time of screening, patients were assigned into 3 different cohorts based on their previous platelet transfusion events (PTE) as well as centrally assessed TPO serum levels (A: TPO<500 ng/l, PTE<6 units/past year; B: TPO<500 ng/l, PTE≥6 units or TPO≥500 ng/l, PTE<6 units, C: TPO≥ 500 ng/l, PTE≥6 units). Bone marrows analysis were centrally reviewed.
Results
From 2015 to 2019, a total of 79 patients were included at 29 trial sites in Germany, France and the Czech Republic. Patients' median age was 74 years (range 42-93), median baseline platelet count was 25.5 G/L (range 3-50 G/L) and they were stratified into cohort A (n=51) or B+C (n=28), respectively. The primary endpoint was met with 34 out of 79 (43%) patients responding (HI-P), with response being markedly higher in cohort A (49%, n=25) vs. cohort B and C (32%, n=9) (p=0.145). Ten (13%) and eight (10%) patients had additional neutrophil (HI-N) and erythroid (HI-E) responses, respectively. During treatment, six patients had transient increases in peripheral blasts to more than 10% and one patient progressed to AML after one month of ROM. Although a higher number of responders was observed in group A, neither TPO level at screening (p=0.21), nor number of pretreatment PTE (p=0.12) were significantly associated with response to ROM treatment. Thus, our findings do not confirm that baseline TPO levels and number of pretreatment PTE alone allow reliable prediction of response to ROM.
With the aim to identify new molecular patterns correlating with response, we performed a targeted NGS analysis for somatic variants in 54 candidate genes in 75 patients at baseline and in 44 patients after 16 weeks of ROM. Responders (R) more frequently exhibited mutations like SRSF2 (R=39%, NR=17%), RUNX1 (R=24%, NR=14%) and TET2 (R=30%, NR=29%), whereas non-responders (NR) exhibited mutations like DNMT3A (R=12%, NR=21%), U2AF1(R=9%, NR=14%) or ASXL1 (R=6%, NR 17%) more frequent. The percentages of patients with a response to ROM were similar regardless of total number of baseline somatic mutations. Comparing responders vs. non-responders, we found no significant changes of variant allelic burden of variants detected pre- and post-ROM (Fig. 1).
We identified the presence of a SRSF2 mutation as a significant predictor of response to ROM treatment (p=0.031, logistic regression). Mutated SRSF2 was significantly more frequent in responders (39%) compared to non-responders (17%) (p=0.036, Fisher's exact test) (Fig. 2A,B). We used logistic regression with stepwise backward selection to assess the influence of the presence of ASXL1, DNMT3A, RUNX1, TET2 and SRSF2 mutations on response. Our final regression model excludes the non-significant ASXL1, DNMT3A, RUNX1 and TET2 mutations and includes the significant SRSF2 mutation, resulting in an overall accuracy of 64.0% for a correct ROM response prediction in this patient cohort.
Conclusion:
This prospective study did not confirm a significant association between response to ROM, pretreatment PTE burden and endogenous TPO levels. Instead, patients with a mutated SRSF2 displayed a significantly higher response to ROM treatment. This may allow personalized treatment approaches in patients with LR-MDS and severe thrombocytopenia. In this study, extended treatment with ROM did not lead to a significant increase in AML cases.
Kubasch: Shire: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Research Funding. Cony-Makhoul:Novartis: Consultancy; Pfizer: Consultancy; Incyte Biosciences: Speakers Bureau; BMS: Consultancy; BMS: Speakers Bureau. Laribi:takeda: Research Funding; novartis: Honoraria, Research Funding; amgen: Research Funding; abbvie: Honoraria, Research Funding. Park:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Other: Travel expenses. Metzeler:Astellas: Honoraria; Otsuka Pharma: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Schlenk:PharmaMar: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Roche: Research Funding; AstraZeneca: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Ades:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; novartis: Research Funding; Celgene/BMS: Research Funding; jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Romiplostim is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP). Limitations of Use: Romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP.
| v2 |
2019-04-28T13:09:52.446Z | 2004-05-01T00:00:00.000Z | 136427510 | s2ag/train | Making Research and Development Data More Meaningful in Ceramic Production
The R&D departments of ceramic tile manufacturing companies must immediately and methodically respond to problems which emerge during production. Therefore, to reduce the number of tests to be carried out is necessary. In this work, an efficient means of evaluating / characterising ceramic compositions was developed and applied not only to raw materials and glazes but also to bodies and engobes. Seger values of SiO2 and Al2O3 for the raw materials and mixtures were calculated by using chemical analyses. Silica versus alumina diagrams were drawn and examined. The ratios of silica to alumina of the compositons were also determined for comparison. Introduction In tile manufacturing, controlling process parameters effectively and maintaining standard properties of end product is dependant upon developing “user friendly” body, engobe and glaze compositions. Once successful recipes have been obtained, modifiying existing compositions (for valid reasons such as substituting a new raw material or unforseeable variations in the properties of materials) may necessitate taking immediate and proper action. This would only be possible when the characterisation of raw materials and compositions have been methodically evaluated in advance. Chemical analysis has been very useful, in this regard. From chemical analysis, Seger values (the molecular value of each ceramic oxide compared with the sum of the molecular values of alkalis and alkaline earths) have been widely used in calculation of glazes. It was also shown that the Seger values of SiO2 and Al2O3 accurately characterise the suitability of clays in brickmaking [1]. In this work, an attempt was made to exhibit the possibility of using Seger values in order to formulate, modify and control the compositions of bodies and engobes as well as glazes in tile manufacturing. Components of The Product Floor and wall tiles are made of different components. These are body, engobe and glaze. Body. Naturally, raw materials have a wide range of chemical and physical characteristics. There is a need to use kaolinitic /illitic clays and felspar/nepheline syenite as flux in body mixtures. The careful selection of raw materials ensures economical processing, and maintenance of good physical properties in the green state for handling various applications safely. Tile bodies are prepared by mixing suitable raw materials to reach an optimum composition which provides the required dimensional, pysical and chemical properties of a tile. Engobe. An engobe is a coating formed from a mixture of clays, fluxes, pigments and nonplastics that is applied on a ceramic body to produce a layer which smoothly covers all surface defects and coarse particles. Key Engineering Materials Online: 2004-05-15 ISSN: 1662-9795, Vols. 264-268, pp 1539-1544 doi:10.4028/www.scientific.net/KEM.264-268.1539 © 2004 Trans Tech Publications Ltd, Switzerland All rights reserved. No part of contents of this paper may be reproduced or transmitted in any form or by any means without the written permission of Trans Tech Publications Ltd, www.scientific.net. (Semanticscholar.org-13/03/20,18:13:49) Engobes are usually made with white firing clays in order to provide a suitable base upon which delicately coloured glazes may be used without suffering harm from iron bearing and other objectionable material [2]. Engobe must be compatible with body. Glazes. Glazes are thin layers of fused silica mixtures covering the surface of the tile. Glazes may be coloured or colourless, transparant or opaque. Frit is the pre-fused portion of a glaze. Apart from frit, glazes may contain quartz, felspar, kaolin, alumina, whiting, dolomite, zinc oxide and opasifiers. Diagrams Seger values of silica and alumina (the ratio of the molecular values of SiO2 and Al2O3 to the sum of the molecular values of R2O + RO) were found by calculating data derived from the chemical analysis given in Table 1, 2, 3 and 4. Table 1. Chemical analyses of the raw materials used for the bodies and glazes [mass-%]. Kaolinitic Clays (Body) K2O Na2O CaO MgO Fe2O3 Al203 SiO2 LOI KB1 1.14 0.13 0.57 0.20 2.00 21.41 65.62 8.93 KB2 2.22 0.33 0.85 0.51 2.46 21.72 63.68 8.23 KB3 0.24 0.13 0.57 0.48 20.18 69.51 8.89 KB4 0.29 0.32 0.13 0.05 0.80 26.22 62.70 9.49 Illitic Clays (Body) IB1 2.45 0.10 0.25 0.92 3.01 26.70 55.88 10.69 IB2 2.50 0.05 0.15 0.40 2.15 22.50 65.00 7.25 IB3 1.92 0.33 2.21 0.97 4.72 17.83 62.59 9.43 Fluxes (Body) FB1 0.53 9.72 1.34 0.10 0.17 19.04 67.98 1.12 FB2 6.57 4.47 1.06 0.22 1.38 17.27 67.56 1.47 FB3 3.79 1.75 0.28 0.10 0.83 16.70 72.48 4.07 FB4 5.05 5.90 0.30 0.20 0.23 18.70 68.41 1.21 Kaolins (Glaze) KG1 2.06 0.06 0.11 0.30 35.76 48.57 13.14 KG2 1.80 0.10 0.40 0.40 1.75 32.00 52.00 11.55 Fluxes (Glaze) FG1 0.15 9.09 0.82 0.11 0.11 16.84 72.05 0.83 FG2 9.41 2.62 0.58 0.07 15.89 71.11 0.32 Table 2. Calculated chemical composition of the bodies [mass-%]. K2O Na2O CaO MgO Fe2O3 Al203 SiO2 LOI BF1 2.82 3.14 0.75 0.38 1.72 21.12 64.52 5.55 BF2 3.01 3.33 1.01 0.43 1.98 19.95 64.84 5.45 BF3 3.38 3.04 0.96 1.16 1.24 22.13 62.30 6.39 BW 1.91 0.50 6.75 0.33 1.58 18.77 57.99 12.15 Table 3. Calculated chemical composition of the engobes [mass-%]. K2O Na2O CaO MgO ZnO Fe2O3 B2O3 Al203 SiO2 ZrO2 LOI EF1 0.69 3.58 0.50 0.20 0.68 25.13 60.11 3.23 5.88 EF2 0.82 2.07 0.99 0.19 0.73 2.21 27.52 52.76 6.74 5.97 EF3 0.68 3.67 0.51 1.15 0.68 20.68 59.51 6.45 6.67 EF4 0.69 3.69 0.56 1.60 0.69 20.17 59.15 6.45 7.00 EF5 0.88 2.89 1.32 0.21 0.72 3.31 19.12 58.02 7.86 5.67 EW 1.88 0.46 2.49 0.81 3.35 0.08 3.54 14.75 57.29 11.88 3.47 1540 Euro Ceramics VIII | v2 |
2019-07-09T21:40:52.491Z | 2017-01-01T00:00:00.000Z | 195875030 | s2ag/train | Structure activity relationship study of glaziovianin A against cell cycle progression and spindle formation of HeLa S 3 cells
Various derivatives of glaziovianin A, an antitumor isoflavone, were synthesized, and the cytotoxicity of each against HeLa S3 cells was investigated. Compared to glaziovianin A, the O-allyl derivative was found to be more cytotoxic against HeLa S3 cells and a more potent M-phase inhibitor. ©2000 Elsevier Science Ltd. All rights reserved. In 2007, glaziovianin A (1) was isolated from the leaves of the Brazilian tree Astelia glazioviana by Yokosuka et al. (Fig. 1). Glaziovianin A (1) exhibited cytotoxicity against HL-60 cells with an IC50 value of 0.29 M. Also, glaziovianin A (1) was evaluated against a panel of 39 human cancer cell lines (termed JFCR39) at the Japanese Foundation for Cancer Research. The pattern of the differential cytotoxicities of glaziovianin A (1) has suggested that the activity of glaziovianin A (1) involves the inhibition of tubulin polymerization as a mechanism of action. Inhibitors of tubulin polymerization have become clinically important drugs against breast cancer. Because glaziovianin A showed antitumor activities in a mouse xenograft model (unpublished data), we think that modification of glaziovianin A (1) can lead to the discovery of novel compounds that possess antitumor activity and that inhibit tubulin polymerization. In this paper, we report the structure–activity relationship study of glaziovianin A (1). Figure 1. Structure of glaziovianin A (1). We previously reported the synthesis of glaziovianin A (1) by using Suzuki–Miyaura coupling as a key step (Scheme 1). The method of synthesizing glaziovianin A analogues was based on our previous strategy. To develop analogues of glaziovianin A (1), its structure can be divided into two structural moieties: an A-ring and a B-ring (Fig. 2). Therefore, we synthesized 3iodochromone derivatives as an A-ring and borone compounds as a B-ring. Scheme 1. Total synthesis of glaziovianin A (1) by our group. Figure 2. Key structural moieties of glaziovianin A. First, we tried to modify a methylene acetal part at the B-ring of glaziovianin A (Scheme 2). The diol group in 3,6-dimethoxybenzene-1,2-diol (6) was converted to compound 7. The bromination of compound 7 gave a monobromo compound, which was converted into arylboronate 8. 2,3,4,5-Tetramethoxyphenylboronic acid (10) was prepared by the lithiation of 1,2,3,4tetramethoxybenzene (9) followed by treatment with trimethyl borate. The Suzuki–Miyaura coupling of 3iodo-6,7-dimethoxy-4H-chromen-4-one (3) with boron compounds, such as arylboronate 8, 2,3,4,5tetramethoxyphenylboronic acid (10), or commercially available 3,4-(methylenedioxy)phenylboronic acid (11), afforded glaziovianin A analogues 12–14, respectively. Scheme 2. Synthesis of B-ring analogues of glaziovianin A. Reagents and conditions: (a) 2-methoxypropene, PPTS, benzene, rt, 72%; (b) NBS, DMF, rt, 69%; (c) bis(pinacolato)diboron, PdCl2(dppf), KOAc, DMF, 150 °C, 28%; (d) n-BuLi, B(OMe)3, THF, rt; (e) 3, PdCl2(dppf), 1 M Na2CO3 aq., 1,4-dioxane, rt {64% for 12, 11% for 13 (from 9), 41% for 14}. Next, we prepared A-ring analogues. Selective protection of the hydroxy group at the C7 position of 15 afforded compound 16 (Scheme 3). Condensation of 16 with N,N-dimethylformamide dimethyl acetal gave an enamine, which was converted to iodochromone 17. We tried a cross coupling reaction with arylboronate 5 and iodochromone compounds, such as 17 or 18, to provide compounds 19 and 20, respectively. The THP group in 19 was removed by using p-TsOH·H2O to give a 7-hydroxy derivative (21), which is a suitable precursor for the synthesis of glaziovianin derivatives. Conversion of the hydroxy group at C7 in 21 into various ethers afforded benzyl ether 22, propargyl ether 23, and allyl ether 24. Scheme 3. Synthesis of A-ring analogues of glaziovianin A. Reagents and conditions: (a) DHP, PPTS, CH2Cl2, rt, 80%; (b) Me2NCH(OMe)2, 90 °C, quant; (c) I2, pyr, CHCl3, rt, 70%; (d) 5, PdCl2(dppf), 1 M Na2CO3 aq., 1,4-dioxane, rt (66% for 19, 16% for 20); (e) p-TsOH·H2O, MeOH, CHCl3, rt, 85%; (f) benzyl bromide, K2CO3, MeCN, rt, 80%; (g) allyl bromide, K2CO3, MeCN, rt, 78%; (h) propargyl bromide, K2CO3, MeCN, rt, 70%. Table 1 summarizes the cytotoxicity of glaziovianin A (1) and its analogues against HeLa S3 cells. Compound 12, which has an acetonide group instead of the methylene acetal group, showed no cytotoxicity even at 100M. Also, compound 13, which has four methoxy groups at the B-ring, was about 40-fold less cytotoxic than glaziovianin A (1). These results indicated that steric hindrance of C3’ and C4’ at the Bring part was shown to reduce cytotoxicity to a large extent. Compound 14, which lacks methoxy groups at C2’ and C5’, was less cytotoxic than glaziovianin A (1), which indicated that the electron density of the B-ring might be essential for cytotoxicity. On the other hand, compound 20, which has an extra methoxy group at C5 of the A-ring, showed no cytotoxicity at 100M. This result showed that the steric hindrance and electron density of the A-ring reduced cytotoxicity to a large extent. While the 7-demethyl derivative 21 exhibited no cytotoxicity, compounds 22–24, which each have an alkyl group at O instead of the methyl group, showed cytotoxicity with IC50 values of 0.75, 0.74, and 0.19 M, respectively. Furthermore, compound 19, which has a THP group at O, showed no cytotoxicity even at 100M. These results indicated that the hydrophobicity of the O-alkyl group in glaziovianin derivatives is important for cytotoxicity. However, the THP group seems to be too large. It is worth noting that allyl ether 24 is more active than glaziovianin A (1) itself. Table 1. Cytotoxicity of glaziovianin A (1) and its analogues against HeLa S3 cells. | v2 |
2020-12-14T20:14:18.415Z | 2020-11-05T00:00:00.000Z | 228921940 | s2ag/train | A Phase I Study of FT819, a First-of-Kind, Off-the-Shelf, iPSC-Derived TCR-Less CD19 CAR T Cell Therapy for the Treatment of Relapsed/Refractory B-Cell Malignancies
Background: Autologous T cells engineered to express a chimeric antigen receptor (CAR) targeting the B-cell lineage antigen CD19 (CAR19) in patients with relapsed/refractory (r/r) aggressive B-cell lymphomas (BCL) and pre-B acute lymphoblastic leukemia (B-ALL) have resulted in transformative improvements in clinical outcomes. However, there remain significant limitations concerning autologous CAR19 T cell manufacturing, including dysfunctional starting material, lack of product consistency and purity following genetic engineering, manufacturing timelines that necessitate the administration of bridging therapy in patients with aggressive disease, and insufficient quantities of CAR19 T cells, especially in severely cytopenic patients, to allow for more than single-dose administration routinely. The ability to consistently administer more than a single dose of CAR19 T cells enables dosing schedules that may reduce the risk of potentially life-threatening toxicities such as cytokine release syndrome and neurotoxicity, while maintaining or improving the depth and durability of anti-tumor responses.
FT819 is a first-of-kind, off-the-shelf CAR19 T cell product candidate derived from a clonal master engineered induced pluripotent stem cell (iPSC) line, which can be used as a renewable source for the mass production of off-the-shelf CAR T cells for broad patient access. FT819 is engineered with the following features designed to improve the safety and efficacy of CAR T cell therapy: a novel 1XX CAR signaling domain, which has been shown to extend T cell effector function without eliciting exhaustion; integration of the CAR transgene directly into the T cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR expression and enhanced T cell potency; and complete bi-allelic disruption of T cell receptor (TCR) expression for the prevention of graft-versus-host disease (GVHD). FT819 has demonstrated antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines comparable to that of donor-derived CAR T cells, and persists and maintains tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia (Mandal et al. 2020). The properties of FT819 and its ability to improve outcomes of patients with B-cell malignancies warrants further clinical investigation.
Study Design and Methods: This study is a multicenter, Phase I clinical trial of FT819 in patients with r/r B-cell malignancies, including BCL, chronic lymphocytic leukemia (CLL), and B-ALL. The primary objective of the trial is to determine the recommended Phase II dose of FT819. Key secondary objectives include evaluation of FT819 safety and tolerability, anti-tumor activity, and pharmacokinetics (PK). Exploratory objectives include characterization of FT819 pharmacodynamics as assessed by peripheral blood biomarkers, and by phenotypic and genetic characterization of the tumor microenvironment from paired pre- and post-treatment tumor biopsies.
The dose-escalation part of the trial utilizes a 3+3 dose-escalation design to identify the maximum tolerated dose for BCL, CLL, and B-ALL. The dose-expansion part of the trial is designed to further characterize the safety, efficacy, and PK of FT819 in multiple indications. Up to a maximum of 300 patients will be enrolled. The trial will test up to four FT819 dose levels ranging from 30 to 900 million cells. Three FT819 dosing regimens each will be tested for BCL, CLL, and B-ALL: Regimen A, FT819 administered as a single dose; Regimen A1, FT819 administered as a single dose in combination with interleukin (IL)-2; and Regimen B, FT819 administered as fractionated doses on Days 1, 3, and 5. Lympho-conditioning will consist of three consecutive days of fludarabine and cyclophosphamide administered prior to the first dose of FT819. Key inclusion criteria include r/r disease after standard approved therapies, documented CD19 expression, and adequate organ function. Key exclusion criteria include ongoing immunosuppression such as systemic GVHD therapy, prior allograft organ transplant, active central nervous system involvement of disease, and known allergy to FT819 components. The trial is expected to begin patient recruitment in 2020.
Park: Novartis: Consultancy; Fate Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Genentech/Roche: Research Funding; Kite: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; GSK: Consultancy; Autolus: Consultancy, Research Funding; Intellia: Consultancy; Minverva: Consultancy; Takeda: Consultancy, Research Funding; AstraZeneca: Consultancy; Servier: Consultancy, Research Funding; Allogene: Consultancy; Juno Therapeutics: Research Funding; Artiva: Membership on an entity's Board of Directors or advisory committees. Jain:Pfizer: Research Funding; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. McGuirk:Bellicum Pharmaceutical: Research Funding; Gamida Cell: Research Funding; Astellas: Research Funding; Pluristem Ltd: Research Funding; Novartis: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding. Diaz:Fate Therapeutics, Inc.: Current Employment. Valamehr:Fate Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company. Chu:Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Roche Holding AG: Current equity holder in publicly-traded company. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.
Cyclophosphamide and fludarabine will be used as lympho-conditioning therapy prior to FT819 administration. IL-2 will be administered in order to promote the expansion and function of FT819 as a T-cell product.
| v2 |
2021-11-26T16:40:00.792Z | 2021-11-05T00:00:00.000Z | 244642890 | s2ag/train | Efficacy and Safety of Eltrombopag Combined with Cyclosporine As First-Line Therapy in Adults with Severe Acquired Aplastic Anemia: Results of the Interventional Phase 2 Single-Arm Soar Study
Background: Severe aplastic anemia (SAA) is a rare bone marrow failure disorder associated with significant morbidity and mortality. SAA is characterized by severe pancytopenia and a hypocellular (<25%) bone marrow. The standard of care treatment is hemopoietic stem cell transplant or immunosuppressive therapy (IST) for patients (pts) who are ineligible for transplant. IST usually comprises an antithymocyte globulin (ATG) derived from horse or rabbit, and cyclosporine A (CsA). Although IST can be an effective treatment, individual intolerance, insufficient response, relapse, and clonal evolution remain significant limitations. The lack of global availability of the more effective horse ATG also leaves many pts with limited treatment options and poorer outcomes. In addition, pts with SAA often require transfusions which can be burdensome and negatively impact their quality of life. Eltrombopag (ETB) is indicated for use in pts with SAA who have had an insufficient response to IST (FDA PI, 2014) or are refractory to IST (EMA SmPC, 2015). More recently in the USA, ETB may also be used in combination with IST as first-line (1L) treatment (FDA PI, 2018).
Aims: To assess the efficacy and safety of ETB + CsA (without ATG) as 1L therapy in adult pts with SAA.
Methods: SOAR (NCT02998645) is a Phase 2, single-arm, multicenter, open-label study. Treatment-naive pts with SAA received ETB + CsA for 6 months; responders continued CsA therapy for an additional 24 months (later reduced to 18 months). The primary efficacy endpoint was overall response rate (ORR) by 6 months. ORR was defined as the proportion of pts with complete response ([CR] = absolute neutrophil count [ANC] ≥1000/μL AND platelet count ≥100,000/μL AND hemoglobin ≥10 g/dL) plus the proportion of pts with partial response ([PR] = any 2 of the following counts: ANC ≥500/μL; platelet count ≥20,000/μL; automated reticulocyte count ≥60,000/μL, but not sufficient for a CR). CR and PR were confirmed by 2 assessments ≥7 days apart; transfusion restrictions were also applied. For the primary endpoint to be considered 'clinically meaningful' at least 17/54 pts treated were required to have a response. Other endpoints included ORR by 3 months, ORR at 6 months (ie, confirmed response at the 6-month visit), and transfusion independence, which was defined as transfusion not being required in a period of ≥28 days for platelet transfusions and ≥56 days for red blood cell (RBC) transfusions.
Results: Pts (N=54) had a median (interquartile range [IQR]) age of 55.0 (40.0-67.0) years and 63.0% were male. The majority of pts were White (40.7%) or Asian (40.7%). The median (IQR) duration of exposure to ETB and CsA was 5.7 (2.5-5.8) months and 5.7 (2.4-8.1) months, respectively, and the median (IQR) daily ETB dose was 150.0 (100.0-150.0) mg/day. In the full analysis set, the primary endpoint was met, with 25/54 pts having a CR or PR by 6 months (ORR 46.3%; 95% confidence interval [CI], 32.6-60.4%). Of the 25 responders, 2 (3.7%) achieved a CR by 6 months. ORR by 3 months was 40.7% (95% CI, 27.6-55.0%; n=22/54), and ORR at 6 months was 37.0% (95% CI, 24.3-51.3%; n=20/54). 70.4% of all pts qualified for ≥1 period of RBC and/or platelet transfusion independence by 6 months, including all 25 (100%) responders and 13/29 (44.8%) non-responders (Fig. 1). 40.7% of all pts (responders: 68.0%; non-responders: 17.2%) qualified for ≥1 period of RBC transfusion independence (corresponding percentages for platelet transfusion independence were the same as for the combined RBC and/or platelet endpoint). Adverse events (AEs) occurred in 52/54 (96.3%) pts; 45 (83.3%) pts experienced treatment-related AEs (TAEs), 23 (42.6%) of whom had a grade ≥3 TAE. The most common all-grade AEs were increased blood bilirubin (40.7%), nausea (29.6%), increased alanine aminotransferase (22.2%), and diarrhea (22.2%). Seven (13.0%) pts discontinued treatment due to grade ≥3 AEs. There were 8 on-treatment deaths (aplastic anemia [n=3]; COVID-19, hemorrhage, multi-organ dysfunction syndrome, pyrexia, and thrombosis [all n=1]); no deaths were considered treatment-related.
Conclusion: Data from the SOAR study indicate that ETB + CsA may be beneficial for pts with SAA ineligible for transplant who cannot access or tolerate ATG. All responders and almost half of non-responders qualified for ≥1 period of transfusion independence by 6 months, suggestive of a decreased transfusion burden. No new safety signals were identified.
Figure 1 Figure 1.
Vallejo: Novartis: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Finelli: Takeda: Consultancy; Celgene BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Calado: Agios: Membership on an entity's Board of Directors or advisory committees; AA&MDS International Foundation: Research Funding; Alexion Brasil: Consultancy; Instituto Butantan: Consultancy; Novartis Brasil: Honoraria; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees. Peffault De Latour: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals Inc: Consultancy, Honoraria; Swedish Orphan Biovitrum AB: Consultancy, Honoraria. Kriemler-Krahn: Novartis: Current Employment. Haenig: Novartis: Current Employment. Maier: Novartis: Current Employment. Scheinberg: Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BioCryst Pharmaceuticals: Consultancy; Roche: Consultancy; Abbvie: Consultancy.
In the United States, eltrombopag is a thrombopoietin receptor agonist indicated in combination with standard immunosuppressive therapy (ATG + CsA) for the first-line treatment of adult and pediatric patients aged 2 years and older with severe aplastic anemia (SAA). It is also indicated for the treatment of patients with SAA who have had an insufficient response to immunosuppressive therapy. The SOAR trial aims to assess the efficacy and safety of eltrombopag + CsA (without ATG) as first-line therapy in adult patients with SAA.
| v2 |
2018-04-03T04:36:20.179Z | 2002-07-05T00:00:00.000Z | 19630770 | s2ag/train | Calling It Something Other Than Cloning
B. Vogelstein and coauthors (“Please don't call it cloning!,” Policy Forum, 15 Feb., p. [1237][1]) suggest that the term “nuclear transplantation” should be used for “somatic cell nuclear transfer to create stem cells.” The use of the term in this context was preempted some 45 years ago to mean a process that leads to cloning—precisely what Vogelstein et al. are trying to avoid! The studies by King and Briggs ([1][2]) and Gurdon ([2][3]) on amphibia are described as nuclear transplantation and remain the classic examples that have been included in numerous textbooks ranging from the second edition of Srb et al. ([3][4]) through Suzuki et al. ([4][5]) to Campbell and Reece ([5][6]). Although most of these texts concentrate on the totipotency of the nuclei transferred, some emphasize [e.g., ([4][5])] that it is the production of series of clones of the original individuals that shows the ultimate success of the nuclear transplantation process. Thus, generations of biology students will immediately think of cloning regardless of the context in which “nuclear transplantation” is used.
1. [↵][7]1. T. J. King, 2. R. Briggs
, Cold Spring Harbor Symp. Quant. Biol. 21, 279 (1956).
[OpenUrl][8]
2. [↵][9]1. J. B. Gurdon
, Q. Rev. Biol. 38, 54 (1963).
[OpenUrl][10][CrossRef][11][Web of Science][12]
3. [↵][13]1. A. M. Srb, 2. R. D. Owen, 3. R. S. Edgar
, General Genetics, ed. 2 (Freeman, San Francisco, 1966).
4. [↵][14]1. D. T. Suzuki, 2. A. J. F. Griffiths, 3. R. C. Lewontin
, An Introduction to Genetic Analysis, ed. 2 (Freeman, San Francisco, 1981).
5. [↵][15]1. N. A. Campbell, 2. J. B. Reece
, Biology, ed. 6 (Benjamin Cummings, Menlo Park, CA, 2002).
# {#article-title-2}
Vogelstein et al. subscribe to the widely held belief that a human being at an early developmental stage does not qualify as human. Certainly, we can all agree that a preimplantation embryo is not sentient and that it is not viable to survive without assistance. But making distinctions about the “humanness” of genetically human organisms on the basis of their developmental stage falls within the realm of opinion, not scientific fact.
Regardless of what opinions are popularly held by members of the scientific community, we need to be careful to preserve the distinction between opinion and fact. An opinion held on a matter of philosophy by a majority of scientists is, nonetheless, an opinion, and is not brought any closer to the realm of testable fact by virtue of being held by highly regarded profesionals.
Vogelstein et al. write “Both of these research goals [“creating stem cells with the patient's own nuclear genome” “Both of these research goals [“creating stem cells with the patient's own nuclear genome” “Both of these research goals [“creating stem cells with the patient's own nuclear genome” “Both of these research goals [“creating stem cells with the patient's own nuclear genome” “Both of these research goals [“creating stem cells with the patient's own nuclear genome” “Both of these research goals [“creating stem cells with the patient's own nuclear genome” “Both of these research goals [“creating stem cells with the patient's own nuclear genome” “Both of these research goals [“creating stem cells with the patient's own nuclear genome” “Both of these research goals [“creating stem cells with the patient's own nuclear genome” and “creating stem cell lines by using the somatic cell nuclei of individuals with heritable diseases”] have nothing to do with producing a human being.” On the contrary, both do indeed involve creating a human being. The authors suggest that certain avenues of research would wrongly be caught by a matter of semantics in legislation, because of the inclusion of the word “cloning”; I argue that such legislation would quite intentionally catch these avenues of research, and it is in fact their assertion that these studies would not involve production of human beings that is relying on semantics to justify its exclusion from these regulations.
Supporting stem cell research and holding to philosophical distinctions between the rights of human beings from different developmental stages are quite a different thing from arguing that human embryos are not human. Our cause is only weakened by relying on such arguments to support it.
# Response {#article-title-3}
We thank Jones for the historical context. We can think of no one better to emulate than King, Briggs, and Gurdon, who have contributed so many elegant studies to modern embryology. “Nuclear transplantation” was a good term when they coined it, and it remains good. It is far more accurate than “therapeutic cloning” and much more easily pronounceable than “somatic cell nuclear transfer.”
Meyer has, unfortunately, missed the point of our Policy Forum. Human cells growing in a Petri dish are not equal to a human being. This is fact, not opinion. Cells in a Petri dish can't talk, think, move, love, laugh, or cry, to name a few of the numerous and obvious differences. Thousands of laboratories around the world already grow human cells (fibroblasts, lymphocytes, etc.) in Petri dishes. Each of these cells has the theoretical capacity to develop into a human being after experimental manipulation. The major medical goal of nuclear transplantation is to produce human cells growing in Petri dishes that can be used for regenerative medicine. The public needs to understand that there is a huge difference between such cells and an actual human being. It is important that the current confusion about these issues does not lead to a ban on the production of certain types of human cells growing in Petri dishes, precluding potential therapies for the millions of human beings who currently suffer from otherwise incurable diseases.
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[15]: #xref-ref-5-1 "View reference 5 in text" | v2 |
2020-02-20T09:11:58.466Z | 2019-11-13T00:00:00.000Z | 213421250 | s2ag/train | Breakthrough Hemolysis in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Ravulizumab: Results of a 52-Week Extension from Two Phase 3 Studies
INTRODUCTION
In patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) receiving eculizumab, approximately 11%-27% may experience breakthrough hemolysis (BTH)-the return of hemolytic disease activity. BTH may be associated with inadequate C5 inhibition or complement-activating conditions (CACs; eg, infection). Although there is no broad consensus regarding the definition of BTH, this study defined BTH based on literature review and expert consensus: ≥1 new or worsening sign or symptom of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 g/dL], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated lactate dehydrogenase (LDH) (≥2 × ULN) after prior LDH reduction to <1.5 × ULN on therapy.
Ravulizumab, an innovative long-acting C5 complement inhibitor, was recently approved in the United States, Japan, and Europe for the treatment of PNH. In two phase 3 trials, ALXN1210-PNH-301 (301; NCT02946463) and ALXN1210-PNH-302 (302; NCT03056040), ravulizumab (q8w) was shown to be noninferior to eculizumab 900 mg (q2w) for all primary and key secondary endpoints (including BTH). Each study had a 26-wk randomized primary evaluation period, followed by an extension period during which pts could receive ravulizumab for up to 2 y. In the current analysis, pt-level data were evaluated to assess causes and clinical parameters associated with BTH incidences reported up to 1 y in the two phase 3 trials.
METHODS
The trials were phase 3, randomized, open-label, noninferiority, multicenter studies. Eligible pts were ≥18 y with confirmed PNH diagnosis. Pts in study 301 were naive to C5 inhibitor therapy, with LDH of ≥1.5 × ULN and ≥1 sign/symptom of PNH at screening. Pts in study 302 were stable receiving eculizumab treatment for ≥6 mo, with LDH of ≤1.5 × ULN at screening. Pts received weight-based dosing of ravulizumab q8w or the approved eculizumab dose (900 mg q2w) for 183 d; in the extension, eligible pts continued (R-R arm) or switched to ravulizumab (E-R arm). The outcome of interest was the proportion of pts with BTH during the extensions of 301 and 302 (wks 27-52), causes, and clinical parameters associated with BTH incidents. BTH causation was determined by clinical review and categorized as related to inadequate C5 inhibition (free C5 ≥0.5 μg/mL), CAC due to an inciting event (eg, infection, trauma, surgery), or unrelated to either event.
RESULTS
Study 301: 243 pts entered the extension period (R-R arm: n=124; E-R arm: n=119). In both groups, 99% of pts who had no BTH during wks 0-26 experienced no BTH incidents during wks 27-52. Four pts in the R-R arm experienced BTH during wks 27-52, of which 3 pts had experienced BTH during wks 0-26. In the E-R arm, there were fewer BTH events during wks 27-52 compared with wks 0-26 (Table A). Two pts experienced BTH after switching to ravulizumab in the E-R arm, of which 1 had experienced BTH during wks 0-26. During wks 27-52, 2 BTH events (1 in each arm) were associated with infection and 4 BTH events in the R-R arm and 1 in the E-R arm were unrelated to free C5 elevation or reported infection. Study 302: 191 pts entered the extension period (R-R arm: n=96; E-R arm: n=95). Of these pts, 97% in the R-R arm and 100% in the E-R arm who had no BTH during wks 0-26 had no BTH incidents during wks 27-52. Three pts in the R-R arm experienced BTH during wks 27-52. In the E-R arm, there were fewer BTH events during wks 27-52 compared with wks 0-26 (Table B). One pt experienced BTH after switching to ravulizumab; this pt previously experienced BTH during wks 0-26. During wks 27-52, 2 BTH events in the R-R arm and 1 event in the E-R arm were associated with infection, and 1 BTH event in the R-R arm was unrelated to free C5 elevation or reported infection. In both studies, no BTH incidents were associated with free C5 of >0.5 μg/mL (the threshold associated with complete inhibition of C5) during wks 27-52 while on ravulizumab treatment.
CONCLUSIONS
During wks 27-52, in both studies, the number of pts who experienced BTH events was similar to that in wks 0-26 in the R-R group, and fewer pts experienced BTH events after switching from eculizumab to ravulizumab. No BTH events were associated with elevations in free C5 to >0.5 μg/mL in pts taking ravulizumab. Similar numbers of pts initially receiving ravulizumab or eculizumab experienced infection-related BTH events, possibly due to proximal complement activation.
Hill: Bioverativ: Honoraria; Alexion: Honoraria; Regeneron: Honoraria; Novartis: Honoraria; Roche: Honoraria; Apellis: Honoraria; Akari: Honoraria; Ra Pharma: Honoraria. Piatek:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Wells:Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Brodsky:Achillion: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuriakose:Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy. Pavani:Alexion: Employment. Liu:Alexion: Employment. Ortiz:Alexion: Employment. Schrezenmeier:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kulasekararaj:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achilleon: Consultancy; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2018-12-17T18:51:31.021Z | 2003-01-01T00:00:00.000Z | 58934540 | s2ag/train | Formation of odour-active compounds in maillard model systems based on proline
The formation of odorants was studied at pH 7 in Maillard model reactions containing glucose and proline (GlcPro) or the corresponding Amadori compound fructosyl proline (Fru-Pro). The major odour-active components found in both systems were 2-acetyl1 pyrroline, 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF), acetic acid, sotolone, diacetyl, and 2-acetyltetrahydropyridine (ATHP). However, the odour intensities, as perceived by gas chromatography-olfactometry, differed depending on the precursor system. The formation of selected odorants was monitored by isotope dilution assay. High amounts of HDMF (up to 250 pg/mmol) were obtained from Fru-Pro. On the contrary, GlcRro favoured the formation of ATHP (up to 50 pg/mmol). These odorants could also be monitored on-line by proton transfer reaction mass spectrometry, applied for the first time to time-resolved analysis of Maillard reaction products. Introduction Maillard reaction systems based on L-proline generate roasty notes that contribute to the aroma of many thermally-treated food products. 2-Acetyl1 -pyrroline and 2-acetyltetrahydropyridine (ATHP) are two roasty-smelling impact odorants identified in prolinecontaining foods such as Basmati rice (Buttery et al., 1983) and bread crust (Schieberle and Grosch, 1985). These volatile compounds, along with 2,3-butanedione (diacetyl) and 4hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF), have also been reported as important odorants generated from Glc/Pro under pyrolytic conditions (Roberts and Acree, 1993). The Amadori compound N-( 1 -deoxy-D-fructos1 -yl)-L-proline (Fru-Pro) has been the subject of several investigations dealing with its thermally-induced degradation. Many volatiles have been identified after pyrolysis of Fru-Pro (Mills and Hodge, 1976; Yaylayan et al., 1987; Debrauwer et al., 199 1) or autoclave treatment (Huyghues-Despointes et al., 1994). However, little is known about the key odorants generated from Fru-Pro. In the following, the Maillard model systems GlcRro and Fru-Pro will be compared in terms of (i) odour-impact compounds formed, (ii) concentration of selected odorants, and (i$ their time-resolved analysis, in order to gain more insight into dynamic changes of odorants occurring during thermal treatment of Maillard precursors. Experimental Chemicals D-Glucose, L-proline, disodium hydrogenphosphate, sodium dihydrogenphosphate, sodium sulphate, and diethyl ether were from Merck (Darmstadt, Germany). 4-Hydroxy8 2,5-dimethyl-3(2H)-furanone (HDMF), 2,3-butandione (diacetyl), 3-hydroxy-4,5-dimethyl5 2(5H)-furanone (sotolone), and acetic acid were from Aldrich (Buchs, Switzerland). 2(or 5)-Ethyl-4-hydroxy-5(or 2)-methyl-3( 2H)-furanone was from Givaudan (Dubendorf, 5 8 Switzerland). The chemicals were of analytical grade. The solvent was distilled prior to use :g t o o on a Vigreux column ( 1 O0 x 1 cm). J KeyFlavour Compounds and Analytical Aspects 459 Syntheses N-( 1 -Deoxy-D-fructos1 -yl)-L-proline (Fru-Pro) was synthesised as described by Yaylayan and Huyghues-Despointes ( 1994). 2-Acetyltetrahydropyridine (ATHP) was obtained according to Buchi and Wust ( 197 1). 2-Acetyl1 -pyrroline was prepared by Duby and Huynh-Ba (1 992). 4-Hydroxy-2(or 5)-[ 13C]methyl-5(or 2)-methyl-3(2H)-[2(or 5)Clfuranone ([13C2]-HDMF) was obtained as reported by Blank et al. (1997). 2H2-5-2Acetyltetrahydropyridine was synthesised by adapting the Buchi and Wust method (197 1). Sample preparation Identification. Equimolar amounts of glucose (O. 1 mol) and proline (O. 1 mol) or Fru-Pro (0.1 mol) were dissolved in a phosphate buffer (0.2 molil, 50 mi). After adjusting to pH 7, the solution was refluxed for up to 7 h. Quantification. This was achieved using Isotope Dilution Assay (IDA) (Schieberle, 1995). As described above, equimolar amounts of glucose and proline or Fru-Pro were dissolved in a phosphate buffer and reacted for 1, 2, and 4 h. Defined amounts of labelled internal standards were added prior to separation into acidic and basic fractions using HC1 (2 N) and NaOH (2 N). Odorants were extracted twice with diethyl ether (5 mi), dried over anhydrous Na2S04, and concentrated to 1 rnl with a stream of nitrogen. Gas chromatography-olfactometry (GC-O) This was performed on a Carlo Erba Mega 2 gas chromatograph equipped with a cold on-column injector and a FID. A DB-Wax fused silica capillary column was used, 30 m x 0.32 mm with a film thickness of 0.25 pm (J&W Sci., Folsom, CA). A splitter was attached to the end of the capillary column to split the effluent 1 : 1 into the FID and the sniffing port. Chromatographic conditions were used as described earlier (Blank and Schieberle, 1993). Gas chromatography and mass spectrometry (GC-MS) GC-MS analyses were carried out on a HP-6890A GC coupled to a HP-5973N mass selective detector (Hewlett-Packard). Samples were injected splitless (1 PI). The MS-EI spectra were generated at 70 eV. Qualitative measurements were performed on a DB-Wax (60 m x 0.25 m, 0.25 pm film thickness) using the chromatographic conditions described above. HDMF was quantified on the DB-Wax capillary column, ATHP on a HP-PONA (60 m x 0.25 mm, 0.25 km film thickness) using the temperature programme 20°C (1 min), 7O"Clmin to 60"C, 4"C/min to 240°C. Proton Transfer Reaction Mass Spectrometry (PTR-MS) PTR-MS combines a soft and sensitive mode of chemical ionisation based on proton transfer from H30+ with a quadrupole mass filter (Lindinger et al., 1993). Volatiles released into the headspace from Maillard model systems (80 ml) were monitored on-line by PTRMS. Experiments were performed at 90°C using a water-heated, double-j acketed reaction vessel, while the headspace (150 mi) was swept with a flow of nitrogen (5000 ml/min). An aliquot of the swept headspace gas (15 ml/min) was introduced into the PTR-MS for online headspace analysis. This high headspace sweep rate allowed the dynamic release of volatiles during the course of the Maillard reaction to be analysed. More details about the PTR-MS technique can be obtained from Lindinger et al. (1998). 13 Results and discussion 3 O Identification of odorants (\1 Q The overall odours of the Maillard reaction samples based on glucose and proline (GlcPro) and the corresponding Amadori compound fructosyl proline (Fru-Pro) were different. While GlcPro was found to be mainly roasty and popcorn-like, Fru-Pro showed a more pronounced caramel-like and also some roasty notes. These differences were also reflected by the solvent extracts obtained from the two Maillard samples. c | v2 |
2020-11-05T09:10:19.076Z | 2020-11-05T00:00:00.000Z | 228905630 | s2ag/train | Adverse Prognostic Factors in Adult Secondary Hemophagocytic Lymphohistiocytosis: Results from Two Tertiary Academic Centers
Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that results in histiocyte proliferation and extensive hemophagocytosis. HLH is classified as primary, which is caused by genetic defects, or secondary, which occurs secondary to infections, malignancies, rheumatologic diseases or other causes. Both types of HLH are rare and have a nonspecific clinical presentation which makes the diagnosis challenging. The diagnosis and treatment of most HLH cases are guided by protocols developed by the Histiocyte Society (HLH-94 and -2004), which are based on data from pediatric populations. There is limited data regarding treatment and outcomes of HLH in adults. In this study, we reviewed the patients with HLH at 2 academic tertiary care centers in 2 different states.
Methods: We retrospectively reviewed patients who had an ICD-10 code of D76.1, corresponding to diagnosis of HLH or macrophage activation syndrome (MAS) at University of Nebraska Medical Center (UNMC) or University of Kentucky Medical Center (UKMC) between January 2008-April 2020. Only patients who were >18 years of age and diagnosed as inpatient where included. Data were collected to assess demographics, etiology, symptoms, diagnostic criteria, H-score, treatment, systemic complications, and overall survival (OS). The Kaplan-Meier method was used to estimate OS and log-rank test was used for comparisons.
Results: A total of 60 patients were identified (27 from UNMC and 33 from UKMC) with a mean age of 55 years (20-87 years). Fifty-two (87%) patients met at least 5 of the HLH 2004 criteria. The median H-score was 241 (119-322). Elevated ferritin was the most common criterion that was met (100%), followed by cytopenias (Figure 1). Median ferritin and soluble IL2 receptor (sIL2R) were approximately 12,699.5 ng/mL (896 to >80,000 ng/ml) and 5416 U/mL (401-121,365 pg/mL), respectively. Most patients had elevated creatinine, hypofibrinogenemia, hyperbilirubinemia and/or significant transaminitis with a median AST/ALT ratio of > 2. Table 1 summarizes demographics, etiologies and laboratory investigations at time of diagnosis. Fifty-one percent of patients were treated based on HLH protocols, 12% received glucocorticoids only, 5% received therapy directed against their malignancy, and the rest received other treatments. Twenty-six (43%) patients achieved complete response, 7 patients relapsed (3 achieved completed response with second treatment, 4 died [one of them after a third relapse]) and 27 patients (45%) died. After a median follow-up of 31 months, there were 35 deaths (58%), with median OS of 2.83 months (CI, 0.89 to 12.99) (Figure 2). At least 16 (27%) patients were alive after one year follow up. Among patients who succumbed to HLH, the median time from admission until death was 21.5 days (4-395 days) (95% CI, 17.5-28.5). On univariate analysis, increased ALT, creatinine, ferritin, LDH and sIL2R at the time of diagnosis were associated with worse OS (Table 2). In addition, patients who developed shock, renal impairment, respiratory or neurologic complications also had worse outcomes. On the other hand, age, sex, BMI, primary vs. secondary etiology, AST, bilirubin, fibrinogen, triglycerides, and absence of hemophagocytosis on tissue were not associated with survival. Only 41 patients (68%) had available data for all relevant predictive variables, which did not allow for full multivariate analysis.
Conclusion: HLH is a rare and life-threatening syndrome. It is associated with high mortality often observed within the 30 days of diagnosis. Poor prognostic factors in our cohort included elevated levels of ferritin, ALT, LDH, creatinine and/or sIL2R at the time of diagnosis as well as subsequent the development of shock, renal, respiratory, and/or neurologic complications during hospital stay. If verified in a prospective manner, these predictors of adverse outcomes may help further refine risk-stratification of adult HLH patients at diagnosis.
Armitage: Samus Therapeutics: Consultancy; Ascentage: Consultancy; Trovagene/Cardiff Oncology: Membership on an entity's Board of Directors or advisory committees. Vose:Janssen: Honoraria; Incyte: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Honoraria, Research Funding; Wugen: Honoraria; Bristol-Myers Squibb: Research Funding; Celgene: Honoraria; Roche/Genetech: Consultancy, Honoraria, Other; Seattle Genetics: Research Funding; Novartis: Research Funding; Loxo: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Allogene: Honoraria; Kite, a Gilead Company: Honoraria, Research Funding. Hildebrandt:Charlottes Webb CWBHF: Other; CVS Health: Other: Stock and Other Ownership Interests ; Axim Biotechnologies: Other: Stock and Other Ownership Interests ; Novartis: Other: Stock and Other Ownership Interests ; Insys Therapeutics: Other: Stock and Other Ownership Interests ; Abbvie: Other: Stock and Other Ownership Interests ; GW Pharmaceuticals: Other: Stock and Other Ownership Interests ; Cardinal Health: Other: Stock and Other Ownership Interests ; Clovis Oncology: Other: Stock and Other Ownership Interests ; Cellectis: Other: Stock and Other Ownership Interests ; Almmune Therapeutics Inc AIMT: Other; Celgene: Other: Stock and Other Ownership Interests ; Bluebird Bio: Other; Bristol-Myers Squibb/Medarex: Other; crispr therapeutics: Other; IDEXX Laboratories: Other; Johnson & Johnson: Other; Pfizer: Other; Procter & Gamble: Other; Vertex: Other; Bayer: Other; Scotts-Miracle: Other; Medical PPTYS TR Inc. MPW: Other; Caretrust Reit Inc CTRE: Other; ANGI Homeservices Inc ANGI: Other; MPW (medical PPTYS): Other; Caretrust (CTRE): Other; Aimmune: Other; Incyte: Consultancy; Takeda: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Astellas Pharma: Research Funding; Falk Foundation: Other; Incyte: Other; Takeda: Other. Baljevic:Amgen: Research Funding; Exelixis: Research Funding; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria; NCCN Hematologic Malignancies Congress: Honoraria; MediCom Myeloma CME: Honoraria.
| v2 |
2019-03-28T13:33:34.594Z | 2018-11-29T00:00:00.000Z | 86583610 | s2ag/train | Short Diagnosis to Treatment Interval (DTI) Is Associated with Inferior Outcome in Newly Diagnosed Patients with Mantle Cell Lymphoma, a MER/LEO and Alliance Collaboration
PURPOSE
Urgency to initiate therapy has to be weighed against the time required for screening and consenting to enroll a patient onto a clinical trial. Exclusion of patients with rapidly progressive or symptomatic disease may lead to selection of patients with less aggressive disease. We recently identified that a short diagnosis to treatment interval (DTI) is associated with adverse clinical factors and inferior outcome in patients with diffuse large B-cell lymphoma (DLBCL) (Maurer et al, JCO 2018); shorter time to treatment was also found to be associated with outcome in other aggressive lymphomas, including mantle cell lymphoma (MCL), in the National Cancer Database (Olszewski et al, BJH 2018). Here we assess the association of DTI with clinical variables and outcome in MCL from an observational cohort with validation in patients enrolled on an NCTN clinical trial.
PATIENTS AND METHODS
Newly diagnosed patients with MCL were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER), now a subcohort of the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study. Patients initially managed with observation were excluded. DTI was defined as the time in days from date of first lymphoma-containing biopsy to the initiation of therapy. Associations of DTI with clinical factors and outcome were examined using a 14 day split based on the previous MER study of DTI in DLBCL. Odds ratios (OR) and Cox model hazard ratios (HR) are reported. Outcome was assessed using event-free survival (EFS) where events were defined as progression/relapse, initiation of new anti-lymphoma therapy, or death due to any cause. A validation cohort was assembled from patients enrolled in CALGB (Alliance) clinical trial 50403. Protocol therapy was high dose chemotherapy with autologous hematopoietic stem cell transplantation (ASCT) consolidation and post-ASCT rituximab followed by bortezomib as either consolidation or maintenance. DTI was defined as time from diagnosis to study registration and outcome was assessed using progression-free survival (PFS) as defined on the clinical trial.
RESULTS
271 patients with MCL enrolled in the MER from 2002-2015 and initiated treatment within 100 days of diagnosis. Median age at diagnosis was 64 years (range 36-76), 211 (78%) were male, and 92% were stage III-IV; MIPI was Low (41%), Intermediate (36%) and High (23%). Induction therapy was R-CHOP based (50%), B-R based (16%), HyperCVAD based (8%), 2-CDA based (11%), and other (15%). Median EFS of the cohort was 41 months (95% CI: 34-46). Median DTI was 26 days (IQR: 14-38) and 28% enrolled within 14 days of diagnosis, exhibiting a longer DTI than DLBCL patients enrolled in the MER during the same time period. Short DTI (0-14 days) was associated with adverse clinical factors including ECOG PS 2-4 (OR=5.74, 95% CI: 2.51-13.1, p<0.0001), elevated LDH (OR=2.30 95% CI: 1.25-4.22, p=0.0072), and higher MIPI score (OR=1.48, 95% CI: 1.04-2.07, p=0.025) but was not significantly associated with age, sex, B-symptoms, or stage (all p>0.30). Short DTI was also associated with inferior EFS (HR=1.78, 95% CI: 1.27-2.49, p=0.0008) which remained significant after adjusting for MIPI score (HR=1.72, 95% CI: 1.23-2.41, p=0.0016).
In the validation cohort, 144 patients enrolled on 50403 within 100 days of diagnosis from 2006-2010. Median age at diagnosis was 59 years (range 29-69), 77% were male, and 97% were stage III-IV; MIPI was Low (51%), Intermediate (31%) and High (17%). Median PFS of the cohort was 84 months (95% CI: 50-109). Median DTI was 35 days (IQR: 22-46) and 11% enrolled within 14 days of diagnosis. Short DTI (0-14 days) was associated with PS (OR=9.00, 95% CI: 1.18-69.0, p=0.034) and) higher MIPI score (OR=2.09, 95% CI: 1.08-4.04, p=0.029) but not elevated LDH (OR=1.27, 95% CI: 0.43-3.74, p=0.66). Short DTI was associated with inferior PFS (HR=2.21, 95% CI:1.19-4.09, p=0.011) which remained clinically significant after adjusting for MIPI score (HR=1.85, 95% CI: 0.98-3.47, p=0.056).
CONCLUSION
A short diagnosis-to-treatment interval is strongly associated with adverse clinical factors and poor outcome in newly diagnosed MCL in the MER. Clinical trials are encouraged to facilitate enrollment of patients with short DTI to avoid potential selection bias.
Support: U01 CA195568, P50 CA097274, U10CA180821, U10CA180882; ClinicalTrials.gov Identifier: NCT00310037 (CALGB 50403)
Figure. Figure.
Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Kaplan:Bayer Pharmaceuticals: Consultancy. Cohen:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Takeda: Research Funding. Martin:Gilead: Consultancy; Kite: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Bayer: Consultancy. Kahl:Abbvie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Acerta: Consultancy; Juno: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy. Bartlett:ImaginAB: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Merck & Co: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Millennium: Research Funding; Genentech: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding. Leonard:Karyopharm: Consultancy; Biotest: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Juno: Consultancy; BMS: Consultancy; Sutro: Consultancy; MEI Pharma: Consultancy; Genentech/Roche: Consultancy; Celgene: Consultancy; Gilead: Consultancy; United Therapeutics: Consultancy.
| v2 |
2021-09-28T15:32:22.443Z | 2021-07-22T00:00:00.000Z | 240705130 | s2ag/train | Estimation of the interior density of a small body given its gravity field
<p><strong>Abstract</strong></p>
<p>We present here a method for the retrieval of the internal density distribution of a small body, via a least squares inversion of its gravity field and rotational state. Multiple solutions are averaged in order to limit the effect of the <em>a priori</em> density distribution. Simulations show successful density map estimations even with little to no initial information on the interior structure of the body.</p>
<p> </p>
<p><strong>1. Introduction</strong></p>
<p>The gravity field of a body is a property among the most readily obtainable by a spacecraft mission. Be it by employing radio-tracking, optical, or gravimetric data, several missions have provided and will provide gravity expansions of degree 2 and higher for small bodies. In turn, the extended gravity field is an effect of the distribution of the mass inside the body. However, the inverse problem of estimating the density distribution from the gravity field is not a trivial one, and generally with non-unique solutions [1].</p>
<p>Here, we propose a method to obtain a unique solution for the internal mass distribution of a small body by restricting our estimation to zones of constant density, which are limited in number by the accuracy of the gravity model [2]. Where available, additional observables such as the libration amplitudes could help in the estimation of the interior structure. Averaging of the solutions obtained for different subdivisions of zones provides then the estimated density map [3].</p>
<p> </p>
<p><strong>2. Methods</strong></p>
<p>The code builds from available software which allows to compute the gravity harmonics of a body approximated by a collection of cubes, each with a given density [4]. Here, the cubes are grouped in subregions of constant density, as many as there are measured coefficients. Each subregion is assigned an initial density, from which the software computes gravity coefficients matching in degree and order those observed. The difference between the coefficients thus computed and the observed ones is then minimized in a least-squares sense [5]. The solution of the regularized least-squares inversion is the density for each of the initial zones, along with its uncertainty. However, this solution is heavily dependent on the initial subdivision of the body into zones. Hence, a wide range of possible initial zones is explored, and the corresponding density solutions averaged together. </p>
<p>From such an average solution, a new set of subregions is generated, with the help of a blob detection algorithm [6]. Finally, the gravity coefficients are inverted using this new zone subdivision. This step is necessary because, while providing a good distribution of the density zones, the density values of the averaged map are biased by solutions coming from inaccurate initial zones subdivisions. </p>
<p>The data used in the inversion are the spherical harmonics coefficients of the gravity field expansion. The advantage of these observables is that they can be measured without the need for specific payload. Although the method can be easily adapted to process surface gravity measurements, the larger errors on the surface gravity coming from the cubes discretization make it less appealing for these type of data.</p>
<p> </p>
<p><strong>3. Discussion and outlook</strong></p>
<p>Figure 1 shows the results obtained when applying the method to a fictitious density distribution for asteroid Bennu. The nominal density distribution, shown in Figure 1a, was used to produce a synthetic gravity field expansion of degree 11. An optimistic noise profile was assumed for these simulated observables, with a 1% error on each gravity coefficient. The spherical harmonics coefficients were then inverted via the iterative process described in Section 2, resulting in the density distribution shown in Figure 1b. </p>
<p>With a gravity field of this resolution, the inversion method is clearly able to distinguish the 4 density anomalies inside the body. Still, the comparison between the nominal and the estimated density models reveals the current limitations of the method in accurately reconstructing the size of the anomalies or their density — which is equivalent, given the constraint on the total mass. </p>
<p>Once a better agreement between the retrieved and the nominal models will be achieved with the current (high) resolution of the gravity harmonics, the synthetic gravity fields will be truncated at lower degrees, making them more realistic as outputs of spacecraft missions to small bodies. Future simulation studies will also make use of more realistic noise profiles, with the errors on the observed coefficient increasing as a function of the degree.</p>
<p>(a)</p>
<p><img src="data:image/png;base64, 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IAROMQSk2T/FBlzdFQLHA4GJrU+6R2++0g3v2d3Q3ndAbCGtGbsNjq98RTPOJyQYEh8T4FHO20m04n12AVv3OolsLxqxRkCIy+NeVgSCPwD28lxnxaAsNRxzLRNt3MAKg90YVgBix91l1tZgNkRdezPBIC0/JvL4ISCElNn | v2 |
2019-11-22T00:44:28.610Z | 2019-11-13T00:00:00.000Z | 209241460 | s2ag/train | Phase 1-2 Study of Pembrolizumab Combined with the Anti-LAG-3 Antibody MK-4280 for the Treatment of Hematologic Malignancies
Background: The prognosis is poor for most patients with lymphoma who do not respond to initial therapy, leaving an unmet need for effective therapies for this patient population. Pembrolizumab, a programmed death 1 (PD-1) inhibitor, has shown clinically meaningful antitumor activity and manageable safety in multiple tumor types, including relapsed or refractory (R/R) classic Hodgkin lymphoma (R/R cHL) and R/R primary mediastinal large B-cell lymphoma. Results of preclinical studies have shown that lymphocyte activation gene-3 (LAG-3), a cell surface immunomodulatory receptor protein, is elevated in hematologic malignancies and that blockade of LAG-3 and the PD-1/PD ligand 1 (PD-L1) axis has synergistic antitumor activity in solid tumors. MK-4280 is a humanized anti-LAG-3 monoclonal antibody that blocks the interaction between LAG-3 and its ligand. The current study will evaluate the safety and efficacy of pembrolizumab combined with MK-4280 in patients with selected hematologic malignancies.
Study Design and Methods: This phase 1-2 multisite, multicohort, open-label study (NCT03598608) will have a safety lead-in phase to establish the preliminary recommended phase 2 dose (RP2D) followed by an efficacy expansion phase. In the safety lead-in phase, a modified toxicity probability interval design will be used to establish the RP2D of pembrolizumab plus MK-4280. Dose-limiting toxicities will be assessed during the first cycle. The study will enroll patients with PD-1/PD-L1 inhibitor-naive R/R cHL (cohort 1), PD-1/PD-L1 inhibitor-refractory R/R cHL (cohort 2), R/R diffuse large B-cell lymphoma (cohort 3), and R/R indolent non-Hodgkin lymphoma (cohort 4). Adult patients (age ≥18 years) with ECOG PS 0 or 1 and adequate organ function who meet the standard eligibility criteria for pembrolizumab studies, such as no prior receipt of anti-PD-1 antibody and no active infection necessitating systemic therapy, will be enrolled. Patients will receive pembrolizumab 200 mg every 3 weeks and MK-4280 for 35 cycles (~2 years) or until documented disease progression, unacceptable toxicity, intercurrent illness preventing further administration of study drug, or withdrawal from study. Tumor response will be assessed by computed tomography/positron emission tomography every 12 weeks to confirm complete response or as clinically indicated, using revised response criteria for malignant lymphoma. Patients will be monitored for adverse events (AEs) until 30 days after study treatment end (90 days for serious AEs). After confirmed disease progression or start of new anticancer therapy, patients will be contacted by telephone every 12 weeks for survival status. All-patients-as-treated (APaT), defined as all patients who received ≥1 dose of the study drug, will constitute the safety population. The full analysis set, defined as all patients with a baseline assessment who have measurable disease by investigator assessment and who were administered a dose of study intervention, regardless of dose level, will constitute the efficacy population. The primary objective is to determine the safety and tolerability of MK-4280 plus pembrolizumab and establish its RP2D. Secondary objectives are to evaluate the objective response rate of MK-4280 when combined with pembrolizumab per investigator assessment and to evaluate the pharmacokinetics of MK-4280 and pembrolizumab. Exploratory objectives are to evaluate overall survival, progression-free survival, and best overall response for MK-4280 and pembrolizumab; to assess the presence of circulating MK-4280 and anti-pembrolizumab antibodies; to assess target engagement and pharmacodynamics of MK-4280 through biomarker evaluation; and to identify molecular biomarkers associated with clinical response/resistance, safety, pharmacodynamics, and/or the mechanism of action of MK-4280 and pembrolizumab. At least 14 patients (≥3 per cohort) will be enrolled in the safety lead-in phase; approximately 120 patients (≤30 per cohort) will be enrolled in the efficacy expansion phase.
Armand: Serventa: Research Funding; Sigma-Tau: Research Funding; Otsuka: Research Funding; Merck & Co.: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Roche: Research Funding; Pfizer Inc: Research Funding; Affimed: Research Funding; Bristol Myers Squibb Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Infinity Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Employment. Zinzani:PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees; SANOFI: Consultancy; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palcza:Merck & Co., Inc.: Employment, Other: Stock ownership. Healy:Merck & Co., Inc.: Employment, Other: Stock ownership. Nahar:Merck & Co., Inc.: Employment. Marinello:Merck & Co., Inc.: Employment, Other: Travel fees, gifts, and others; stock or other ownership. Gregory:Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: grant pending, Research Funding; Monash University: Research Funding; Janssen: Other: grant pending, Research Funding; Roche: Speakers Bureau; Beigene: Other: Grant pending, Research Funding; Melbourne Haematology: Consultancy, Honoraria, Other: Travel fees and conference support, Speakers Bureau; Celgene: Other: grant pending, Research Funding; MSD: Other: grant pending, Research Funding.
| v2 |
2021-11-26T16:04:19.717Z | 2021-11-05T00:00:00.000Z | 244652420 | s2ag/train | Combined Blockade of CD47-Sirpa Interaction By 5F9 (Magrolimab) and Azacitidine/Venetoclax Therapy Facilitates Macrophage-Mediated Anti-Leukemia Efficacy in AML Pre-Clinical Models
CD47 expressed on cells functions as a "don't eat me" signal by binding SIRPa on macrophages and blocking phagocytosis. Cancer cells including AML evade phagocytosis by overexpressing CD47, and high CD47 expression in AML has been associated with inferior outcomes. Here we studied the pre-clinical activity of the 5F9 (magrolimab), an antibody that blocks the CD47, combined with BCL-2 inhibitor venetoclax with azacitidine (VEN/AZA) in AML both in vitro and in vivo.
We first tested the combined efficacy of VEN/AZA and 5F9 in vitro in phagocytosis assay, utilizing monocytes isolated from seven healthy donors by CD16 positive selection and inducing macrophage differentiation with recombinant human M-CSF (rhM-CSF, 500ng/ml) for 1 week. Three paired isogenic AML cell lines MOLM-13, VEN-resistant (VEN-RE) MOLM-13, and p53-mutant MOLM-13 harboring R248W mutation, were pre-treated with DMSO or combination of 10nM VEN and 1uM AZA for 24hrs. Leukemia cells were labeled with Calcein and co-cultured with macrophages for 1h at a ratio of 2:1 (T:M), followed by flow cytometry read-out, quantifying Calcein+ macrophages that engulfed leukemia cells. The active phagocytosis was calculated as the percentage of Calcein+CD206+ cells from total CD206+ cells (Figure 1A, experimental schema). The 5F9/VEN-AZA combination significantly increased phagocytosis not only in parental but also in VEN-RE and p53-mutant MOLM-13 cells when compared with 5F9 or VEN/AZA alone treatments (Figure 1B). The treatment of VEN or AZA induced AnnexinV in MOLM-13 cells which may function as a pro-phagocytic signal and contribute to the enhanced phagocytosis (Figure 1C). Further proteomics studies to identify additional "eat me" signals following VEN/AZA treatment are ongoing and will be presented.
Next, we examined the therapeutic efficacy of 5F9 alone or combined with VEN/AZA in the AML patient-derived xenografts (PDX) models. NSG mice were engrafted with VEN-RE AML PDX #344 (no canonical AML mutations detected by targeted sequencing) and #574 (FLT3-ITD, DNMT3A, NPM1-mutated). After confirmed bone marrow (BM) engraftment by flow cytometry, mice were randomized to receive vehicle, 5F9 (10mg/kg/d, ip. twice a week, 3 weeks), VEN (50mg/kg/g, po. qd, 14 days) / AZA (2.5mg/kg/d, ip, qd, 7 days), or their combination. Circulating leukemia burden was monitored by hCD45 flow cytometry in peripheral blood (PB) (Figure 1D), and mice survival was followed. 5F9 reduced leukemia burden, delayed leukemia progression and significantly extended mice' survival in both models, with the median survival of 276.5 days of 5F9 group compared to 197 days of vehicle in #344, and 81.5 vs 52 days in #574 (Figure 1E ). On the contrary, VEN/AZA therapy had no or minimal impact on tumor burden or survival. Notably, the combination of 5F9 and VEN/AZA resulted in elimination of circulating blasts and significant extension of survival in both models, median of 385 days in #344 and 124.5 days in #574.
In summary, the VEN/AZA combined with 5F9 increased phagocytosis in isogenic MOLM-13 cells in vitro regardless of VEN resistance or p53 status and prolonged the survival in vivo in VEN/AZA refractory AML PDX models. The mechanisms of increased phagocytosis by combination treatment and the induction of "eat-me signals" by VEN/AZA is currently under investigation and will be presented. This triplet combination is currently being tested in a clinical trial (NCT04435691, Daver et al., ASH 2021) with high preliminary efficacy.
Figure 1 Figure 1.
Chao: Gilead Sciences, Inc.: Current Employment; TigaTx: Membership on an entity's Board of Directors or advisory committees; Stanford University: Patents & Royalties; Hepatx Inc: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Iconovir Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Stanford University Medical School: Membership on an entity's Board of Directors or advisory committees; Foresite capital: Consultancy; Bioverge: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Chimera Bioengineering: Current equity holder in publicly-traded company. Maute: Gilead Sciences: Ended employment in the past 24 months. Andreeff: Syndax: Consultancy; Karyopharm: Research Funding; ONO Pharmaceuticals: Research Funding; Senti-Bio: Consultancy; AstraZeneca: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Breast Cancer Research Foundation: Research Funding; Medicxi: Consultancy; Aptose: Consultancy; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Oxford Biomedica UK: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy; Amgen: Research Funding. Daver: Hanmi: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novimmune: Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; ImmunoGen: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Konopleva: Rafael Pharmaceuticals: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Ascentage: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Stemline Therapeutics: Research Funding; Ablynx: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Cellectis: Other: grant support; Sanofi: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding.
| v2 |
2014-10-01T00:00:00.000Z | 1998-10-29T00:00:00.000Z | 15269050 | s2ag/train | Objects, Components, and Frameworks with UML: The Catalysis Approach
Preface. I. OVERVIEW. 1. A Tour of Catalysis. Objects and Actions. Refinement: Objects and Actions at Different Scales. Development Layers. Business Modeling. Model Frameworks as Templates. Zooming In on the Software: System Context. Requirements Specification Models. Components. Assigning Responsibilities. Object-Oriented Design. The Development Process. Three Constructs Plus Frameworks. Three Levels of Modeling. Three Principles. Summary. II. MODELING WITH OBJECTS. 2. Static Models: Object Attributes and Invariants. What Is a Static Model? Object State: Objects and Attributes. Implementations of Object State. Modeling Object State: Types, Attributes, and Associations. Static Invariants. The Dictionary. Models of Business Models of Components. Static Models: Summary. 3. Behavior Models: Object Types and Operations. Object Behavior: Objects and Actions. More Precise Action Specifications. Two Java Implementations of a Calendar. Type Specification of Calendar. Actions with Invariants. Interpreting an Action Specification. Subtypes and Type Extension. Factoring Action Specifications. State Charts. Outputs of Actions. Subjective Model: The Meaning of Containment. Type Specifications: Summary. Programming Language: Classes and Types. 4. Interaction Models: Use Cases, Actions, and Collaborations. Designing Object Collaborations. Actions (Use Cases) Abstract Complex Interactions. Use Cases Are Joint Actions. Actions and Effects. Concurrent Actions. Collaborations. Uses of Collaborations. Collaboration Specification. Collaborations: Summary. 5. Effective Documentation. What's It All For? Documentation Is Easy and Fun, and It Speeds Design. Reaching the Documentation Audience. The Main Documents: Specification and Implementation. Documenting Business Models. Documenting Component Specifications. Documenting Component Implementations. Summary. III. FACTORING MODELS AND DESIGNS. 6. Abstraction, Refinement, and Testing. Zooming In and Out: Why Abstract and Refine? Documenting Refinement and Conformance. Spreadsheet: A Refinement Example. Spreadsheet: Model Refinement. Spreadsheet: Action Refinement. Spreadsheet: Object Refinement. Spreadsheet: Operation Refinement. Refinement of State Charts. Summary. Process Patterns for Refinement. Pattern 6.1 The OO Golden Rule (Seamlessness or Continuity). Pattern 6.2 The Golden Rule versus Other Optimizations. Pattern 6.3 Orthogonal Abstractions and Refinement. Pattern 6.4 Refinement Is a Relation, Not a Sequence. Pattern 6.5 Recursive Refinement. 7. Using Packages. What Is a Package? Package Imports. How to Use Packages and Imports. Decoupling with Packages. Nested Packages. Encapsulation with Packages. Multiple Imports and Name Conflicts. Publication, Version Control, and Builds. Programming Language Packages. Summary. 8. Composing Models and Specifications. Sticking Pieces Together. Joining and Subtyping. Combining Packages and Their Definitions. Action Exceptions and Composing Specs. Summary. 9. Model Frameworks and Template Packages. Model Framework Overview. Model Frameworks of Types and Attributes. Collaboration Frameworks. Refining Frameworks. Composing Frameworks. Templates as Packages of Properties. Templates for Equality and Copying. Package Semantics. Down to Basics with Templates. Summary of Model Framework Concepts. IV. IMPLEMENTATION BY ASSEMBLY. 10. Components and Connectors. Overview of Component-Based Development. The Evolution of Components. Building Components with Java. Components with COM+. Components with CORBA. Component Kit: Pluggable Components Library. Component Architecture. Defining Cat One-A Component Architecture. Specifying Cat One Components. Connecting Cat One Components. Heterogeneous Components. Pattern 10.1 Extracting Generic Code Components. Pattern 10.2 Componentware Management. Pattern 10.3 Build Models from Frameworks. Pattern 10.4 Plug Conformance. Pattern 10.5 Using Legacy or Third-Party Components. Summary. 11. Reuse and Pluggable Design Frameworks in Code. Reuse and the Development Process. Generic Components and Plug-Points. The Framework Approach to Code Reuse. Frameworks: Specs to Code. Basic Plug Technology. Summary. Pattern 11.1 Role Delegation. Pattern 11.2 Pluggable Roles. 12. Architecture. What Is Architecture? Why Architect? Architecture Evaluation with Scenarios. Architecture Builds on Defined Elements. Architecture Uses Consistent Patterns. Application versus Technical Architecture. Typical Four-Tier Business Architecture. User Interfaces. Objects and Databases. Summary. V. HOW TO APPLY CATALYSIS. 13. Process Overview. Model, Design, Implement, and Test-Recursively. General Notes on the Process. Typical Project Evolution. Typical Package Structure. Main Process Patterns. Pattern 13.1 Object Development from Scratch. Pattern 13.2 Reengineering. Pattern 13.3 Short-Cycle Development. Pattern 13.4 Parallel Work. 14. How to Build a Business Model. Business Modeling Process Patterns. Pattern 14.1 Business Process Improvement. Pattern 14.2 Make a Business Model. Pattern 14.3 Represent Business Vocabulary and Rules. Pattern 14.4 Involve Business Experts. Pattern 14.5 Creating a Common Business Model. Pattern 14.6 Choose a Level of Abstraction. Modeling Patterns. Pattern 14.7 The Type Model Is a Glossary. Pattern 14.8 Separation of Concepts: Normalization. Pattern 14.9 Items and Descriptors. Pattern 14.10 Generalize and Specialize. Pattern 14.11 Recursive Composite. Pattern 14.12 Invariants from Association Loops. Video Case Study: Abstract Business Model. Video Business: Use Case Refinement. Pattern 14.13 Action Reification. 15. How to Specify a Component. Patterns for Specifying Components. Pattern 15.1 Specify Components. Pattern 15.2 Bridge Requirements and Specifications. Pattern 15.3 Use-Case-Led System Specification. Pattern 15.4 Recursive Decomposition: Divide and Conquer. Pattern 15.5 Make a Context Model with Use Cases. Pattern 15.6 Storyboards. Pattern 15.7 Construct a System Behavior Spec. Pattern 15.8 Specifying a System Action. Pattern 15.9 Using State Charts in System Type Models. Pattern 15.10 Specify Component Views. Pattern 15.11 Compose Component Views. Pattern 15.12 Avoid Miracles, Refine the Spec. Pattern 15.13 Interpreting Models for Clients. Video Case Study: System Specifications. System Context Diagram. System Specification. Using Model Frameworks. 16. How to Implement a Component. Designing to Meet a Specification. Pattern 16.1 Decoupling. Pattern 16.2 High-Level Component Design. Pattern 16.3 Reifying Major Concurrent Use Cases. Pattern 16.4 Separating Facades. Pattern 16.5 Platform Independence. Pattern 16.6 Separate Middleware from Business Components. Pattern 16.7 Implement Technical Architecture. Pattern 16.8 Basic Design. Pattern 16.9 Generalize after Basic Design. Pattern 16.10 Collaborations and Responsibilities. Pattern 16.11 Link and Attribute Ownership. Pattern 16.12 Object Locality and Link Implementation. Pattern 16.13 Optimization. Detailed Design Patterns. Pattern 16.14 Two-Way Link. Pattern 16.15 Role Decoupling. Pattern 16.16 Factories. Pattern 16.17 Observer. Pattern 16.18 Plug-Points and Plug-Ins. Video Case Study: Component-Based Design. Appendix A: Object Constraint Language. Appendix B: UML Perspective. Appendix C: Catalysis Support Tools, Services, and Experiences. Notes. Glossary. Index. 0201310120T04062001 | v2 |
2019-03-18T14:04:18.002Z | 2018-11-16T00:00:00.000Z | 81350740 | s2ag/train | Sacubitril/valsartan and the risk of sudden cardiac death
Patients with heart failure (HF) with reduced left ventricle ejection fraction (HFrEF) are at high risk of sudden cardiac death (SCD). Therefore HFrEF treatment requires further improvement, which may be accomplished with the use of sacubitril/valsartan. Sacubitril/valsartan reduce the risks of allcause mortality, cardiovascular mortality, SCD, HF mortality, HF and all-cause hospitalizations, as well as symptoms of HF. It was also shown that use of sacubitril/valsartan may be associated with a reduced number of adequate and inadequate device interventions in HFrEF patients with an implantable cardioverter defibrillator, and an increased percentage of biventricular pacing in patients with cardiac resynchronization therapy. Sacubitril/valsartan blocks the angiotensin II receptor (valsartan) and inhibits neprilysin (sacubitril) simultaneously. It results in inhibited sympathetic activity, as well as decreased cardiac remodeling and fibrosis, resulting in a decreased pro-arrhythmogenic effect. Current trends show that the prevalence of heart failure (HF) is still increasing(1). Patients with HF with reduced left ventricle ejection fraction (HFrEF) are at high risk of sudden cardiac death (SCD)(2). In the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial approximately 40% of deaths of HFrEF patients were related to SCD caused mainly by ventricular arrhythmia(3). The risk of SCD in HFrEF may be reduced with guideline-recommended treatment with angiotensin converting enzyme inhibitors (ACE-I), beta-blockers, mineralocorticoid receptor antagonists (MRA), as well as with device therapies such as implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT). Angiotensin-receptor blockers (ARB) should be restricted to patients unable to tolerate ACE-I or potentially used in addition to ACE-I instead of MRA in the case of intolerance(2). The PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With an Angiotensin-ConK. Ozieranski et al. 60 verting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study was terminated ahead of time (after a median of 27 months of observation) because of observed clear benefits of sacubitril/valsartan compared to enalapril. Sacubitril/valsartan significantly reduced the risks of all-cause mortality, cardiovascular mortality, SCD, HF mortality, HF and all-cause hospitalizations, as well as symptoms of HF(3). It is important that the advantages of treatment with sacubitril/valsartan persist even after the need for dose reduction and are similar to those observed in patients without any dose reduction(4). It was also shown that use of sacubitril/valsartan was also associated with a reduced number of adequate and inadequate device interventions in HFrEF patients with an implanted ICD. Sacubitril/valsartan reduced the risk of sustained and nonsustained ventricular tachycardia, as well as the risk of premature ventricular contractions, which translated into a higher rate of biventricular pacing in patients with CRT. In addition, a trend was observed to reduce the incidence of paroxysmal atrial tachycardia and atrial fibrillation(5). In the PARADIGM-HF study patients treated with sacubitril/valsartan were less likely to require implantation of a cardiac device or cardiac transplantation(3). Sacubitril/valsartan blocks the angiotensin II receptor (valsartan) and inhibits neprilysin (sacubitril) simultaneously. Inhibition of the AT2 receptor results in decreased sympathetic activity and inhibits cardiac hypertrophy, reverse remodeling and fibrosis, and therefore inhibits the pro-arrhythmogenic effect. Neprilysin is an enzyme that degrades natriuretic and vasoactive peptides and is overstimulated in patients with HF. Neprilysin inhibition, by sacubitril, causes beneficial effects on the cardiovascular system through the vasodilating effect and increasing the availability of natriuretic peptides, which in turn leads to growth of natriuresis and diuresis, as well as reduction of left ventricular and vascular remodeling(6, 7). The reduction of the risk of ventricular arrhythmia in the PARADIGM trial might have resulted from intensification of HF treatment through connection of these two molecules – sacubitril and valsartan. Reduction of preload and afterload, improvement of the left ventricular function obtained by neprilysin inhibition, as well as reduction of myocardial fibrosis, myocardial ischemia and sympathetic tone by valsartan, might play an important role in modification of the substrate for fatal ventricular arrhythmias. Mortality benefits of sacubitril/valsartan use are particularly related to modification of the risk for SCD and death due to HF worsening, giving a real chance for further improvement in HF therapy. References 1. Yancy CW, Januzzi JL, Jr., Allen LA, Butler J, Davis LL, Fonarow GC, et al. 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018;71(2):201-30. 2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. [2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure]. Kardiol Pol. 2016;74(10):1037-147. 3. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 4. Vardeny O, Claggett B, Packer M, Zile MR, Rouleau J, Swedberg K, et al. Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial. Eur J Heart Fail. 2016;18(10):1228-34. 5. de Diego C, Gonzalez-Torres L, Nunez JM, Centurion Inda R, Martin-Langerwerf DA, Sangio AD, et al. Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices. Heart Rhythm. 2018;15(3):395-402. 6. Nessler J, Straburzynska-Migaj E, Windak A, Solnica B, Szmitkowski M, Paradowski M, et al. [Expert consensus on the usefulness of natriuretic peptides in heart failure.]. Kardiol Pol. 2018;76(1):215-24. 7. Mills J, Vardeny O. The role of neprilysin inhibitors in cardiovascular disease. Curr Heart Fail Rep. 2015;12(6):389-94. | v2 |
2019-11-22T01:08:58.169Z | 2019-11-13T00:00:00.000Z | 209235820 | s2ag/train | Early Intervention with Hypomethylating Agents in Transfusion-Independent Patients with Myelodysplastic Syndrome
Background: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndrome (MDS), but their role in those with lower-risk MDS has not been well-established. A randomized phase 2 study evaluating low-dose decitabine and low-dose azacitidine in patients with lower-risk MDS showed that treatment with attenuated dose schedules of HMA therapy are both well-tolerated and effective in patients with lower-risk MDS (Jabbour E, Blood 2017). However, their use as early intervention in transfusion-independent patients with lower-risk MDS remains unknown. Consequently, we performed a retrospective analysis of a cohort of transfusion-independent lower-risk MDS patients to evaluate the safety and clinical activity of low-dose HMAs in this patient population.
Methods: Fifty-four adult patients with low-risk or intermediate-1-risk disease by the International Prognostic Scoring System (IPSS) and transfusion-independence at baseline treated on clinical trial NCT01720225 from November 2012 to February 2016 were included in the analysis. Patients were treated with either decitabine 20 mg/m2 intravenously (IV) daily for 3 days or azacitidine 75 mg/m2 IV daily for 3 days every 28 days. Dose reductions for grade 3 or 4 toxicities were allowed on the clinical trial, and responding patients were allowed to continue therapy indefinitely.
Results: Patient characteristics included a median age of 70 with 38 males (70%) and median bone marrow (BM) blast percentage of 3%. Twelve patients (22%) had low-risk disease and 42 patients (78%) had intermediate-1-risk disease by IPSS, and risk groups by revised IPSS (IPSS-R) included very low-risk in 8 patients (15%), low-risk in 22 patients (41%), intermediate-risk in 12 patients (24%), and high-risk in 11 patients (20%). The most commonly observed mutations were TET2 (26%), RUNX1 (9%), ASXL1 (7%), and TP53 (7%). Thirty-three patients (61%) were treated with decitabine while 21 patients (39%) were treated with azacitidine. Grade 3 or 4 adverse events included pneumonia (4%), syncope (4%), myalgias/joint pains (2%), dizziness (2%), and neutropenia (2%). Otherwise, the most common toxicities were grade 1-2 fatigue (17%), nausea (13%), and constipation (11%). No early mortality was observed during the first 60 days. Of the 54 patients included in the analysis, 50 patients (93%) were evaluable for response based on BM blast percentage and cytopenias. Of the 17 patients with BM blasts > 5%, 11 patients achieved complete remission (CR), 4 patients reached marrow CR, and 2 patients had no response. Of the 33 patients with BM blasts ≤ 5% and at least 1 cytopenia, 13 patients demonstrated hematological improvement, 10 patients exhibited stable disease, 8 patients did not respond, and 2 patients progressed. At a median follow-up of 37 months, the median overall survival was not reached, and the median event-free survival was 24.9 months. Four patients (7%) eventually became transfusion-dependent, and 5 patients (9%) ultimately transformed to acute myeloid leukemia (AML).
Conclusions: Overall, attenuated doses of decitabine and azacitidine were safe and tolerated in patients with transfusion-independent lower-risk MDS. Higher rates and longer durations of response with improved survival and lower rates of AML transformation were observed. Though patients with lower-risk MDS who are transfusion-independent have traditionally undergone surveillance, early intervention with low-dose HMAs may be beneficial in these patients. Prospective studies, such as with clinical trial NCT02269280, are warranted.
Jabbour: Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Ravandi:Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Borthakur:FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xbiotech USA: Research Funding; NKarta: Consultancy; AbbVie: Research Funding; Janssen: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Eli Lilly and Co.: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Incyte: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Bayer Healthcare AG: Research Funding; GSK: Research Funding. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Merus: Consultancy, Honoraria, Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kantarjian:Astex: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Takeda: Honoraria; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Ariad: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.
| v2 |
2019-12-12T08:03:23.740Z | 2019-11-13T00:00:00.000Z | 209274150 | s2ag/train | Anti-Leukemic Activity of Single Agent Venetoclax in Newly Diagnosed Acute Myeloid Leukemia: A Sub-Set Analysis of the Caveat Study
Background:The small molecule BCL-2 inhibitor Venetoclax (VEN) has emerged as a promising frontline therapy in combination with low dose cytarabine (LDAC) or hypomethylating agents in older patients with acute myeloid leukemia (AML)(DiNardo et al, Lancet Oncol 2018, Blood 2019; Wei et al,JCO 2019). The anti-leukemic activity of single agent VEN as monotherapy in newly diagnosed AML is unknown. This information would be useful for studies considering VEN as a maintenance therapy. We have previously presented preliminary outcomes from a phase 1b/2 study: Chemotherapy and Venetoclax in Elderly AML Trial (CAVEAT), which incorporated a 7-day single agent VEN run-in phase prior to combination with chemotherapy (Wei et al, ASH 2018). The study procedures incorporated a bone marrow assessment performed at study screening and on day 8, prior to commencement of chemotherapy (Figure 1A). This allowed us to explore the single agent activity of venetoclax on bone marrow blasts in treatment naïve patients with AML and to assess molecular dynamics of response.
Methods:The CAVEAT trial included 51 de novo or secondary patients with AML aged ≥65 years and considered fit for intensive chemotherapy. The study enrolled patients to 5 VEN dose cohorts (50-100-200-400-600mg). VEN was administered on days 1-14 during induction. Chemotherapy commenced on day 8, with a 7-day VEN monotherapy pre-phase. Molecular studies:a 54-gene myeloid NGS panel (Illumina TruSight) and MassARRAY MALDI-TOF mass spectrometry was performed on DNA extracted from bone marrow aspirates. FLT3-ITD testing was by fragment analysis, PCR and capillary electrophoresis. Minimal residual disease (MRD) testing was performed by digital droplet PCR for IDH mutations (assay sensitivity: 10-4-10-5).
Results: A total of 46 patients had paired BM assessments at screening and on day 8 for comparison. A ≥50% relative reduction in BM blasts was recorded in 13/46 (28%) patients. Figure 1B shows the relative BM blast reduction stratified by molecular subgroups. Patients with NPM1(n=9) or IDH2 (n=8) mutation achieved greater BM blast reductions (median of 56% and 55%, respectively) than IDH1 (n=6), TP53 (n=10) or FLT3-ITD (n=5) mutant cases (median of 37%, 17% and 7%, respectively). Three NPM1 mutant cases with <25% blast reduction had contemporaneous kinase activating mutations (FLT3-ITD, FLT3-TKD and c-KIT). Molecular studies were performed on serial screening and day 8 bone marrow samples in 21 patients (Figure 1C). Variant allele frequency (VAF) reductions were observed in 6/8 (75%) NPM1 and 6/11 (55%) IDH 1/2 mutant cases. 1/8 (13%) NPM1 mutant and 4/11 (36%) IDH 1/2 mutant cases had reduction in molecular burden to below the limit of detection (5%) by day 8. Minimal reduction in VAF was seen in DNMT3A, SRSF2, NRAS/KRAS and FLT3-ITD mutations. 4 out of 5 (80%) FLT3-ITD mutant cases had an increase in VAF at day 8.
Clinically, complete remission (CR) and CR with incomplete count recovery (CRi) rates after chemotherapy were seen for the following mutations: NPM1(80%), IDH2 (100%), IDH1 (62%) and TP53 (36%) (Figure 1D). Despite all four response-evaluable patients with FLT3-ITD achieving CR/CRi, 3/4 relapsed with detectable FLT3-ITD (at 0.8, 1.5 and 12.3 months respectively). Median survival for each genomic sub-group were NPM1 (12.5m), IDH2 (not reached), IDH1 (6.1m),TP53 (3.8m), FLT3-ITD (5.5m).
CyTOF analyses for changes in BCL-2 family expression are underway and results will be presented at the meeting.
Conclusion: Treatment naïve NPM1 and IDH2 mutant AML blasts are highly sensitive to VEN alone and combination with cytarabine and anthracycline chemotherapy results in a high clinical response rate. TP53 and FLT3-ITD mutant cases were more resistant and outcomes were poor despite VEN combined with chemotherapy.
Figure 1
Reynolds: Alfred Health: Employment, Other: Biostatistician for trials funded by the Australian government and Abbvie, Amgen, Celgene, GSK, Janssen-Cilag, Merck, Novartis, Takeda, but sponsored by Alfred Health.; AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP (ALLG): Consultancy; Novartis AG: Equity Ownership; Novartis Australia: Honoraria. Fong:Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy; Novartis: Speakers Bureau. Ting:NHMRC: Research Funding. Fleming:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Ariad: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Moujalled:Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Share in venetoclax royalties . Ivey:Novartis: Honoraria. Roberts:AbbVie: Research Funding; Janssen: Research Funding; Walter and Eliza Hall Institute: Employment, Patents & Royalties: receives a fraction of its royalty stream related to venetoclax. Wei:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria.
Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on correlative study results in the CAVEAT trial which combines venetoclax with modified intensive chemotherapy in AML, which is not an approved indication.
| v2 |
2021-11-26T16:39:03.507Z | 2021-11-05T00:00:00.000Z | 244658990 | s2ag/train | Bispecific Vγ9Vδ2-T and Type 1 NKT Cell Engager Lava-051 As First-in-Class Clinical Candidate to Target CD1d Expressing CLL, MM and AML
Background. Bispecific antibodies that target tumors by engaging innate-like T cell subsets with inherent antitumor activity, such as Vγ9Vδ2-T and type 1 natural killer T (NKT) cells, may combine high therapeutic efficacy with limited off-tumor toxicity. Type 1 NKT cells respond to self and foreign (glyco)lipid antigens presented in the context of the MHC class I like molecule CD1d which is expressed on various malignancies. Vγ9Vδ2-T cells respond to intracellular accumulation of phosphoantigens in cancer cells by sensing conformational alterations in the butyrophilin (BTN) 2A1-3A1 complex. CD1d is expressed by the majority of patients with CLL and MM, while expression in AML is most pronounced on (myelo)monocytic subtypes.
Methods. LAVA-051 is a 27kD humanized bispecific single domain antibody (bsVHH) that directly engages CD1d and the Vδ2-TCR chain of Vγ9Vδ2-T cells. The anti-CD1d VHH specifically stabilizes the interaction between CD1d and the type 1 NKT cell TCR and thereby triggers strong activation of type 1 NKT cells (Nature Cancer 2020;1:1054-1065). Vγ9Vδ2-T and type 1 NKT effector cell activation, proliferation, cytokine production and target cell lysis were assessed in in vitro, ex vivo, and in vivo studies. Due to lack of cross reactivity of LAVA-051 with non-human primate (NHP) CD1d and Vγ9Vδ2-T cells, a cross-reactive surrogate bispecific engager was generated to assess tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) parameters.
Results. The CD1d-Vδ2 bsVHH LAVA-051 triggers activation of both Vγ9Vδ2-T and type 1 NKT cells (EC 50 4 pM for Vγ9Vδ2-T and 366 pM for type 1 NKT; induction of > 80% degranulation in 4h assays) and mediates potent killing of CD1d expressing tumor cells by engagement of Vγ9Vδ2-T and/or type 1 NKT cells (EC 50 1 pM for Vγ9Vδ2-T and 216 pM for type 1 NKT; > 85% target cell lysis in 16h assays at a low 1:2 E:T ratio). Further, LAVA-051 triggered pro-inflammatory cytokine production, proliferation of Vγ9Vδ2-T and type 1 NKT cells, and exerted substantial antitumor activity against patient AML, CLL and MM cells that express CD1d and improved survival in in vivo T-ALL, AML and MM mouse models. Multiple dose studies in NHP (7 daily doses up to 1 mg/kg iv) showed clear Vγ9Vδ2-T cell engagement and some cytokine release after the first administration, but no clinical, laboratory, or histopathological toxicity. Reflecting the low molecular size of this bispecific engager, PK studies revealed a short plasma half-life which was however compensated for by prolonged (up to 5 days) binding of the engager to peripheral blood Vγ9Vδ2-T cells allowing intermittent dosing.
Conclusions. In this study, we demonstrate that the CD1d-Vδ2 bsVHH LAVA-051 triggers activation of both type 1 NKT and Vγ9Vδ2-T cells, which translates directly into antitumor activity. Based on the expression of CD1d in CLL, MM, and AML, the strong preclinical activity of LAVA-051 against CD1d-expresssing tumors, and the favorable tolerability profile of the surrogate engager in NHP, LAVA-051 is currently evaluated in a first-in-human clinical Phase 1/2a study in patients with CD1d-expressing CLL, MM, or AML refractory to prior therapy (NCT04887259).
Lameris: Lava Therapeutics: Honoraria, Patents & Royalties, Research Funding. Ruben: Lava Therapeutics: Current Employment, Honoraria, Research Funding. Weerdt: LAVA Therapeutics: Research Funding. Roovers: LAVA Therapeutics: Current Employment, Current equity holder in publicly-traded company. van de Donk: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding. Broyl: Amgen: Honoraria; Bristol-Meyer Squibb: Honoraria; Celgene: Honoraria; Janssen Pharmaceuticals: Honoraria; Sanofi: Honoraria. Kater: Abbvie: Honoraria, Other: Ad Board, Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Riedl: LAVA THerapeutics: Current Employment, Current equity holder in publicly-traded company; Genmab BV: Current equity holder in publicly-traded company. Iglesias: LAVA therapeutics: Current Employment. Winograd: LAVA therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Celgene: Ended employment in the past 24 months; BMS: Current equity holder in publicly-traded company. Adang: LAVA therapeutics: Current Employment, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. de Gruijl: LAVA therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; DCPrime: Membership on an entity's Board of Directors or advisory committees; Macrophage Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Idera Pharmaceuticals: Research Funding; ORCA Therapeutics: Patents & Royalties. Parren: Lava Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Sparring Bioconsult BV: Membership on an entity's Board of Directors or advisory committees; Genmab: Patents & Royalties; Roche: Consultancy. Vliet: Lava Therapeutics: Current Employment, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Glycostem: Research Funding.
| v2 |
2018-04-03T03:16:17.869Z | 2017-07-28T00:00:00.000Z | 2069780 | s2ag/train | Oral versus intravenous fluoropyrimidines for colorectal cancer.
BACKGROUND
Patients prefer oral to intravenous (IV) palliative chemotherapy, provided that oral therapy is not less effective. We compared the efficacy and safety of oral and IV fluoropyrimidines for treatment of colorectal cancer (CRC).
OBJECTIVES
To compare the effects of oral and IV fluoropyrimidine chemotherapy in patients treated with curative or palliative intent for CRC.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 5), along with OVID MEDLINE, OVID Embase, and Web of Science databases, in June 2016. We also searched five clinical trials registers, several conference proceedings, and reference lists from study reports and systematic reviews. We contacted pharmaceutical companies to identify additional studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing oral and IV fluoropyrimidine chemotherapy in patients treated with curative or palliative intent for CRC.
DATA COLLECTION AND ANALYSIS
Three review authors extracted data and assessed risk of bias independently. We assessed the seven domains in the Cochrane 'Risk of bias' tool and three additional domains: schedules of outcome assessment and/or follow-up; use of intention-to-treat analysis; and baseline comparability of treatment arms.
MAIN RESULTS
We included nine RCTs (total of 10,918 participants) that examined treatment with curative intent for CRC with neoadjuvant and/or adjuvant chemotherapy. We included 35 RCTs (total of 12,592 participants) that examined treatment with palliative intent for inoperable advanced or metastatic CRC with chemotherapy (31 first-line studies, two second-line studies, and two studies of first- or second-line chemotherapy). All studies included male and female participants, and no studies included participants younger than 18 years of age. Patients treated with curative intent for CRC with neoadjuvant and/or adjuvant chemotherapy • Disease-free survival (DFS): DFS did not differ between participants treated with oral versus IV fluoropyrimidines (hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.87 to 1.00; seven studies, 8903 participants; moderate-quality evidence).• Overall survival (OS): OS did not differ between participants treated with oral versus IV fluoropyrimidines (HR 0.92, 95% CI 0.84 to 1.00; seven studies, 8902 participants analysed; high-quality evidence).• Grade ≥ 3 adverse events (AEs): Participants treated with oral fluoropyrimidines experienced less grade ≥ 3 neutropenia/granulocytopenia (odds ratio (OR) 0.14, 95% CI 0.11 to 0.16; seven studies, 8087 participants; moderate-quality evidence), stomatitis (OR 0.21, 95% CI 0.14 to 0.30; five studies, 4212 participants; low-quality evidence), and any grade ≥ 3 AEs (OR 0.82, 95% CI 0.74 to 0.90; five studies, 7741 participants; low-quality evidence). There was more grade ≥ 3 hand foot syndrome (OR 4.59, 95% CI 2.97 to 7.10; five studies, 5731 participants; low-quality evidence) in patients treated with oral fluoropyrimidines. There were no differences between participants treated with oral versus IV fluoropyrimidines in occurrence of grade ≥ 3 diarrhoea (OR 1.12, 95% CI 0.99 to 1.25; nine studies, 9551 participants; very low-quality evidence), febrile neutropenia (OR 0.59, 95% CI 0.18 to 1.90; four studies, 2925 participants; low-quality evidence), vomiting (OR 1.05, 95% CI 0.83 to 1.34; eight studies, 9385 participants; low-quality evidence), nausea (OR 1.21, 95% CI 0.97 to 1.51; seven studies, 9233 participants; low-quality evidence), mucositis (OR 0.64, 95% CI 0.25 to 1.62; four studies, 2233 participants; very low-quality evidence), and hyperbilirubinaemia (OR 1.67, 95% CI 0.52 to 5.38; three studies, 2757 participants; very low-quality evidence). Patients treated with palliative intent for inoperable advanced or metastatic CRC with chemotherapy • Progression-free survival (PFS): Overall, PFS was inferior in participants treated with oral versus IV fluoropyrimidines (HR 1.06, 95% CI 1.02 to 1.11; 23 studies, 9927 participants; moderate-quality evidence). Whilst PFS was worse in participants treated with oral compared with IV fluoropyrimidines when UFT/Ftorafur or eniluracil with oral 5-fluorouracil (5-FU) was used, PFS did not differ between individuals treated with oral versus IV fluoropyrimidines when capecitabine, doxifluridine, or S-1 was used.• OS: Overall, OS did not differ between participants treated with oral versus IV fluoropyrimidines (HR 1.02, 95% CI 0.99 to 1.05; 29 studies, 12,079 participants; high-quality evidence). OS was inferior in participants treated with oral versus IV fluoropyrimidines when eniluracil with oral 5-fluorouracil (5-FU) was used.• Time to progression (TTP): TTP was inferior in participants treated with oral versus IV fluoropyrimidines (HR 1.07, 95% CI 1.01 to 1.14; six studies, 1970 participants; moderate-quality evidence).• Objective response rate (ORR): ORR did not differ between participants treated with oral versus IV fluoropyrimidines (OR 0.98, 95% CI 0.90 to 1.06; 32 studies, 11,115 participants; moderate-quality evidence).• Grade ≥ 3 AEs: Participants treated with oral fluoropyrimidines experienced less grade ≥ 3 neutropenia/granulocytopenia (OR 0.17, 95% CI 0.15 to 0.18; 29 studies, 11,794 participants; low-quality evidence), febrile neutropenia (OR 0.27, 95% CI 0.21 to 0.36; 19 studies, 9407 participants; moderate-quality evidence), stomatitis (OR 0.26, 95% CI 0.20 to 0.33; 21 studies, 8718 participants; low-quality evidence), mucositis (OR 0.17, 95% CI 0.12 to 0.24; 12 studies, 4962 participants; low-quality evidence), and any grade ≥ 3 AEs (OR 0.83, 95% CI 0.74 to 0.94; 14 studies, 5436 participants; low-quality evidence). There was more grade ≥ 3 diarrhoea (OR 1.66, 95% CI 1.50 to 1.84; 30 studies, 11,997 participants; low-quality evidence) and hand foot syndrome (OR 3.92, 95% CI 2.84 to 5.43; 18 studies, 6481 participants; moderate-quality evidence) in the oral fluoropyrimidine arm. There were no differences between oral and IV fluoropyrimidine arms in terms of grade ≥ 3 vomiting (OR 1.18, 95% CI 1.00 to 1.40; 23 studies, 9528 participants; low-quality evidence), nausea (OR 1.16, 95% CI 0.99 to 1.36; 25 studies, 9796 participants; low-quality evidence), and hyperbilirubinaemia (OR 1.62, 95% CI 0.99 to 2.64; nine studies, 2699 participants; low-quality evidence).
AUTHORS' CONCLUSIONS
Results of this review should provide confidence that treatment for CRC with most of the oral fluoropyrimidines commonly used in current clinical practice is similarly efficacious to treatment with IV fluoropyrimidines. Treatment with eniluracil with oral 5-FU was associated with inferior PFS and OS among participants treated with palliative intent for CRC, and eniluracil is no longer being developed. Oral and IV fluoropyrimidines have different patterns of side effects; future research may focus on determining the basis for these differences. | v2 |
2020-12-14T20:14:37.820Z | 2020-11-05T00:00:00.000Z | 228807350 | s2ag/train | The Addition of Navitoclax to Ruxolitinib Demonstrates Efficacy within Different High-Risk Populations in Patients with Relapsed/Refractory Myelofibrosis
Background: There are limited therapeutic options for patients (pts) with myelofibrosis (MF) who lose response to ruxolitinib (Rux). The combination of navitoclax (Nav) plus Rux (NCT03222609) has been shown to induce clinically meaningful spleen volume (SV) responses, improvement in Total Symptom Score (TSS), and reduction in bone marrow fibrosis (BMF) grading in pts with MF who no longer benefit from Rux. At diagnosis, pts with primary MF who have high-molecular-risk (HMR) mutations, defined as mutations in ASXL1, SRSF2, EZH2, U2AF1, and IDH1/2, have shorter overall survival and/or increased risk of leukemic transformation. In addition to mutations in HMR genes, the total number of all genes mutated (regardless of whether they are HMR genes) also correlates with reduced SV responses, treatment (Tx) duration, and overall survival. This phase 2 study explored whether the presence of HMR, or the total number of genes mutated at study entry, correlated with clinical outcomes (SV reduction ≥35% [SVR35], reductions in TSS and BMF) and reductions in driver gene (JAK2 p.V617F and mutated CALR) variant allele frequency (VAF) following Nav plus Rux. As pts with MF have demonstrated a markedly abnormal cytokine profile at baseline, the ability of Nav plus Rux to mediate known MF inflammatory cytokines was also assessed.
Methods: MF pts with Rux failure who had received ≥12 weeks of continuous Rux and had persistent splenomegaly that required a new Tx were enrolled. Pts continued Rux, and Nav was started at 50 mg QD with stepwise escalation to 300 mg on the basis of tolerability. Study endpoints included SVR35 (by MRI), change in TSS (MF Symptom Assessment Form version 4.0) at week (Wk) 24, and change in BMF (locally assessed). At baseline and Wk 24, mutational analyses including VAF measurement were performed in peripheral blood by next-generation sequencing with the 54-gene Focus::Myeloid™ panel (3% limit of detection). At baseline, Wk 12 and 24, levels of inflammatory cytokines were measured in plasma with the 133-analyte ExplorerMAP™ panel.
Results: As of February 28, 2020, 34 pts with MF had received ≥1 dose of Nav plus Rux. At study entry, 33 pts were evaluable for biomarker analysis. JAK2 was mutated in 26/33 (79%) pts and 7/33 (21%) pts were positive for mutated CALR. Median VAFs for JAK2- and CALR-mutated pts were 88% and 39%, respectively. Baseline mutational analysis revealed the presence of HMR genes in 19/33 (58%) pts; of these, 8/19 (42%) had ≥2 HMR genes mutated. Mutation rates for ASXL1, SRSF2, EZH2, U2AF1, and IDH1 were 13/19 (68%), 7/19 (37%), 4/19 (21%), 2/19 (10%), and 1/19 (5%), respectively (Figure 1). At baseline, the median number of all genes mutated was 3, and 17/33 (52%) pts harbored ≥3 mutations. At Wk 24, among evaluable pts, 9/34 (27%) achieved SVR35, 6/20 (30%) reached ≥50% reduction in TSS (TSS50), 7/34 (21%) had -1/-2 grade improvement in BMF, and 12/26 (46%) had >10% driver gene VAF reductions. Pts who achieved either SVR35, TSS50, BMF improvement, or VAF reduction were assessed and the distribution of pts with or without HMR mutations, and with ≥3 or <3 total genes mutated was determined. Wk 24 clinical responses and VAF reductions were observed independent of the presence of HMR mutations and number of genes mutated. Notably, 5/9 (56%) pts who achieved SVR35 at Wk 24 had HMR mutations. The frequency of pts with HMR mutations or ≥3 mutations in responders is consistent with that observed in the entire cohort.
Further analyses revealed a direct correlation between changes from baseline in known MF-associated cytokines and SV changes (Figure 2A and 2B) (ie, beta-2 microglobulin [B2M; Wk 12 and 24], tumor necrosis factor receptor 2 [TNFR2; Wk 12], tissue inhibitor of metalloproteinases 1 [TIMP-1; Wk 12], and vascular cell adhesion molecule 1 [VCAM-1; Wk 12]). The Wk 24 TNFR2, TIMP-1, and VCAM-1 analyses will be available for presentation. These 4 cytokines have also been shown historically to correlate with TSS improvement.
Conclusions: Pts with MF previously treated with Rux who then receive Nav plus Rux in combination achieved clinically meaningful SVR, TSS improvement, reduction in BMF, and driver gene VAF reductions independent of HMR mutations and the total number of genes mutated. Ongoing cytokine analyses suggest that the combination of Nav plus Rux may have a role in modulating key cytokines implicated in TSS improvement in pts with MF with suboptimal response to Rux alone.
Pemmaraju: MustangBio: Honoraria; Pacylex Pharmaceuticals: Consultancy; Samus Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Cellectis: Research Funding; Plexxikon: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Novartis: Honoraria, Research Funding; Roche Diagnostics: Honoraria; Blueprint Medicines: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Incyte Corporation: Honoraria; DAVA Oncology: Honoraria; SagerStrong Foundation: Other: Grant Support; LFB Biotechnologies: Honoraria. Garcia:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Eli Lily: Research Funding. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Holes:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Harb:AbbVie: Current Employment, Other: may hold stock or stock options. Jung:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Hutti:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Verstovsek:Blueprint Medicines Corp: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding. Harrison:CTI Biopharma Corp: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau; Sierra Oncology: Honoraria; Shire: Honoraria, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Roche: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Promedior: Honoraria.
| v2 |
2019-02-02T14:07:27.352Z | 2018-11-29T00:00:00.000Z | 59540170 | s2ag/train | Preliminary Results from a Phase II Study of the Combination of Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome
Background: The survival of patients with myelodysplastic syndrome (MDS) after hypomethylating agent (HMA) failure is poor at about 4 to 6 months. The exposure of CD34 positive cells from patients with MDS to HMA has been shown to result in increased expression of PD-1 and PD-L1, with a sequential increase in the expression of PD-1 and PD-L1 particularly in patients that have failed HMA (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with ligands PD-L1 and PD-L2, that has been FDA-approved for certain solid tumors. Consequently, we designed an ongoing phase II clinical trial to evaluate the safety and clinical activity of the combination of azacitidine and pembrolizumab in patients with higher-risk MDS.
Methods: Adult patients with intermediate-1 or higher disease by the International Prognostic Scoring System (IPSS) were eligible for the study. Patients were divided into two cohorts: those who had not received prior therapy and those who had not responded to, progressed on, or relapsed after HMA therapy, with a goal enrollment of 20 patients per cohort. Patients received azacitidine 75 mg/m2 IV or SQ daily for 7 days on a 28-day cycle and pembrolizumab 200 mg IV starting on cycle 1 day 1 and every 3 weeks thereafter independent of azacitidine dosing schedule. The endpoints were overall response rate and safety. Patients were discontinued from the clinical trial if there was disease progression, unacceptable adverse experiences, intercurrent illness preventing further administration of study treatment, confirmed positive serum pregnancy test, noncompliance, loss to follow-up, completion of 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of the study medication (whichever occurred later), lack of efficacy, or any other reason leading to the investigator's decision for withdrawal. Clinical trial information: NCT03094637.
Results: At data cut-off (July 2018), 18 patients have been treated with azacitidine and pembrolizumab with a median follow-up time of 16 weeks and 9 patients continuing on treatment in cycles 1-6. Twelve patients were enrolled in the HMA failure cohort and 6 patients in the previously untreated MDS cohort. Of the 12 patients evaluable for response, 7 were in the HMA failure cohort and 5 in the previously untreated MDS cohort. In the HMA failure cohort, 1 patient achieved CR, 1 patient demonstrated hematological improvement with mCR or CRi, and 5 patients progressed. In the previously untreated MDS cohort, 1 patient attained CR, 2 patients exhibited hematological improvement, 1 patient showed progression, and 1 patient died due to treatment-unrelated causes. The most frequently observed mutations in the 5 responding patients were TET2 in 3 patients and ASXL1, DNMT3A, and RUNX1 in 2 patients each. Three of the responders had diploid cytogenetics, 1 had del(10), and 1 had complex karyotype.
Treatment was overall well-tolerated. Most common treatment-related adverse events (all grades) were neutropenia (22%); elevated ALT, elevated AST, anemia, and injection site reactions (17%); and constipation, joint pain, anorexia, pneumonitis, and pneumonia (11%).
Conclusions: In this ongoing phase II trial, preliminary data suggest that azacitidine and pembrolizumab was relatively safe and may have antitumor activity in patients who failed HMA.
Cortes: Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. DiNardo:Karyopharm: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Bayer: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Daver:Sunesis: Research Funding; ARIAD: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy; Otsuka: Consultancy; Kiromic: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; Novartis: Consultancy; Incyte: Research Funding; Alexion: Consultancy; Novartis: Research Funding; ImmunoGen: Consultancy; Pfizer: Research Funding. Jain:Adaptive Biotechnologioes: Research Funding; Pfizer: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Celgene: Research Funding; BMS: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Incyte: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Pharmacyclics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Verastem: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2021-10-13T06:16:51.900Z | 2021-10-12T00:00:00.000Z | 238637370 | s2ag/train | Treatment for telangiectasias and reticular veins.
BACKGROUND
Telangiectasias (spider veins) and reticular veins on the lower limbs are very common, increase with age, and have been found in 41% of women. The cause is unknown and the patients may be asymptomatic or can report pain, burning or itching. Treatments include sclerotherapy, laser, intense pulsed light, microphlebectomy and thermoablation, but none is established as preferable.
OBJECTIVES
To assess the effects of sclerotherapy, laser therapy, intensive pulsed light, thermocoagulation, and microphlebectomy treatments for telangiectasias and reticular veins.
SEARCH METHODS
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, AMED and CINAHL databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 16 March 2021. We undertook additional searches in LILACS and IBECS databases, reference checking, and contacted specialists in the field, manufacturers and study authors to identify additional studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and quasi-RCTs that compared treatment methods such as sclerotherapy, laser therapy, intensive pulsed light, thermocoagulation, and microphlebectomy for telangiectasias and reticular veins in the lower limb. We included studies that compared individual treatment methods against placebo, or that compared different sclerosing agents, foam or laser treatment, or that used a combination of treatment methods.
DATA COLLECTION AND ANALYSIS
Three review authors independently performed study selection, extracted data, assessed risks of bias and assessed the certainty of evidence using GRADE. The outcomes of interest were resolution or improvement (or both) of telangiectasias, adverse events (including hyperpigmentation, matting), pain, recurrence, time to resolution, and quality of life.
MAIN RESULTS
We included 3632 participants from 35 RCTs. Studies compared a variety of sclerosing agents, laser treatment and compression. No studies investigated intensive pulsed light, thermocoagulation or microphlebectomy. None of the included studies assessed recurrence or time to resolution. Overall the risk of bias of the included studies was moderate. We downgraded the certainty of evidence to moderate or low because of clinical heterogeneity and imprecision due to the wide confidence intervals (CIs) and few participants for each comparison. Any sclerosing agent versus placebo There was moderate-certainty evidence that sclerosing agents showed more resolution or improvement of telangiectasias compared to placebo (standard mean difference (SMD) 3.08, 95% CI 2.68 to 3.48; 4 studies, 613 participants/procedures), and more frequent adverse events: hyperpigmentation (risk ratio (RR) 11.88, 95% CI 4.54 to 31.09; 3 studies, 528 participants/procedures); matting (RR 4.06, 95% CI 1.28 to 12.84; 3 studies, 528 participants/procedures). There may be more pain experienced in the sclerosing-agents group compared to placebo (SMD 0.70, 95% CI 0.06 to 1.34; 1 study, 40 participants; low-certainty evidence). Polidocanol versus any sclerosing agent There was no clear difference in resolution or improvement (or both) of telangiectasias (SMD 0.01, 95% CI -0.13 to 0.14; 7 studies, 852 participants/procedures), hyperpigmentation (RR 0.94, 95% CI 0.62 to 1.43; 6 studies, 819 participants/procedures), or matting (RR 0.82, 95% CI 0.52 to 1.27; 7 studies, 859 participants/procedures), but there were fewer cases of pain (SMD -0.26, 95% CI -0.44 to -0.08; 5 studies, 480 participants/procedures) in the polidocanol group. All moderate-certainty evidence. Sodium tetradecyl sulphate (STS) versus any sclerosing agent There was no clear difference in resolution or improvement (or both) of telangiectasias (SMD -0.07, 95% CI -0.25 to 0.11; 4 studies, 473 participants/procedures). There was more hyperpigmentation (RR 1.71, 95% CI 1.10 to 2.64; 4 studies, 478 participants/procedures), matting (RR 2.10, 95% CI 1.14 to 3.85; 2 studies, 323 participants/procedures) and probably more pain (RR 1.49, 95% CI 0.99 to 2.25; 4 studies, 409 participants/procedures). All moderate-certainty evidence. Foam versus any sclerosing agent There was no clear difference in resolution or improvement (or both) of telangiectasias (SMD 0.04, 95% CI -0.26 to 0.34; 2 studies, 187 participants/procedures); hyperpigmentation (RR 2.12, 95% CI 0.44 to 10.23; 2 studies, 187 participants/procedures) or pain (SMD -0.10, 95% CI -0.44 to 0.24; 1 study, 147 participants/procedures). There may be more matting using foam (RR 6.12, 95% CI 1.04 to 35.98; 2 studies, 187 participants/procedures). All low-certainty evidence. Laser versus any sclerosing agent There was no clear difference in resolution or improvement (or both) of telangiectasias (SMD -0.09, 95% CI -0.25 to 0.07; 5 studies, 593 participants/procedures), or matting (RR 1.00, 95% CI 0.46 to 2.19; 2 studies, 162 participants/procedures), and maybe less hyperpigmentation (RR 0.57, 95% CI 0.40 to 0.80; 4 studies, 262 participants/procedures) in the laser group. All moderate-certainty evidence. High heterogeneity of the studies reporting on pain prevented pooling, and results were inconsistent (low-certainty evidence). Laser plus sclerotherapy (polidocanol) versus sclerotherapy (polidocanol) Low-certainty evidence suggests there may be more resolution or improvement (or both) of telangiectasias in the combined group (SMD 5.68, 95% CI 5.14 to 6.23; 2 studies, 710 participants), and no clear difference in hyperpigmentation (RR 0.83, 95% CI 0.35 to 1.99; 2 studies, 656 participants) or matting (RR 0.83, 95% CI 0.21 to 3.28; 2 studies, 656 participants). There may be more pain in the combined group (RR 2.44, 95% CI 1.69 to 3.55; 1 study, 596 participants; low-certainty evidence).
AUTHORS' CONCLUSIONS
Small numbers of studies and participants in each comparison limited our confidence in the evidence. Sclerosing agents were more effective than placebo for resolution or improvement of telangiectasias but also caused more adverse events (moderate-certainty evidence), and may result in more pain (low-certainty evidence). There was no evidence of a benefit in resolution or improvement for any sclerosant compared to another or to laser. There may be more resolution or improvement of telangiectasias in the combined laser and polidocanol group compared to polidocanol alone (low-certainty evidence). There may be differences between treatments in adverse events and pain. Compared to other sclerosing agents polidocanol probably causes less pain; STS resulted in more hyperpigmentation, matting and probably pain; foam may cause more matting (low-certainty evidence); laser treatment may result in less hyperpigmentation (moderate-certainty evidence). Further well-designed studies are required to provide evidence for other available treatments and important outcomes (such as recurrence, time to resolution and delayed adverse events); and to improve our confidence in the identified comparisons. | v2 |
2018-04-03T01:33:43.113Z | 2015-06-02T00:00:00.000Z | 29990210 | s2ag/train | Antenatal dietary education and supplementation to increase energy and protein intake.
BACKGROUND
Gestational weight gain is positively associated with fetal growth, and observational studies of food supplementation in pregnancy have reported increases in gestational weight gain and fetal growth.
OBJECTIVES
To assess the effects of education during pregnancy to increase energy and protein intake, or of actual energy and protein supplementation, on energy and protein intake, and the effect on maternal and infant health outcomes.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2015), reference lists of retrieved studies and contacted researchers in the field.
SELECTION CRITERIA
Randomised controlled trials of dietary education to increase energy and protein intake, or of actual energy and protein supplementation, during pregnancy.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and assessed risk of bias. Two review authors independently extracted data and checked for accuracy. Extracted data were supplemented by additional information from the trialists we contacted.
MAIN RESULTS
We examined 149 reports corresponding to 65 trials. Of these trials, 17 were included, 46 were excluded, and two are ongoing. Overall, 17 trials involving 9030 women were included. For this update, we assessed methodological quality of the included trials using the standard Cochrane criteria (risk of bias) and the GRADE approach. The overall risk of bias was unclear. Nutritional education (five trials, 1090 women) Women given nutritional education had a lower relative risk of having a preterm birth (two trials, 449 women) (risk ratio (RR) 0.46, 95% CI 0.21 to 0.98, low-quality evidence), and low birthweight (one trial, 300 women) (RR 0.04, 95% CI 0.01 to 0.14). Head circumference at birth was increased in one trial (389 women) (mean difference (MD) 0.99 cm, 95% CI 0.43 to 1.55), while birthweight was significantly increased among undernourished women in two trials (320 women) (MD 489.76 g, 95% CI 427.93 to 551.59, low-quality evidence), but did not significantly increase for adequately nourished women (MD 15.00, 95% CI -76.30 to 106.30, one trial, 406 women). Protein intake increased significantly (three trials, 632 women) (protein intake: MD +6.99 g/day, 95% CI 3.02 to 10.97). No significant differences were observed on any other outcomes such as neonatal death (RR 1.28, 95% CI 0.35 to 4.72, one trial, 448 women, low-quality evidence), stillbirth (RR 0.37, 95% CI 0.07 to 1.90, one trial, 431 women, low-quality evidence), small-for-gestational age (RR 0.97, 95% CI 0.45 to 2.11, one trial, 404 women, low-quality evidence) and total gestational weight gain (MD -0.41, 95% CI -4.41 to 3.59, two trials, 233 women). There were no data on perinatal death. Balanced energy and protein supplementation (12 trials, 6705 women)Risk of stillbirth was significantly reduced for women given balanced energy and protein supplementation (RR 0.60, 95% CI 0.39 to 0.94, five trials, 3408 women, moderate-quality evidence), and the mean birthweight was significantly increased (random-effects MD +40.96 g, 95% CI 4.66 to 77.26, Tau² = 1744, I² = 44%, 11 trials, 5385 women, moderate-quality evidence). There was also a significant reduction in the risk of small-for-gestational age (RR 0.79, 95% CI 0.69 to 0.90, I² = 16%, seven trials, 4408 women, moderate-quality evidence). No significant effect was detected for preterm birth (RR 0.96, 95% CI 0.80 to 1.16, five trials, 3384 women, moderate-quality evidence) or neonatal death (RR 0.68, 95% CI 0.43 to 1.07, five trials, 3381 women, low-quality evidence). Weekly gestational weight gain was not significantly increased (MD 18.63, 95% CI -1.81 to 39.07, nine trials, 2391 women, very low quality evidence). There were no data reported on perinatal death and low birthweight. High-protein supplementation (one trial, 1051 women)High-protein supplementation (one trial, 505 women), was associated with a significantly increased risk of small-for-gestational age babies (RR 1.58, 95% CI 1.03 to 2.41, moderate-quality evidence). There was no significant effect for stillbirth (RR 0.81, 95% CI 0.31 to 2.15, one trial, 529 women), neonatal death (RR 2.78, 95% CI 0.75 to 10.36, one trial, 529 women), preterm birth (RR 1.14, 95% CI 0.83 to 1.56, one trial, 505 women), birthweight (MD -73.00, 95% CI -171.26 to 25.26, one trial, 504 women) and weekly gestational weight gain (MD 4.50, 95% CI -33.55 to 42.55, one trial, 486 women, low-quality evidence). No data were reported on perinatal death. Isocaloric protein supplementation (two trials, 184 women)Isocaloric protein supplementation (two trials, 184 women) had no significant effect on birthweight (MD 108.25, 95% CI -220.89 to 437.40) and weekly gestational weight gain (MD 110.45, 95% CI -82.87 to 303.76, very low-quality evidence). No data reported on perinatal mortality, stillbirth, neonatal death, small-for-gestational age, and preterm birth.
AUTHORS' CONCLUSIONS
This review provides encouraging evidence that antenatal nutritional education with the aim of increasing energy and protein intake in the general obstetric population appears to be effective in reducing the risk of preterm birth, low birthweight, increasing head circumference at birth, increasing birthweight among undernourished women, and increasing protein intake. There was no evidence of benefit or adverse effect for any other outcome reported.Balanced energy and protein supplementation seems to improve fetal growth, and may reduce the risk of stillbirth and infants born small-for-gestational age. High-protein supplementation does not seem to be beneficial and may be harmful to the fetus. Balanced-protein supplementation alone had no significant effects on perinatal outcomes.The results of this review should be interpreted with caution. The risk of bias was either unclear or high for at least one category examined in several of the included trials, and the quality of the evidence was low for several important outcomes. Also, as the anthropometric characteristics of the general obstetric population is changing, those developing interventions aimed at altering energy and protein intake should ensure that only those women likely to benefit are included. Large, well-designed randomised trials are needed to assess the effects of increasing energy and protein intake during pregnancy in women whose intake is below recommended levels. | v2 |
2018-04-03T06:20:52.090Z | 2016-10-31T00:00:00.000Z | 46431760 | s2ag/train | Pentasaccharides for the prevention of venous thromboembolism.
BACKGROUND
Venous thromboembolism (VTE) is a common condition with potentially serious and life-threatening consequences. The standard method of thromboprophylaxis uses an anticoagulant such as low molecular weight heparin (LMWH) or warfarin. In recent years, another type of anticoagulant, pentasaccharide, an indirect factor Xa inhibitor, has shown good anticoagulative effect in clinical trials. Three types of pentasaccharides are available: short-acting fondaparinux, long-acting idraparinux and idrabiotaparinux. Pentasaccharides cause little heparin-induced thrombocytopenia and are better tolerated than unfractionated heparin, LMWH and warfarin. However, no consensus has been reached on whether pentasaccharides are superior or inferior to other anticoagulative methods.
OBJECTIVES
To assess effects of pentasaccharides versus other methods of thromboembolic prevention (thromboprophylaxis) in people who require anticoagulant treatment to prevent venous thromboembolism.
SEARCH METHODS
The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (last searched March 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2). The CIS searched trial databases for details of ongoing and unpublished studies. Review authors searched LILACS (Latin American and Caribbean Health Sciences) and the reference lists of relevant studies and reviews identified by electronic searches.
SELECTION CRITERIA
We included randomised controlled trials on any type of pentasaccharide versus other anticoagulation methods (pharmaceutical or mechanical) for VTE prevention.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials, assessed methodological quality and extracted data in predesigned tables.
MAIN RESULTS
We included in this review 25 studies with a total of 21,004 participants. All investigated fondaparinux for VTE prevention; none investigated idraparinux or idrabiotaparinux. Studies included participants undergoing abdominal surgery, thoracic surgery, bariatric surgery or coronary bypass surgery; acutely ill hospitalised medical patients; people requiring rigid or semirigid immobilisation; and those with superficial venous thrombosis. Most studies focused on orthopaedic patients. We lowered the quality of the evidence because of heterogeneity between studies and a small number of events causing imprecision.When comparing fondaparinux with placebo, we found less total VTE (risk ratio (RR) 0.24, 95% confidence interval (CI) 0.15 to 0.38; 5717 participants; 8 studies; I2 = 64%; P < 0.00001), less symptomatic VTE (RR 0.15, 95% CI 0.06 to 0.36; 6503 participants; 8 studies; I2 = 0%; P < 0.0001), less total DVT (RR 0.25, 95% CI 0.15 to 0.40; 5715 participants; 8 studies; I2 = 67%; P < 0.00001), less proximal DVT (RR 0.12, 95% CI 0.04 to 0.39; 2746 participants; 7 studies; I2 = 64%; P = 0.0004) and less total pulmonary embolism (PE) (RR 0.16, 95% CI 0.04 to 0.62; 6412 participants; 8 studies; I2 = 0%; P = 0.008) in the fondaparinux group. The quality of the evidence was moderate for total VTE, total DVT and proximal DVT, and high for symptomatic VTE and total PE.When fondaparinux was compared with LMWH, analyses indicated that fondaparinux reduced total VTE and DVT (RR 0.55, 95% CI 0.42 to 0.73; 9339 participants; 11 studies; I2 = 64%; P < 0.0001; and RR 0.54, 95% CI 0.40 to 0.71; 9356 participants; 10 studies; I2 = 67%; P < 0.0001, respectively), and showed a trend toward reduced proximal DVT (RR 0.58, 95% CI 0.33 to 1.02; 8361 participants; 9 studies; I2 = 53%; P = 0.06). Symptomatic VTE (RR 1.03, 95% CI 0.65 to 1.63; 12240 participants; 9 studies; I2 = 35%; P = 0.90) and total PE (RR 1.24, 95% CI 0.65 to 2.34; 12350 participants; 10 studies; I2 = 0%; P = 0.51) indicated no difference between fondaparinux and LMWH. The quality of the evidence was moderate for total VTE, symptomatic VTE, total DVT and total PE, and low for proximal DVT.We showed that fondaparinux increased major bleeding compared with both placebo and LWMH (RR 2.56, 95% CI 1.48 to 4.44; 6659 participants; 8 studies; I2 = 0%; P = 0.0008; moderate-quality evidence; and RR 1.38, 95% CI 1.09 to 1.75; 12,501 participants; 11 studies; I2 = 24%; P = 0.008; high-quality evidence, respectively). All-cause mortality was not different between fondaparinux and placebo or LMWH (RR 0.76, 95% CI 0.48 to 1.22; 6674 participants; 8 studies; I2 = 14%; P = 0.26; moderate-quality evidence; and RR 0.88, 95% CI 0.63 to 1.22; 12,400 participants; 11 studies; I2 = 0%; P = 0.44; moderate-quality evidence, respectively).One study compared fondaparinux with variable and fixed (1 mg per day) doses of warfarin after elective hip or knee replacement surgery and showed no difference in primary and secondary outcomes between fondaparinux and both variable and fixed doses of warfarin. The quality of the evidence was very low. One small study compared fondaparinux with edoxaban in patients with severe renal impairment undergoing lower-limb orthopaedic surgery and reported no thromboembolic events, major bleeding events or deaths in either group. The quality of the evidence was very low. One small study compared fondaparinux with mechanical thromboprophylaxis. Results showed no difference in total VTE and total DVT between fondaparinux and mechanical thromboprophylaxis. This study reported no cases pertaining to the other outcomes of this review. The quality of the evidence was low.There were insufficient studies to permit meaningful conclusions for subgroups of clinical conditions other than orthopaedic surgery.
AUTHORS' CONCLUSIONS
Moderate to high quality evidence shows that fondaparinux is effective for short-term prevention of VTE when compared with placebo. It can reduce total VTE, DVT, total PE and symptomatic VTE, and does not demonstrate a reduction in deaths compared with placebo. Low to moderate quality evidence shows that fondaparinux is more effective for short-term VTE prevention when compared with LMWH. It can reduce total VTE and total DVT and does not demonstrate a reduction in deaths when compared with LMWH. However, at the same time, moderate to high quality evidence shows that fondaparinux increases major bleeding when compared with placebo and LMWH. Therefore, when fondaparinux is chosen for the prevention of VTE, attention should be paid to the person's bleeding and thrombosis risks. Most data were derived from patients undergoing orthopaedic surgery. Therefore, the conclusion predominantly pertains to these patients. Data on fondaparinux for other clinical conditions are sparse. | v2 |
2019-11-22T00:43:58.761Z | 2019-11-13T00:00:00.000Z | 209261000 | s2ag/train | Use of Bendamustine for Lymphodepletion before Tisagenlecleucel (anti-CD19 CAR T cells) for Aggressive B-Cell Lymphomas
Background: Two commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are currently approved by the FDA for r/r aggressive B-cell lymphomas: axicabtagene ciloleucel (approved in October 2017) and tisagenlecleucel (tisa-cel, approved in May 2018). In published clinical trials, CART19 therapy results in long term remissions in 30-40% of patients (pts). While most CART19 protocols use cyclophosphamide/fludarabine (Cy/Flu) for lymphodepleting chemotherapy (LDC) prior to CART19 infusion, the phase 2 JULIET trial (NCT02445248) with tisa-cel allowed investigator's choice of Cy/Flu or bendamustine. LDC was not required for pts with WBC <1000 cells/μL within one week prior to tisa-cel infusion. In JULIET, 75 (73%) pts received Cy/Flu, 21 (20%) pts received bendamustine, and 7 (7%) pts received no LDC (Schuster et al, NEJM 2019). Grade 3 or 4 cytopenias not resolved by Day 28 following tisa-cel included thrombocytopenia (40%) and neutropenia (25%) among JULIET pts (FDA package insert). Many r/r lymphoma pts are Cy-resistant and bendamustine is not cross-resistant with Cy. Prolonged cytopenias can be seen with Cy/Flu in addition to lymphopenia. In an effort to reduce tumor volume and minimize cytopenias, bendamustine is frequently used for LDC at our institution. We report our experience with bendamustine as LDC before commercially supplied tisa-cel.
Methods: We conducted a single center, retrospective, IRB-approved analysis of r/r lymphoma pts receiving commercial tisa-cel at the University of Pennsylvania. Responses were based on treating physician's assessment utilizing Revised Response Criteria for Malignant Lymphoma (Cheson et al, JCO 2014). Unless the pt had signs or symptoms of progressive lymphoma, response assessment was generally performed at 3 months from tisa-cel infusion per our institutional practice and based on evidence that 3-month response outcomes are more predictive of long-term efficacy than 1-month outcomes. Cytokine release syndrome (CRS) was assessed using Penn criteria (Porter et al, J Hematol Oncol 2018). Neurotoxicity was graded using CARTOX-based scale (Neelapu et al, Nat Rev Clin Oncol 2018). Cytopenias were graded using Common Terminology Criteria for Adverse Events, version 5.
Results: We identified 28 pts with DLBCL or transformed lymphoma who received commercially supplied tisa-cel between June 2018 and June 2019 with bendamustine as LDC and a follow-up of at least 30 days from the infusion. Pt characteristics are described in Table 1. Median age was 65.5 years (range: 38-81). Bendamustine dose was 90 mg/m2 intravenously daily for 2 days in 23/28 (82%) pts with remaining 5/28 (18%) pts receiving lower doses at the discretion of the treating physician.
Twenty-four of 28 pts received bendamustine for LDC and had at least 3-month follow-up or progression prior to 3 months. The 3-month overall response rate was 11/24 (46%) with complete response rate 9/24 (38%). With median follow-up 5.5 months, 3-month progression-free survival estimate was 52% (95%CI: 30%-70%). In terms of toxicities in this cohort, there were no deaths related to tisa-cel. CRS was experienced by 8/28 (29%) of pts with no grade 3 or 4 events by Penn scale. Neurotoxicity was seen in 2/28 (7%) pts with 1 (4%) experiencing transient grade 3 by CARTOX-based grading. At day 28 post tisa-cel infusion, 3/28 (11%) pts had grade 3 or higher neutropenia and 3/28 (11%) had grade 3 or higher thrombocytopenia. Most pts were treated as outpatients with only 2/28 (7%) receiving tisa-cel infusion as inpatient.
Conclusion: Three-month complete response rates are considered reasonably predictive of outcome for CART19 therapies. Although our follow-up is short, our experience shows that bendamustine as LDC for tisa-cel performs well outside of a clinical trial, is an option for LDC before tisa-cel therapy for pts with r/r aggressive B-cell lymphomas treated in the outpatient setting, and may have an improved safety profile with regard to cytopenias.
Svoboda: Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding. Chong:Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Hughes:Genzyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Dwivedy Nasta:Millenium/takeda: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Merck: Consultancy, Other: data safety monitorin; 47 (Forty Seven): Research Funding; Roche: Research Funding; Rafael: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Triphase: Research Funding; Takeda: Research Funding. Barta:Bayer: Consultancy, Research Funding; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Ruella:Novartis: Patents & Royalties: CART for cancer; AbClon: Membership on an entity's Board of Directors or advisory committees; Nanostring: Consultancy, Speakers Bureau. Frey:Novartis: Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Wiley and Sons: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees. Schuster:Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees.
| v2 |
2021-05-07T00:03:55.474Z | 2021-03-01T00:00:00.000Z | 233804500 | s2ag/train | Depth of Response to Isatuximab, Carfilzomib, Lenalidomide and Dexamethasone (Isa-KRd) in Front-Line Treatment of High-Risk Multiple Myeloma: Interim Analysis of the GMMG-CONCEPT Trial
Background: High-risk (HR) multiple myeloma (MM) has an impaired prognostic outcome. Addition of anti-CD38 monoclonal antibodies to standard-of-care regimens improved response rates and depth of response. Here, we report a prespecified interim analysis (IA) following induction therapy with the quadruplet regimen isatuximab, carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in newly diagnosed (ND) HR MM patients (pts) in the phase II multicentric GMMG-CONCEPT trial (NCT03104842).
Methods: 153 pts with HR NDMM were enrolled into the trial, the IA reports on the first 50 pts evaluable for IA. Pts receive Isa-KRd in induction, consolidation and Isa-KR maintenance. Transplant eligible pts undergo high-dose therapy. This IA reports on overall response rates (ORR) during induction.
Findings: 50 pts were included in the IA population for ORR. HR MM was defined by del17p in 52%, t(4;14) in 38%, t(14;16) in 12% and > 3 copies 1q21 in 42% and ISS stage 2/3 disease. 46/50 pts completed induction treatment. ORR was 100%, with 5 pts (10·0%) showing partial response (PR), 22 (44·0%; including 4 in arm B) very good partial response (VGPR) and 23 (46·0%) complete response (CR). Hematologic grade 3/4 treatment-emergent adverse events (≥ 10%) were neutropenia (34·0%), leukopenia (26·0%) and thrombocytopenia (14·0%). Main non-hematologic toxicities grade 3/4 were hypertension (12·0%) and infection (8·0%).
Interpretation: We report for the first time on a trial investigating Isa-KRd quadruplet treatment in solely HR NDMM. Isa-KRd induction induces rapid and deep responses. The overall safety profile is consistent with previous reports.
Trial Registration: The trial is registered at clinicaltrials.gov (NCT03104842).
Funding Statement: Study drug and financial support by Amgen, Celgene-BMS and Sanofi.
Declaration of Interests:
Dr. Leypoldt reports grants and non-financial support from Celgene-BMS, grants and non-financial support from Sanofi, grants and non-financial support from Amgen, during the conduct of the study; non-financial support from GSK, non-financial support from Abbvie, outside the submitted work;
Dr. Asemissen has nothing to disclose.
Dr. Besemer has nothing to disclose.
Dr. Hanel reports personal fees from Celgene, personal fees from Novartis, personal fees from Takeda, personal fees from Amgen, during the conduct of the study;
Dr. Blau has nothing to disclose.
Dr. Gorner has nothing to disclose.
Dr. Ko has nothing to disclose.
Dr. Reinhardt reports personal fees from Abbvie, grants from Gilead, personal fees from Merck, other from CDL Therapeutics GmbH, outside the submitted work;
Dr. Staib reports grants, personal fees, non-financial support and other from Abbvie, grants, personal fees, non-financial support and other from Amgen, grants, personal fees, non-financial support and other from Celgene, grants, personal fees, non-financial support and other from Janssen-Cilag, grants, personal fees, non-financial support and other from Novartis, grants, personal fees, non-financial support and other from Gilead, grants, personal fees, non-financial support and other from Pfizer, grants, personal fees, non-financial support and other from Roche, outside the submitted work;
Dr. Mann has nothing to disclose.
Dr. Lutz has nothing to disclose.
Dr. Munder reports personal fees and non-financial support from Janssen, personal fees and
non-financial support from Amgen, grants from Incyte, personal fees and non-financial
support from BMS, personal fees from Abbvie, personal fees from Sanofi, personal fees from
GSK, personal fees from Takeda, outside the submitted work;
Dr. Graeven reports personal fees from Amgen, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Daichi Sankyo, personal fees from Servier, personal fees from Celgene, personal fees from Astra Zeneca, personal fees from Johnson Johnson, non-financial support from Merck, personal fees from MSD, personal fees from BMS, during the conduct of the study;
Dr. Peceny reports grants and personal fees from Sanofi Genzyme, grants from Novartis, grants from DRK Blutspendedienst NSTOB, grants from Boehringer Ingelheim Pharma GmbH & Co KG, grants from Celgene, outside the submitted work;
Dr. Salwender reports personal fees from Bristol-Myers Squibb/Celgene, personal fees from Janssen Cilag, personal fees from Glaxo Smith Kline, personal fees from Oncopeptides, personal fees from Takeda, personal fees from Sanofi, personal fees from AbbVie, personal fees from Amgen, outside the submitted work;
Dr. Jauch has nothing to disclose.
Dr. Zago has nothing to disclose.
Axel Benner has nothing to disclose.
Dr. Tichy has nothing to disclose.
Dr. Bokemeyer reports personal fees from Sanofi Aventis, personal fees from Merck KgA, personal fees from Bristol-Myers Squibb, personal fees from Merck Sharp & Dohme, personal fees from Lilly Imclone, personal fees from Bayer Healthcare, personal fees from GSO Contract research, personal fees from AOK-Rheinland-Hamburg, personal fees from Novartis, outside the submitted work;
Dr. Goldschmidt reports grants, personal fees, non-financial support and other from Amgen, grants, personal fees, non-financial support and other from BMS, grants, personal fees, non-financial support and other from Celgene, grants, personal fees, and other from Chugai, grants, personal fees, non-financial support and other from Janssen, grants, personal fees, non-financial support and other from Sanofi, other from Incyte, other from Molecular Partners, other from Merck Sharp and Dohme (MSD), other from Mundipharma, grants, personal fees, non-financial support and other from Takeda, personal fees and other from Novartis, personal fees from Adaptive Biotechnology, personal fees from GlaxoSmithKline (GSK), outside the submitted work.
Dr. Weisel reports grants from AMGEN, grants from Celgene, grants from Sanofi, during the conduct of the study; grants, personal fees and non-financial support from Amgen, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from Celgene, personal fees from Adaptive Biotech, grants, personal fees and non-financial support from Janssen, personal fees and non-financial support from GSK, personal fees from Karyopharm, grants, personal fees and non-financial support from Sanofi, personal fees and non-financial support from Takeda, personal fees from Oncopeptides, personal fees from Roche, outside the submitted work.
Ethics Approval Statement: All patients provided written informed consent. The trial was approved by the competent authorities and the Tuebingen University Ethics Committee. | v2 |
2019-06-26T22:19:46.251Z | 2018-01-01T00:00:00.000Z | 195744850 | s2ag/train | STUDY ON NODAL ANATOMY , LEAF ANATOMY AND EPIDERMAL FEATURES OF ROTALA DENSIFLORA ( ROTH EX R & S ) KOHENE BELONGS TO FAMILY LYTHRACEAE
The present investigation deals with the study of leaf anatomy, nodal anatomy and stomatal features of Rotala densiflora (Roth ex R &S) kohene belongs to family Lythraceae. The species of Rotala found in moist, muddy and rocky places. The leaves are opposite decussate and sessile. The node is unilacunar one traced. The leaves are dorsiventral and amphistomatic Stomata are more on lower surface of leaf. The mucilage cells are common in occurrence. The vascular bundle is bicollateral, solitary and arc shaped parenchymatous cortex with large air spaces. KEY WORD: Anatomy of node, Leaf, epidermal cells and stomata, Rotala. INTRODUCTION The genus Rotala is consist of about 44 species distributed all over the world according to Mabberley (2005) some species reported from peninsular India (Yadav et.al. 2010, Gaikawad et.al. 2013, Anto et. al. 2014, Lemiya and Pradeep, 2015) The Rotala densiflora is belonging to family lythraceae considering anatomical features of node, leaf and epidermal characters are very important for the segregation of species. Anatomical studies of stem and leaves of the two herbaceous genera Ammannia and Rotala has been worked out by Panigrahi 1980, 1988. The Rotala shows diversity in region of tropical Asia Cook (1979) an anatomical character studied in the genus Rotala is very rare (Solereder 1908, Metcalfe and chalk 1950, Panigrahi 1988). Therefore for the detail anatomical and epidermal studies of Rotala densiflora are taken into consideration. MATERIAL AND METHODS: The plant material of Rotala densiflora (Roth ex R &S) kohene was collected from Panhala of Kolhapur (Maharashtra state). The serial free hand section of leaf and node was taken with fine razor for study of anatomical characters. The stomata are observed by simple peeling method or by using conc. Nitric Acid solution. The sections of leaf were mounting and stained with regular used methods. OBSERVATIONS: 1) Nodal anatomy of R. densiflora: The serial sections of nodal region was undertaken by free hand or with the help of rotary microtome machine and observed that the axial cylinder bears median trace which is an arc shaped later on it is extend into the leaf. As shown in figure 1, a, b c and d. Hence the node is unilacunar one traced are noted. STUDY ON NODAL ANATOMY, LEAF ANATOMY AND EPIDERMAL FEATURES OF..... vOlUme – 7 | issUe 11 | aUGUst 2018 _______________________________________________________________________________________ ________________________________________________________________________________________ Available online at www.lbp.world 2 Figure 1: Anatomy of Node in Rotala densiflora. 2) Leaf anatomy of R. densiflora: It is observed that the leaves are sessile, ovate or elliptic oblong, apex acute to acuminate. It is leaf is dorsiventral and amphistomatic. The adaxial epidermis is of comparatively larger cells with thin outer wall. The cuticle is thin the stomata are more on the lower surface the mucilage was common. The mesophyll is comprised of palisade and spongy tissue. The palisade is one to two layered of unequal sized cells. The spongy tissues are loosely arranged cells with air spaces. The vascular bundles are bicollateral they are extending through spongy tissues. ( Figure 2 a). The vascular bundle is capped with parenchymatous bundles sheath. In midrib region the epidermis is followed by parenchymatous cortex with many large air spaces. The midrib vascular bundles are solitary and slightly arc shaped. Figure 2: Anatomy of leaf in Rotala densiflora. 3) Epidermal features (Stomata): Epidermal cells are more or less large, thin and cuticularised. Stomata are observed on both surfaces of leaf hence leaf is amphistomatic and type of stomata is Anomocytic (Figure 3 leaf adaxial and Figure 4 leaf abaxial) STUDY ON NODAL ANATOMY, LEAF ANATOMY AND EPIDERMAL FEATURES OF..... vOlUme – 7 | issUe 11 | aUGUst 2018 _______________________________________________________________________________________ ________________________________________________________________________________________ Available online at www.lbp.world 3 Figure 3: Leaf adaxial surface stomata. Figure 4: Leaf abaxial surface stomata. DISCUSSION: The anatomical studies play an important role in segregation of taxa. The present investigation brings out some interesting features. The node is single unilacunar one traced. The nodal anatomy in some species of Rotala was studied by Kshirsagar (2017) the leaf is dorsiventral and amphistomatic with presence of spongy and mesophyll tissues. Leaf anatomy of Rotala serpyllifolia was studied by Kshirsagar (2018). Stomata are Anomocytic. The foliar epidermal features and their taxonomic significance of Rotala noted by Kshirsagar and Vaikos (2013). REFRENCES: [1] Anto P.V, Jacob C.S, Abraham P, Varghese C.D. & I. Antony (2014) A new species of Rotala L. (Lythraceae) from the hills of Thirssur district India. [2] Cook, C. D. K. (1979) A revision of the genus Rotala (Lythraceae), Boissiera 29:1-156 [3] Gaikawad S.P. Sardesai M.M. & S.R.Yadav (2013) Rotala sahyadrica spp. Nov (Lythraceae) from Western Ghats India. Nordic J.Botany 32(5): 575-577. [4] Kshirsagar A. A. & N.P.Vaikos (2013) Foliar epidermal features and their taxonomic Significance in Rotala L. (Lythraceae) Asian journal of plant science & Research.3 (3): 117120 [5] Kshirsagar A. A (2017) Nodal anatomy in some species of Rotala L.(Lythraceae) Bioscience Discovery, 8(4):833-836. [6] Kshirsagar A. A (2018) Leaf anatomy & epidermal features in Rotala serpyllifolia (Roth), Bremek Lythraceae. Review of research Vol.7 (5): 1-3. [7] Lemiya K.M. & S.R. Yadav (2105) A new species of Rotala (Lythraceae) from Kerala. India. Rheedea 25: 159-163. [8] Mabberley D.J. (2005) The plant book Cambridge University press. [9] Metcalfe C.R. and Chalk L. (1950) Anatomy of the Dicotyledons-I Clarendon Press, Oxford. [10] Panigrahi, S.G. (1980). Contribution of Anatomy to the systematic of Ammannia. Phytomorphology 30:320-330. [11]Panigrahi, S.G. (1988). Contribution of anatomy to the systematic of Rotala (Lythraceae) Bull. Bot. Surv. India Vol.30: 90-100. [12] Prasad K.S. Biju P. Raveendran K. & K.K.Bhat (2012) Rotala thulmadensis. Sp. Nov (Lythraceae) from Kerala, India. Nordiac J.Botany 30: 59-60. [13] Solereder H. (1908) Systematic Anatomy of the Dicotyledons-I Clarendon Press, Oxford. STUDY ON NODAL ANATOMY, LEAF ANATOMY AND EPIDERMAL FEATURES OF..... vOlUme – 7 | issUe 11 | aUGUst 2018 _______________________________________________________________________________________ ________________________________________________________________________________________ Available online at www.lbp.world 4 [14] Yadav.S.R. , Malpure N.V. & Chandore (2010) Rotala belgumensis (Lythraceae) from the western Ghats India. Nordiac J.Botany 28: 499-500. | v2 |
2019-04-03T13:16:04.582Z | 1976-01-01T00:00:00.000Z | 92664540 | s2ag/train | Atomic masses and fundamental constants : International Conference on Atomic Masses and Fundamental Constants, 5th, Paris, 1975
1 The Fundamental Constants and Metrology.- The Measurement of Fundamental Constants (Metrology) and Its Effect on Scientific and Technical Progress.- Constantes Physiques et Metrologie.- 2 Gamma rays.- Gamma-Ray Energies for Calibration of Ge(Li) spectrometers.- Primary Standards for Gamma Energy Determinations.- Precision Measurements of Relative ?-Ray Energies with a Curved Crystal Diffractometer.- Visible to Gamma-Ray Wavelength Ratio.- Determination of Proton Binding Energies for 89Y, 90Zr, 91Nb and 93Tc from (p, ?) Reaction Q-values.- A New Method for Measurement of Proton Beam Energies.- 3 Alpha and Beta Decays.- Superallowed ?-decay : From Nuclear Masses to the Z Vector Boson.- Masses of TZ = +5/2 Nuclei in the s-d Shell from ?-Decay Measurements.- Mass Differences of Proton-Rich Atoms near A=116 and A=190 Unisor Consortium.- Total ?-Decay Energies of Nuclei Far from Stability: Evidence for the Wigner Symmetry Energy in Rb and Kr Masses.- Total Beta Decay Energies of Neutron-Rich Fission Products.- Far Beta-Unstable Alpha-Particle Emitting Nuclei.- 4 Nuclear Reactions.- Precision Measurement of Q-values by Means of the Munich Time-of-flight System and the Q3D-Spectrograph.- Measurements of Nuclear Masses Far from Stability.- Some (p,n) and (?,n) Reaction Energies Relevant to Superallowed Beta Decay.- Accurate Q-value Measurements and Masses in the Iron Region.- Precision Energy Measurements with the MSU cyclotron.- New Tests of the Isobaric Multiplet Mass Equation.- Isobaric Mass Quartets.- 5 Mass Spectrometry.- This part is dedicated to the memory of L.G. Smith, 1912-1972. The Mass Spectroscopic Work of L.G. Smith.- L.G. Smith's Precision RF Mass Spectrometer Transferred from Princeton to Delft.- Present Status of the Program of Atomic Mass Determinations at the University of Manitoba.- Recent Doublet Results and Measurement Technique Development at the University of Minnesota.- Double Focussing Mass Spectrometers of Second Order.- On a Two-Stage Double-Focussing Mass Spectroscope under Construction at Osaka University.- Atomic Mass Measurement Using Time-of-Flight Mass Spectroscopy.- Mass Spectrometry of Unstable Nuclei.- The Activities of the II Physical Institute of the University of Giesen in the Investigation of Short-Lived Heavy Nuclei.- Attempts to Obtain Highly Resolved Mass Spectra of Short-Lived Fission Products with the Lohengrin Separator.- 6 Theory of Nuclear Binding Energies.- The Mass Determination in Relation to Nuclear Structure and to the Theory of Nuclear Matter.- Self-Consistent Calculations of Nuclear Total Binding Energies.- Shell and Pairing Effects in Spherical Nuclei Close to the Nucleon Drip Lines.- Hartree-Fock Calculation of Nuclear Binding Energy of Sodium Isotopes.- Nuclear Mass Systematics and Exotic Nuclei.- The Validity of the Strutinsky Method for the Determination of Nuclear Masses.- Nucleon Correlation Effects in Mass Systematics.- 7 Atomic Mass Formulae.- Interpolation Mass Formulae.- Nuclidic Mass Relationships and Mass Equations.- The Liquid Drop Mass Formula as a Shell Model Average.- Magic Neutron-Rich Nuclei and a New Semi-Empirical Shell-Correction Term.- Structure of Nuclear Energy Surface and the Atomic Mass Formula.- Atomic Mass Extrapolations.- 8 Time and Frequency Measurements and the Speed of Light.- Time and Frequency.- Applications of Frequency Standards.- Stabilized Lasers and the Speed of Light.- The Realization of the Second.- Stability and Reproducibility of He-Ne Lasers Stabilized by Saturated Absorption in Iodine.- Performance and Limitations of Iodine Stabilized Lasers.- Reproducibility of Methane- and Iodine-Stabilized Optical Frequency Standards.- Some Experimental Factors Affecting the Reproducibility and Stability of Methane-Stabilized Helium-Neon Lasers.- Molecular Beam Stabilized Argon Laser.- Frequency Stabilization of an Ar+ Laser with Molecular Iodine.- Saturated-Absorption-Stabilized N2O Laser for New Frequency Standards.- Optically Pumped Far-Infrared Laser for Infrared Frequency Measurements.- Two-Photon Lasers.- Light-Shifts Precision Measurements of the O-O Transition in a 133Cs Gas Cell.- 9 Wavelength Comparison.- Comparaison de Longueurs d'Onde a l'Aide d'un Interferometre de Michelson.- Wavelength Intercomparison of Laser Radiations Using Servo-Lock Interferometry.- A Field Compensated Interferometer for Wavelength Comparison.- Determination of New Wavelength Standards in the Infrared by Vacuum Fourier Spectroscopy.- Preliminary Wavelength Measurements of a 127I2 Stabilized Laser at IMGC.- Wavelength Measurements in the UV and Vacuum UV.- 10 The Josephson Effects and 2e/h.- Applications of the Josephson Effect.- A Brief Review of the A C Josephson Effect Determination of 2e/h.- Determination of 2e/h at the BIPM.- 2e/h Determination by Josephson Effect in ETL.- Etape d'une Determination absolue du coefficient 2e/h au LCIE.- Cryogenic Voltage Standard at PTB.- 11 Magnetic Moments.- Review of the Measurement of ?p/?n.- Magnetic Moment of the Proton in H2O in Units of the Bohr Magneton.- A Progress Report on the (g-2) Resonance Experiments.- New Electron and Positron (g-2) Experiments at the University of Michigan.- New Measurement of (g-2) of the Muon.- Status of Anomalous Magnetic Moment Calculations for Electron and Muon.- A New Mass-Spectrometric Method for the Measurement of ?p'.- Experiment with Magnetically Isolated Calculable Solenoid for ?p' Determination.- Determination of the Gyromagnetic Ratio of the Proton ?p'.- A Measurement of the Gyromagnetic Ratio of the Proton by the Strong Field Method.- 12 Miscellaneous Constants.- Recent Estimates of the Avogadro Constant.- Re-evaluation of the Rydberg Constant.- Rydberg Constant Measurement Using CW Dye Laser and H* Atomic Beam.- Fast Beam Measurement of Hydrogen Fine Structure.- A New Determination of the Faraday by Means of the Silver Coulometer.- A Value for the Faraday Based on a High-Precision Coulometric Titration of 4-Aminopyridine.- Initial Results from a New Measurement of the Newtonian Gravitational Constant.- Constants of Electric and Magnetic Polarizibilities of Proton.- A New Determination of the Gas Constant by an Acoustic Technique.- A Determination of the Density and Dilatation of Pure Water of Known Isotopic Composition.- 13 Relativity, Time Variation of the Constants, and Philosophical Considerations.- Recent Solar Oblateness Observations : Data, Interpretation and Significance for Experimental Relativity.- A Laboratory Experiment to Measure the Time Variation of Newton's Gravitational Constant.- An Experimental Limit on the Time Variation of the Fine Structure Constant.- Bound on the Secular Variation of the Gravitational Interaction.- Understanding the Fundamental Constants.- 14 Evaluation.- Present Status of Atomic Masses.- Present Status of the Fundamental Constants.- 15 Conference Summary.- Summary of the Conference. | v2 |
2020-10-28T19:11:58.352Z | 2020-10-08T00:00:00.000Z | 242733150 | s2ag/train | Using band ratioed CaSSIS imagery and analysis of fracture morphology to characterise Oxia Planum’s clay-bearing unit
<p><strong>Introduction:</strong></p><p>In an effort to aid the characterisation of Oxia Planum, selected as the Rosalind Franklin rover’s landing site partly due to its extensive Noachian-era clay deposits [1, 2], a comparison of fractured terrains at Oxia and Gale Crater along with an analysis of Colour and Stereo Surface Imaging System (CaSSIS) [3] imagery are currently underway.</p><p>An analysis of fractured terrains is a useful tool for determining the history and material properties of Oxia, as the form a fracture network takes varies depending both on the mechanisms which generated it as well as the materials within which the fracturing occurred [4-6]. Comparisons between fractured terrains across Oxia, as well as with those at Gale crater due to the ground truth provided by the Curiosity rover, are being made. This is done in an effort to predict material properties and the fracture’s formation mechanisms, along with determining how fractures across Oxia relate to one another.</p><p>CaSSIS is a high-resolution (4.5 m/pixel) 4-band VNIR imager with the ability to take stereo images in a single pass of a target. From a study carried out using CaSSIS, along with co-analysis from CRISM and HiRISE colour imagery, two spectrally and morphologically distinct subunits of the Oxia clay unit [7] were identified. These were a lower member showing metre-scale fracturing and spectral signatures indicative of Fe/Mg-rich clay minerals, and an upper member showing decametre scale fracturing with Fe/Mg-rich clay mineral/olivine signatures. To expand upon the mapping carried out using HiRISE colour and CRISM data, which was limited by data coverage [7], CaSSIS and HiRISE RED i.e. greyscale imagery, was used to identify these sub-units. This was done to aid future planning of rover traverses to high priority surface targets.</p><p> </p><p><strong>Methods:</strong></p><p><em>Fracture Analysis.</em> Our fracture analysis involves tracing out a given fracture network in HiRISE imagery using ArcGIS, then using a tool developed at the Open University (as seen in [8]) to measure metrics of the fractures or the polygons formed by them, such as the angle between intersecting fractures, polygon area, etc. These were then mapped out for comparison using Kernel Density Estimation (KDE) diagrams, and compared statistically via two-sample Kolmogorov-Smirnov tests.</p><p><em>CaSSIS mapping.</em> Radiometrically and geometrically corrected images are initially band ratioed and combined into an RGB image, allowing CaSSIS images to distinguish between ferrous and ferric minerals [9]. This is important given that the lower clay unit has a ferric component potentially due to the presence of hematite/ferric oxides [2], in contrast to the ferrous component of the upper member due to containing olivine [7], making the two members distinguishable with CaSSIS.</p><p>The band ratios (BR’s) used were NIR/PAN, PAN/BLU and PAN/NIR, with CaSSIS’s RED channel replacing its NIR depending on which was available from a given CaSSIS image [10]. These are sensitive to ferric and ferrous minerals for the former two and latter one respectively. Dark Subtraction [11] was then applied to minimize the effects of dust-derived atmospheric scatter. These images were used in conjunction with assessment of fracture length using HiRISE imagery to map out the two members. It has previously been identified [7, 12] that high dust opacity at the time of imaging likely skews the apparent ferric content of the image. This has been noted and is addressed via repeat imaging of such affected areas over Oxia Planum.</p><p> </p><p><strong>Results: </strong></p><p><em>Fracture Analysis.</em> The Gale sites which have comparable metric distributions to those at Oxia are the NE section of Yellowknife Bay’s Sheepbed member [13], which has similarities to several sites seen in the centre of the Oxia landing ellipses, and a site at Vera Rubin ridge similar to an area adjacent to Coogoon Vallis in the SE of Oxia Planum and another abutting the capping unit in the centre of the landing ellipses. Both of these are at the 2-sigma level of certainty for the majority of the metrics. See Figure 1 for examples of the KDE graphs used.</p><p><em>CaSSIS mapping.</em> Figure 2 shows the current extent of the mapping within the 1-sigma landing ellipses at Oxia. There are fewer upper member exposures in the area mapped in fig.2, in line with what has been identified previously [7].</p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gnp.b5a087c033fe59306992951/sdaolpUECMynit/0202CSPE&app=m&a=0&c=b9994cff1998dcd5ad66275f281ae606&ct=x&pn=gnp.elif" alt=""></p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gnp.eebb3ed033fe52606992951/sdaolpUECMynit/0202CSPE&app=m&a=0&c=b04f07a821cf306b93101cbb1eb37349&ct=x&pn=gnp.elif" alt=""></p><p> </p><p><strong><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gnp.e100fbf033fe51906992951/sdaolpUECMynit/0202CSPE&app=m&a=0&c=99a3a39709689d0cd187016f7ae02fc2&ct=x&pn=gnp.elif" alt=""></strong></p><p> </p><p><strong>Discussion: </strong></p><p><em>Fracture Analysis.</em> While the results from this study show that there are similarities between some of the fractured terrains examined at Oxia Planum and Gale Crater, what the shared properties of these sites are that leads to these similarities is still being considered. Possibilities include possessing a similar grain size, or sharing the same formation mechanism such as hydraulic fracturing [1].  </p><p><em>CaSSIS mapping.</em> Mapping is ongoing for the 1-sigma landing ellipses, with the intention for it to cover the 3-sigma ellipses ultimately. That the map utilises distinctly lower resolution colour imagery of CaSSIS in conjunction with the 0.25 m/pixel HiRISE imagery for observation of fracturing raises the issue of misidentification of the two units where they are in close proximity. Pan-sharpening is being investigated as a solution to this; currently work is ongoing to remove artifacts within the generated products prior to their use in future mapping efforts.</p><p> </p><p><strong>References: </strong>[1] Quantin-Nataf C. et al. (submitted in Astrobiology), [2] Carter et al. (in prep), [3] Thomas et al. (2017) SSR 212, [4] Tang C-S. at. al. (2011) Geoderma, 166(1):111-118, [5] Plummer P. S. et. al. (1981) JSP, 51:1147-1156, [6] Goehring L. et. al. (2010) SM, 6:3562-3567, [7] Mandon L. et al. (submitted in Astrobiology), [8], Brooker L. M. et al. (2018) Icarus 302:386-406 [9] Tornabene L. L. et al. (2018) SSR, 214, [10] Tornabene L. L. et al. (2019) LPSC 50, Abstract #2678, [11] Chavez et al., (1988), RSE, 24.3: 459-479, [12] Parkes Bowen A. et al. (2020) BPSC #2, [13] Grotzinger J. P. et al. (2014) Science, 343:6169</p>
| v2 |
2021-08-03T00:04:31.250Z | 2021-03-03T00:00:00.000Z | 236712120 | s2ag/train | Radial Evolution of the Solar Wind and Associating Turbulence Based on the Synergetic Measurement from Parker Solar Probe and 1 au Observations
<div>
<div>The 4th encounter (~30 Rs away from the sun) of the Parker Solar Probe (PSP) is a great opportunity to observe the radial evolution of the solar wind from the inner heliosphere to the near-earth environment when the sun, PSP, and the earth are quasi-radial aligned. Similar features of the solar wind are observed from both PSP and Wind (at 1 au) measurements. The accelerating-solar-wind model could be more suitable than the constant speed model for the observation, which means the solar wind is still accelerating from 30 Rs to 1 au. Both PSP and Wind measure the co-existence of the Alfvenic and compressive fluctuations in the solar wind. The correlated radial velocity (dVR), proton density (dn) and temperature (dT) fluctuations indicate the nature of the compressive fluctuations are outward-propagating slow waves. However, dn and dB is not correlated from PSP, but correlated from Wind, which indicates the propagating direction of the slow waves is changed. Comparing the radial evolution of the energies of both Alfvenic and compressive fluctuations with the WKB model, we find the observed energy decays slower than the theoretical prediction, which indicates an extra energy injection during the solar wind propagation.</div>
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 | v2 |
2019-03-28T13:33:23.626Z | 2018-11-29T00:00:00.000Z | 86423700 | s2ag/train | Bortezomib-Thalidomide-Dexamethasone Versus Thalidomide-Dexamethasone before and after Double Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: Final Analysis of Phase 3 Gimema-MMY-3006 Study and Prognostic Score for Survival Outcomes
Introduction: The phase 3 GIMEMA-MMY-3006 trial comparing bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (MM) provided the first demonstration of increased CR rate, the primary study endpoint, and prolonged PFS with VTD (Cavo M et al, Lancet 2010). However, updating trial results with longer follow-up than earlier reported is needed to assess the effects of treatment interventions on OS and to identify factors predicting for favorable long term outcomes.
Aims: We performed a post-hoc analysis of that study to evaluate long term results and construct a prognostic index of survival.
Methods: 474 patients were enrolled, 236 randomized to VTD and 238 to TD. Median follow-up for surviving patients was 124 months (IQR: 117-131). Analyses were performed on an intention-to-treat basis. Semi-parametric Cox regression analysis was used to construct the prognostic index. To assess the evolution of prognosis over time, conditional survival CS(t|s) estimate for PFS was calculated as the probability of surviving without progression a further 2 (t) years (yrs) after having already survived s yrs.
Results: Estimates of PFS and OS at 10 yrs for the VTD arm were 34% (HR=0.62; 95% CI=0.50-0.77; p<0.001) and 60% (HR=0.68, 95% CI=0.51-0.90; p=0.007), respectively, compared with TD (corresponding values, 17% and 46%), representing a 38-32% reduction in the risk of progression and death with VTD. Outcome benefits with VTD were seen for patients with high-risk cytogenetic abnormalities (HCRA), including t(4;14) and/or del(17p) by FISH, (PFS: 17% vs 3% at 10 yrs, HR=0.45, 95% CI=0.30-0.69; p<0.001; OS: 42% vs 22% at 10 yrs, HR=0.54, 95% CI=0.34-0.88; p=0.011) and lacking HRCA (PFS: 40% vs 20%, HR=0.60, 95% CI=0.46-0.79; p<0.001; OS: 67% vs 52%, HR=0.66, 95% CI=0.46-0.95; p=0.025). On multivariate Cox regression analysis, randomization to VTD predicted for both prolonged PFS (HR=0.60, 95% CI=0.48-0.76; p<0.001) and OS (HR=0.68, 95% CI=0.50-0.91; p=0.010). Specific multivariate regression analysis not including therapy revealed that the leading factors adversely affecting PFS were the presence of HRCA (HR=1.86, 95% CI=1.45-2.38; p<0.001), ISS stage II+III (HR=1.38, 95% CI=1.10-1.74; p=0.006), and failure to achieve CR as time-dependent variable (HR=2.01, 95% CI=1.59-2.53; p<0.001). The three variables were used to build a scoring system that stratified patients into three risk groups with divergent clinical outcomes: low-risk (LR) (22%, none of the 3 adverse variables), intermediate-risk (IR) (39%, 1 adverse variable), and high-risk (HR) (39%, 2 or 3 adverse variables). Estimated 10-yr PFS rates were 44% for patients in LR, 28% for IR, and 9% for HR (p<0.001). Estimated 10-yr OS rates were 76%, 58%, and 32%, respectively (p<0.001). Consensually, the prognostic score identified three groups with statistically different PFS and OS within the TD and VTD arm (p<0.001). On VTD, the 10-yr PFS and OS rates were 51% and 79% for LR, 41% and 62% for IR, 13% and 43% for HR, respectively. Randomization to receive VTD was associated with longer PFS for the IR (41% vs 15% at 10 yrs, HR=0.50, 95% CI=0.34-0.73; p<0.001) and HR (13% vs 7% at 10 yrs, HR=0.66, 95% CI=0.47-0.92; p=0.015) subgroups compared with TD. Moreover, HR patients assigned to VTD had significantly longer OS in comparison with the same group of patients on TD (43% vs 23% at 10 yrs, HR=0.65, 95% CI=0.43-0.97; p=0.033). Assessment of conditional survival revealed that the probability of surviving without progression a further 2 yrs improved progressively after 36 months, being 65% and reaching the 91% at 96 months (p value for trend=0.009). The conditional PFS became superimposable after 78 months for the LR and IR (87% and 86%, respectively), while resulted significantly lower in the HR (62.5%) (p=0.008).
Conclusions: With a follow up of 10 yrs, the final analysis of the GYMEMA MMY-3006 trial comparing VTD versus TD showed a persistent PFS benefit translating into extended OS for the VTD arm. A prognostic model based on cytogenetic, ISS stage and achievement of CR, identified three risk groups with statistically different long-term survival probabilities. Both IR and HR groups significantly benefited from VTD. A PFS time of 78 months predicted for long term survival outcomes in the LR and IR groups.
Tacchetti: Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Zamagni:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Offidani:Celgene: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Montefusco:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Cavo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2021-11-25T16:07:14.623Z | 2021-11-05T00:00:00.000Z | 244544140 | s2ag/train | Contemporary "Real World" Molecular Testing and Tyrosine Kinase Inhibitor Adherence Patterns Among Older Pts with Chronic Myeloid Leukemia in the United States
Introduction:
Patients (pts) with chronic-phase chronic myeloid leukemia (CML) are recommended to have quantitative BCR-ABL1 polymerase chain reaction (qPCR) testing every 3 months (mo) during the 1 st year of tyrosine kinase inhibitor (TKI) treatment to assure achievement of milestone response goals. Adherence to TKI therapy is also critical to achieving responses and ultimately functional cure. Prior evaluations of qPCR testing/TKI adherence have only focused on imatinib-treated and/or younger pts. We sought to evaluate older CML pts in the United States using the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset.
Methods:
Using the SEER-Medicare database, we assembled a population-based cohort of CML pts diagnosed in 2007-17 who: 1) were age 66-99 years at diagnosis, 2) had continuous Medicare Parts A/B coverage from 1 year before diagnosis to end of follow-up, 3) Medicare Part D coverage from 3 mo before diagnosis to end of follow-up, 4) did not receive a TKI within 3 mo before diagnosis, and 5) received a TKI after diagnosis. To ensure adequate time to assess 1 st-year adherence/monitoring, we only included pts followed for ≥13 mo from TKI initiation. As suggested by guidelines, we assessed qPCR tests at 3, 6, 9, an 12 mo (all ±30 days) after TKI initiation. Optimal monitoring was defined as having a qPCR test at ≥3 milestones during the 1 st year of treatment. First-year TKI adherence was measured by the proportion of days covered (PDC); adherence was defined as a PDC >80%. Pearson's χ 2 tests and Wilcoxon rank tests were used to compare patient characteristics in a bivariate manner, and multivariable logistic regression was used to assess factors associated with optimal monitoring and its impact on TKI adherence. All statistical tests were two-sided and conducted with SAS (Version 9.4).
Results: We identified 1188 newly-diagnosed CML pts with a median age at diagnosis of 74.5 (interquartile range [IQR]: 70-80) years. Median time from diagnosis to TKI initiation was 42 (IQR: 27-72) days with 970 pts (81.7%) initiating TKI within 90 days of diagnosis. Of 745 pts starting frontline imatinib, 17.9% switched to a 2 nd generation TKI; of 443 pts starting a frontline 2 nd generation TKI, 127 (30.9%) received a subsequent TKI with 89 (70.0%) switching to imatinib.
In the 1 st year after TKI initiation, 962 pts (81.0%) had a qPCR test with a median of 3 (IQR: 2-4) tests. Among pts who had ≥2 tests, the median days between two consecutive tests was 89 (IQR: 63-105). Only 876 pts (73.7%) had at least one test around the 4 milestones with 329 (27.7%) and 547 (46.0%) of pts had tests at ≥3 and 1-2 milestones, respectively. The most recently diagnosed pts were more likely to receive a test at a milestone (Figure 1a), but even among pts diagnosed in the latest study period of 2015-17, only 126 (32.0%) had optimal monitoring. Compared with less frequently monitored pts, those with optimal monitoring were more likely to be non-Hispanic white (p=0.01), diagnosed in more recent years (p<0.01), not have low-income subsidy (p<0.01), reside in a high socioeconomic (SES) neighborhood (p<0.01) and have received an influenza vaccination within 12 mo preceding CML diagnosis (p=0.01). Second generation TKI users who did not switch during the 1 st year had significantly more testing at the 9-mo milestone (p=0.02) and were more likely to have optimal monitoring when compared with imatinib users (p<0.01)(Figure 1b). In the multivaraible model, only year of diagnosis increased the odds of having optimal monitoring (2011-14 odds ratio [OR]=1.66, 95% confidence interval [CI]: 1.16-2.37, p=0.01; 2015-19 OR=1.78, 95% CI: 1.22-2.58, p<0.01).
The median 1 st-year PDC was 90.3% (IQR: 70.6-98.3%) with 795 (66.9%) adherent pts. The median PDC among pts with qPCR tests at 0, 1-2 and ≥3 milestones was 86.4%, 90.1% and 93.1%, respectively (p<0.01, Figure 2). Compared with less monitored pts, those with optimal qPCR monitoring were more adherent (73.9% vs 64.3%, p<0.01). After adjusting for demographic, SES and comorbidities, pts with optimal monitoring were more likely to be adherent (OR=1.44, 95% CI: 1.08-1.94, p=0.01).
Conclusions:
We describe "real world" CML management patterns of 1 st-year molecular testing and TKI adherence using a large dataset. Our analyses showed that many older pts do not have recommended molecular monitoring, which was associated with decreased TKI adherence. This work was supported by the Frederick A. DeLuca Foundation.
Figure 1 Figure 1.
Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Zeidan: Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Agios: Consultancy; Astex: Research Funding; Pfizer: Other: Travel support, Research Funding; Jazz: Consultancy; Geron: Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; AstraZeneca: Consultancy; BeyondSpring: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Ionis: Consultancy; Astellas: Consultancy; Acceleron: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Genentech: Consultancy; BioCryst: Other: Clinical Trial Committees; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Epizyme: Consultancy; Janssen: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Jasper: Consultancy; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Huntington: Thyme Inc: Consultancy; Bayer: Honoraria; AstraZeneca: Consultancy, Honoraria; TG Therapeutics: Research Funding; DTRM Biopharm: Research Funding; SeaGen: Consultancy; Genentech: Consultancy; Flatiron Health Inc.: Consultancy; Novartis: Consultancy; Servier: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Neparidze: Janssen: Research Funding; GlaxoSmithKline: Research Funding; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ma: Celgene/Bristol Myers Squibb: Consultancy, Research Funding. Podoltsev: Pfizer: Honoraria; Blueprint Medicines: Honoraria; Novartis: Honoraria; Incyte: Honoraria; PharmaEssentia: Honoraria; CTI BioPharma: Honoraria; Bristol-Myers Squib: Honoraria; Celgene: Honoraria.
| v2 |
2021-05-27T06:19:19.804Z | 2021-05-24T00:00:00.000Z | 235198640 | s2ag/train | New generation antidepressants for depression in children and adolescents: a network meta-analysis.
BACKGROUND
Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and physical and mental health and well-being. There is an association between major depressive disorder and suicidal ideation, suicide attempts, and suicide. Antidepressant medication is used in moderate to severe depression; there is now a range of newer generations of these medications.
OBJECTIVES
To investigate, via network meta-analysis (NMA), the comparative effectiveness and safety of different newer generation antidepressants in children and adolescents with a diagnosed major depressive disorder (MDD) in terms of depression, functioning, suicide-related outcomes and other adverse outcomes. The impact of age, treatment duration, baseline severity, and pharmaceutical industry funding was investigated on clinician-rated depression (CDRS-R) and suicide-related outcomes.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (CDSR)), together with Ovid Embase, MEDLINE and PsycINFO till March 2020.
SELECTION CRITERIA
Randomised trials of six to 18 year olds of either sex and any ethnicity with clinically diagnosed major depressive disorder were included. Trials that compared the effectiveness of newer generation antidepressants with each other or with a placebo were included. Newer generation antidepressants included: selective serotonin reuptake inhibitors; selective norepinephrine reuptake inhibitors (SNRIs); norepinephrine reuptake inhibitors; norepinephrine dopamine reuptake inhibitors; norepinephrine dopamine disinhibitors (NDDIs); and tetracyclic antidepressants (TeCAs).
DATA COLLECTION AND ANALYSIS
Two reviewers independently screened titles/abstracts and full texts, extracted data, and assessed risk of bias. We analysed dichotomous data as Odds Ratios (ORs), and continuous data as Mean Difference (MD) for the following outcomes: depression symptom severity (clinician rated), response or remission of depression symptoms, depression symptom severity (self-rated), functioning, suicide related outcomes and overall adverse outcomes. Random-effects network meta-analyses were conducted in a frequentist framework using multivariate meta-analysis. Certainty of evidence was assessed using Confidence in Network Meta-analysis (CINeMA). We used "informative statements" to standardise the interpretation and description of the results.
MAIN RESULTS
Twenty-six studies were included. There were no data for the two primary outcomes (depressive disorder established via clinical diagnostic interview and suicide), therefore, the results comprise only secondary outcomes. Most antidepressants may be associated with a "small and unimportant" reduction in depression symptoms on the CDRS-R scale (range 17 to 113) compared with placebo (high certainty evidence: paroxetine: MD -1.43, 95% CI -3.90, 1.04; vilazodone: MD -0.84, 95% CI -3.03, 1.35; desvenlafaxine MD -0.07, 95% CI -3.51, 3.36; moderate certainty evidence: sertraline: MD -3.51, 95% CI -6.99, -0.04; fluoxetine: MD -2.84, 95% CI -4.12, -1.56; escitalopram: MD -2.62, 95% CI -5.29, 0.04; low certainty evidence: duloxetine: MD -2.70, 95% CI -5.03, -0.37; vortioxetine: MD 0.60, 95% CI -2.52, 3.72; very low certainty evidence for comparisons between other antidepressants and placebo). There were "small and unimportant" differences between most antidepressants in reduction of depression symptoms (high- or moderate-certainty evidence). Results were similar across other outcomes of benefit. In most studies risk of self-harm or suicide was an exclusion criterion for the study. Proportions of suicide-related outcomes were low for most included studies and 95% confidence intervals were wide for all comparisons. The evidence is very uncertain about the effects of mirtazapine (OR 0.50, 95% CI 0.03, 8.04), duloxetine (OR 1.15, 95% CI 0.72, 1.82), vilazodone (OR 1.01, 95% CI 0.68, 1.48), desvenlafaxine (OR 0.94, 95% CI 0.59, 1.52), citalopram (OR 1.72, 95% CI 0.76, 3.87) or vortioxetine (OR 1.58, 95% CI 0.29, 8.60) on suicide-related outcomes compared with placebo. There is low certainty evidence that escitalopram may "at least slightly" reduce odds of suicide-related outcomes compared with placebo (OR 0.89, 95% CI 0.43, 1.84). There is low certainty evidence that fluoxetine (OR 1.27, 95% CI 0.87, 1.86), paroxetine (OR 1.81, 95% CI 0.85, 3.86), sertraline (OR 3.03, 95% CI 0.60, 15.22), and venlafaxine (OR 13.84, 95% CI 1.79, 106.90) may "at least slightly" increase odds of suicide-related outcomes compared with placebo. There is moderate certainty evidence that venlafaxine probably results in an "at least slightly" increased odds of suicide-related outcomes compared with desvenlafaxine (OR 0.07, 95% CI 0.01, 0.56) and escitalopram (OR 0.06, 95% CI 0.01, 0.56). There was very low certainty evidence regarding other comparisons between antidepressants.
AUTHORS' CONCLUSIONS
Overall, methodological shortcomings of the randomised trials make it difficult to interpret the findings with regard to the efficacy and safety of newer antidepressant medications. Findings suggest that most newer antidepressants may reduce depression symptoms in a small and unimportant way compared with placebo. Furthermore, there are likely to be small and unimportant differences in the reduction of depression symptoms between the majority of antidepressants. However, our findings reflect the average effects of the antidepressants, and given depression is a heterogeneous condition, some individuals may experience a greater response. Guideline developers and others making recommendations might therefore consider whether a recommendation for the use of newer generation antidepressants is warranted for some individuals in some circumstances. Our findings suggest sertraline, escitalopram, duloxetine, as well as fluoxetine (which is currently the only treatment recommended for first-line prescribing) could be considered as a first option. Children and adolescents considered at risk of suicide were frequently excluded from trials, so that we cannot be confident about the effects of these medications for these individuals. If an antidepressant is being considered for an individual, this should be done in consultation with the child/adolescent and their family/caregivers and it remains critical to ensure close monitoring of treatment effects and suicide-related outcomes (combined suicidal ideation and suicide attempt) in those treated with newer generation antidepressants, given findings that some of these medications may be associated with greater odds of these events. Consideration of psychotherapy, particularly cognitive behavioural therapy, as per guideline recommendations, remains important. | v2 |
2019-05-03T13:06:03.367Z | 1996-01-01T00:00:00.000Z | 142967730 | s2ag/train | Introductory, statistics, research methods, and history
Volume 1: Introductory, Statistics, Research Methods, and History. Contents: Preface. Part I: Introductory. Section 1: Promoting Active Participation. M.E. Gorman, A. Law, T. Lindegren, Making Students Take a Stand: Active Learning in Introductory Psychology. R.L. Kellogg, The Mini-Biographical Approach to Psychology Instruction. R. Wesp, Conducting Introductory Psychology Activity Modules as a Requirement in Advanced Undergraduate Courses. Section 2: Introducing Research Methods. J.A. Bates, Teaching Hypothesis Testing by Debunking a Demonstration of Telepathy. J.A. Polyson, K.A. Blick, Basketball Game as Psychology Experiment. A. Kohn, M. Brill, An Introductory Demonstration Laboratory Produced Entirely by Undergraduates. N. Lutsky, Undergraduate Research Experience Through the Analysis of Data Sets in Psychology Courses. R.A. Ward, A.F. Grasha, Using Astrology to Teach Research Methods to Introductory Psychology Students. J.C. Larkin, H.A. Pines, J.W. Julian, Science, Psychology and Self: A Demonstration Experiment for Introductory Psychology. Section 3: Using Computers. T. Brothen, Three Computer-Assisted Laboratory Exercises for Introductory Psychology. T. Brothen, J. Schneider, A Computerized Application of Psychology's Top 100. J.K. Bare, Microcomputers in the Introductory Laboratory. Section 4: Integrating Supplementary Literature. D.C. Appleby, Using Psychology Today Articles to Increase the Perceived Relevance of the Introductory Course. L.L. Schwartz, Tying It All Together: Research, Concepts, and Fiction in an Introductory Psychology Course. D. Winzenz, M. Winzenz, Individualized Reading for Introductory Psychology. Section 5: Employing Introductory Laboratories. T.A. Fish, I.H. Fraser, The Science Fair: A Supplement to the Lecture Technique. A.N. Katz, Inexpensive Animal Learning Exercises for Huge Introductory Laboratory Classes. Part II: Statistics. Section 1: Starting the Semester. K.M. Dillon, Statisticophobia. M.W. Hastings, Statistics: Challenge for the Students and the Professor. K.W. Jacobs, Instructional Techniques in the Introductory Statistics Course: The First Class Meeting. Section 2: Making Statistics Relevant. B. Beins, Teaching the Relevance of Statistics Through Consumer-Oriented Research. M.A. Shatz, The Greyhound Strike: Using a Labor Dispute to Teach Descriptive Statistics. K.A. Weaver, Elaborating Selected Statistical Concepts With Common Experience. M.C. Dillbeck, Teaching Statistics in Terms of the Knower. Section 3: Generating Data. L.J. Cake, R.C. Hostetter, DATAGEN: A BASIC Program for Generating and Analyzing Data for Use in Statistics Courses. P. Hettich, The Student as Data Generator. W.P. McGown, W.B. Spencer, For Statistics Classes: Data Sets With Integer Means and Standard Deviations. F.J. Dudek, Data Sets Having Integer Means and Standard Deviations. Section 4: Teaching Specific Concepts. J.D. Duke, Tables to Help Students Grasp Size Differences in Simple Correlations. S.W. Huck, S.P. Wright, S. Park, Pearson's r and Spread: A Classroom Demonstration. D.E. Johnson, Demonstrating the Central Limit Theorem. J. Karylowski, Regression Toward the Mean Effect: No Statistical Background Required. J.R. Levin, Modifications of a Regression-Toward-the-Mean Demonstration. D.J. Zerbolio, Jr., A "Bag of Tricks" for Teaching About Sampling Distributions. M. Moore, An Empirical Investigation and a Classroom Demonstration of Reliability Concepts. D.E. Johnson, An Intuitive Approach to Teaching Analysis of Variance. R.H. Williams, A New Method for Teaching Multiple Regression to Behavioral Science Students. J.L. Buck, A Demonstration of Measurement Error and Reliability. G.A. Allen, The X2 Statistic and Weber's Law. Section 5: Combining Statistics and Research Methods. J.S. Rossi, How Often Are Our Statistics Wrong? A Statistics Class Exercise. K.H. Dillon, A Funny Thing Happened to Me One Day in Statistics Class. Part III: Research Methods. Section 1: Reviewing the Literature. L.E. Gardner, A Relatively Painless Method of Introduction to the Psychological Literature Search. J.B. Mathews, "Hunting" for Psychological Literature: A Methodology for the Introductory Research Course. V.H. Parr, Course-Related Library Instruction for Psychology Students. V.H. Parr, Online Information Retrieval and the Undergraduate. R.A. Feinberg, D. Drews, D. Eynman, Positive Side Effects of Online Information Retrieval. L.K. Lewis, Bibliographic Computerized Searching in Psychology. Section 2: Teaching Experimental Design and Methods of Observation. W.M. Stallings, Return to Our Roots: Raising Radishes to Teach Experimental Design. D.J. Zerbolio, Jr., J.T. Walker, Factorial Design: Binocular and Monocular Depth Perception in Vertical and Horizontal Stimuli. K.W. Kerber, Rewards, Costs, and Helping: A Demonstration of the Complementary Nature of Experimental and Correlational Research. K.W. Kerber, Beyond Experimentation: Research Projects for a Laboratory Course in Psychology. A.S. Zeren, V.P. Makosky, Teaching Observational Methods: Time Sampling, Event Sampling, and Trait Rating Techniques. H.A. Herzog, Jr., Naturalistic Observation of Behavior: A Model System Using Mice in a Colony. Section 3: Teaching Research Ethics. B.C. Beins, Using the Barnum Effect to Teach About Ethics and Deception in Research. R.L. Rosnow, Teaching Research Ethics Through Role-Play and Discussion. D.B. Strohmetz, A.A. Skleder, The Use of Role-Play in Teaching Research Ethics: A Validation Study. H.A. Herzog, Discussing Animal Rights and Animal Research in the Classroom. Section 4: Teaching Principles, Concepts, and Skills. J.W. Hatcher, Jr., Using Riddles to Introduce the Process and Experience of Scientific Thinking. L.R. Vandervert, Operational Definitions Made Simple, Lasting, and Useful. A. Kohn, Defying Intuition: Demonstrating the Importance of the Empirical Technique. J. Yoder, Teaching Students to Do Interviewing. V.P. Falkenberg, A Funding Simulation for Use in an Advanced Experimental Laboratory Class. D.W. Carroll, Use of the Jigsaw Technique in Laboratory and Discussion Classes. B.F. Peden, Teaching the Importance of Accuracy in Preparing References. P.A. Gore, Jr., C.J. Camp, A Radical Poster Session. B. Gibson, Research Methods Jeopardy: A Tool for Involving Students and Organizing the Study Session. Section 5: Using Computers. R.J. Gregory, Introduction to Computer Data Generators. A.A. Hartley, L.A. Fisher, J.T. Hartley, Teaching the Arts of Psychological Research. A.A. Hartley, D.G. Smith, Vitamin C and the Common Cold: A Simulation for Teaching Methods of Research. J.O. Benedict, B.D. Butts, Computer Simulation or Real Experimentation: Is One Better for Teaching Experimental Design? B.F. Peden, Learning About Microcomputers and Research. J.R. Hovancik, Using Microcomputers in the Undergraduate Laboratory. B.F. Peden, G.D. Steinhauer, FACES in the Lab and Faces in the Crowd: Integrating Microcomputers Into the Psychology Course. Section 6: Using Popular Media and Scholarly Publications. P.A. Connor-Greene, From the Laboratory to the Headlines: Teaching Critical Evaluation of Press Reports of Research. S.V. McCarthy, Interview With a Former Host | v2 |
2021-09-28T15:28:23.745Z | 2021-07-22T00:00:00.000Z | 242246540 | s2ag/train | Attracting public interest in astronomy through art and cultural heritage
<p>This paper is an overview of the cultural project ''Second star to the right”, which is an Astro-tourism project carried out by the Italian Institute for Astrophysics (INAF) and the creative agency Bas Bleu Illustration. An interdisciplinary good practice that aims at connecting art, tourism, history and astronomy thus bringing science closer to the public, targeting different audiences.</p>
<p>Astronomy and astronomical phenomena have always inspired art, music, literature and had an important role in our culture. Many of the major monuments in Italy are impressively connected to Astronomy. Just to mention a few examples: the world-famous Brunelleschi Dome of the Cathedral in Florence hosts the world tallest sundial; the Halley comet painted by Giotto in the Scrovegni Chapel in Padua inspired the tradition of a comet star in Nativity scenes from then onwards; the Royal Norman Palace in Palermo holds the telescope used for the discovery of the first asteroid in history.</p>
<p>Walking downtown in the historic cities the project “Second Star to the right” explores the various ways in which astronomy crept into art and culture: the sun, the moon, planets, constellations and minor bodies are often hidden in the masterpieces of art, pictured in the marble inlays of many churches and in byzantine mosaics, painted in ceilings and frescoes. Italian cultural heritage unveils  “astronomical secrets” - clocks, meridian lines, Zodiacs, painted skies and constellations, ancient geographical maps, places connected to scientists such as Galileo Galilei or great explorers such as Amerigo Vespucci, instruments with an ancient charm that undoubtedly reveal the importance that the study of the sky and its movements always had for mankind.</p>
<p>The work of a research institution (INAF) with a creative agency (Bas Bleu Illustration) led to the design and production of a cultural project able to reach a wider public through different products:</p>
<ul>
<li>The astronomical guidebook series “Second star to the right”: it is a series of paper guidebooks that brings citizens and visitors to discover Italian cities “from an astronomical point of view” (Padua, 2015; Florence, 2019; Palermo, presumably September 2021). Each guide is an attractive, simple, and not-specialist book describing the Astronomy content of many major monuments and places connected to past and modern science. They have a nice and appealing graphic look, an easy format, and are full of curiosities and simple explanations, leading the visitors in the search for Science into artistic masterpieces, historical monuments, churches, museums, places that tell us about illustrious scientists and current research. The books help the visitors follow different colored routes, for different themes (e.g. the measuring time; following Galileo or other important astronomers footprints; representing earth and sky; etc.);</li>
<li>A map of the city, representing astronomical routes and highlighting the main astronomical places</li>
<li>Events such as “walking tours with the astronomer”, family activities, students’ visits, and laboratories, etc.; these events are carried out in collaboration with the relevant institutions (Churches, Museums, etc), creating new important cultural synergies locally and implementing the cultural role of scientific institutions in the cities.</li>
<li>A guidebook addressed to children (aged 8-11), with graphic elements and illustrations (“Padova a testa in su”, 2017; other cities under study)</li>
</ul>
<p>New Technologies and different media and communication languages that we are going to implement to attract different audiences, especially young people: Virtual Reality enhancements, Zap code, serious games such as “treasure hunt”, App deepening.</p>
<p><img src="data:image/jpeg;base64, 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| v2 |
2019-03-18T14:04:43.425Z | 2018-11-29T00:00:00.000Z | 80865940 | s2ag/train | Outcome of Patients with Myelofibrosis after Ruxolitinib Failure: Role of Disease Status and Treatment Strategies in 214 Patients
Introduction . Ruxolitinib (RUX) is the only targeted therapy available for the treatment of myelofibrosis (MF)-related splenomegaly and symptoms. Significant clinical responses may be achieved in around 50% of patients (pts). However, half of responding pts lose the response over time.
Aims . To report the outcome of a large cohort of MF pts after RUX failure, in terms of disease status, treatment strategies and survival.
Methods . A clinical database was created in 23 European Hematology Centers including retrospective data of 537 MF pts treated with RUX from Jan 2011 to July 2018. Updated information at the date of July 15th 2018 was available in 442 pts who were included in the present analysis. Spleen and symptoms response (SR & SyR) to RUX were evaluated according to the 2013 IWG-MRT criteria. RUX-related toxicity and infections were graded according to the WHO scale. Overall (OS) was estimated from the date of RUX discontinuation to the date of death or last contact, using the Kaplan-Meyer method (log-rank test).
Results . After a median follow-up of 30.5 months (1.7-84.3), 214 out of 442 evaluable (48.4%) pts had discontinued RUX. 43 (20.1%) died while on therapy because of: MF progression (34.9%), infections (25.6%), heart disease (16.3%), second neoplasia (7%), hemorrhages (7%), other (9.2%).
The median follow-up after RUX discontinuation for the remaining 171 pts was 11.3 months (0.5-66.7). Causes of RUX discontinuation were: drug-related toxicity (28.6%), loss/lack of response (23.4%), MF progression (12.3%), acute leukemia (AL) (13.4%), allogeneic stem cell transplantation (ASCT) (11.1%), second solid neoplasia (4.1%), other unrelated causes (i.e. pts decision; 7.1%).
After stopping RUX, 68 pts received 1 line of therapy, 21 received 2 lines and 9 received >2 treatments; 73 pts did not receive any therapy. Treatments received after RUX discontinuation, alone or in combination, included hydroxyurea (HU) (n. 61, 62.2%), ASCT (n. 20, 20.4%), second-generation JAK2 inhibitors (momelotinib/fedratinib/pacritinib) (n. 11, 11.2%), splenectomy (n. 7, 7.1%), azacytidine/decitabine (n. 5, 5.1%), chemotherapy (n. 4, 4.1%), investigational agents (imetelstat/PRM151: n. 4), danazole (n. 4), erythropoietin-stimulating agents (ESA) (n. 4).
A total of 95 pts (55.6%) died after RUX discontinuation, because of: MF progression (30.5%), AL (25.4%), infections (14.7%), second neoplasia (9.5%), hemorrhages (4.2%), heart disease (4.2%), ASCT (4.2%), thrombosis (2.1%), other (5.2). Median survival time from RUX stop of the 171 evaluable pts was 22.6 mos (95% CI, 13.2-30.7).
Among baseline features, survival after discontinuation was significantly influenced by the dynamic international prognostic score (DIPSS) category (p<0.001), transfusion dependency (p<0.001) and driver mutation status (with triple-negative pts having the worst survival compared to JAK2V617F and CALR-mutated pts, p=0.01).
During therapy, 45 out of 153 (29.4%) and 123 out of 161 (76.4%) evaluable pts achieved a SR and a SyR at any time. Survival was not affected by the previous response to RUX at any time-point. Conversely, survival significantly differed according to the reason for stopping RUX, with pts discontinuing because of AL evolution/second solid neoplasia having the worst outcome (Figure 1a, p<0.001). In pts who discontinued RUX in chronic phase, the use of second generation TKIs and other investigational agents tended to prolong survival compared to the administration of conventional medical treatments (i.e. HU, danazole, ESA) (Figure 1b, p=0.07)
Discussion . After RUX failure, very limited therapeutic options are available and the prognosis of MF pts is dismal, particularly for those pts starting RUX with advanced stage disease (i.e. high DIPSS category and transfusion dependency). Also, disease evolution into AL and occurrence of a second solid neoplasia significantly reduced life expectancy. In chronic phase pts, survival probability may be improved by the use of medical therapies that are still in the experimental phase. Novel investigational agents are needed.
Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abruzzese:BMS: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo:Gilead: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2019-01-21T14:14:33.068Z | 2018-11-29T00:00:00.000Z | 58306810 | s2ag/train | Long-Term Follow-up of SWOG S0816: Response-Adapted Therapy for Stage III/IV Hodgkin Lymphoma Demonstrates Limitations of PET-Adapted Approach
Introduction
For patients with Stage III/IV Hodgkin lymphoma (HL), lack of response as assessed by PET scan following cycle 2 (PET2) of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is predictive of poor clinical outcomes. SWOG Study S0816 utilized response-adapted therapy, where patients achieving a complete remission (CR) on PET2 (Deauville Score ≤ 3) continued 4 additional cycles of ABVD and those patients unable to achieve a complete remission (CR) on PET2 (Deauville Score > 3) were switched to therapy with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. This study demonstrated a 2-year PFS of 64% in the PET2+ patients after switching to eBEACOPP, which was much higher than expected (Press 2016). Herein, we report the 5-year follow-up of survival and toxicities of the patients treated on S0816.
Methods
Patients with Stage III/IV HL were enrolled to S0816 from 7/1/09-12/2/12 (n=358). Eligible patients were age 18-60 years, had measurable disease, no prior lymphoma therapy, a Zubrod performance status of 0-2, and no serious medical comorbidities. Patients were treated with response-adapted therapy as above. A subset of 336 eligible and HIV-negative patients were analyzed. Of 336, 331 had central review of PET2. PFS and OS estimates were calculated using the Kaplan-Meier method. The two-sided Fisher's exact test was used to compare the rate of second cancer between patients switched to treatment eBEACOPP and those treated with continued ABVD after 2 initial cycles of ABVD.
Results
The median age of patients was 32 years (range, 18-60). All were Stage III/IV and 51% had an International Prognostic Score of ≥ 3. PET2 was negative in 271 patients (82%) and positive in 60 patients (18%). Of PET2+ patients, 49 (82%) switched to eBEACOPP as planned and 11 (18%) declined. Median follow-up is now 5.9 years (range, 0.2-8.3 years). Eighty-five (25%) patients have either progressed or died, for an estimated 5-year PFS of 74% (95% CI: 69%-79%; Figure 1). There were 64 (24%) events in those patients who were PET2- for a 5-year PFS of 76% (95% CI: 71-81%; Figure 2). There were 20 (33%) events in those patients who were PET2+ for a 5-year PFS of 65% (95% CI: 51-76%; Figure 2). One event occurred in a patient without central review of PET2. Nineteen patients have died for an estimated 5-year overall survival of 94% (95% CI: 91%-96%; Figure 1). Eleven (3%) patients died of HL including 6 (2%) that had PET2- and 5 (8%) that had PET2+. Other causes of death included: treatment-related toxicity [sepsis (eBEACOPP n=1), bleomycin lung injury (eBEACOPP n=1; ABVD n=1), and graft versus host disease (ABVD n=1)]; second primary cancers [(eBEACOPP n=2; cervical cancer and non-Hodgkin lymphoma (NHL)]; and unknown causes (ABVD n=2). Post-therapy grade 3 adverse events were uncommon but included 1 case each of heart failure, peripheral neuropathy, prolonged neutropenia, diarrhea, DVT (catheter-related) in patients who received continued ABVD and osteonecrosis of hips/shoulders in patients who received eBEACOPP. There were 13 (4%) cases of reported second cancers, including 7 (14%) in patients treated with eBEACOPP [1 each of myelodysplastic syndrome, kidney, melanoma, NHL, cervical, medullary thyroid, and basal cell carcinoma] and 6 (2%) in patients treated with ABVD (1 each of kidney, melanoma, NHL, bladder, prostate, and squamous cell carcinoma; 2-sided Fisher's exact P value = 0.001).
Conclusions
The long-term overall survival of the patients treated on S0816 remains high (94%) at 5 years. Despite historical data suggesting favorable clinical outcomes in patients with a negative PET2, nearly 25% of these patients experienced relapse events, demonstrating limitations of a PET-adapted approach and of standard frontline therapy with ABVD. In patients who were PET2+, PFS was favorable relative to historical series, but was associated with a high rate of secondary malignancies. Our results emphasize the importance of long-term follow-up in this disease, and the need for better biomarkers at diagnosis of HL and less toxic approaches for patients with a positive PET2.
Acknowledgment
In memory of Oliver W. Press, principal investigator of this trial, who died in 2017.
Straus: DAVA Oncology: Consultancy, Honoraria; Medical Crossfire: Speakers Bureau; Millenium (Takeda): Consultancy, Research Funding; JUNO: Consultancy; Bayer: Consultancy; Onco Tracker: Consultancy; Seattle Genetics: Consultancy; Roch China: Speakers Bureau; InPractice Elselvier: Consultancy; Memorial Sloan Kettering Cancer Center: Employment. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Bartlett:ImaginAB: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria. Barr:AbbVie, Gilead: Consultancy. Leonard:Gilead: Consultancy; Sutro: Consultancy; BMS: Consultancy; Juno: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Biotest: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Genentech/Roche: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy. Kahl:Genentech: Consultancy; Celgene: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Juno: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.
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2018-12-12T20:18:07.572Z | 2013-01-01T00:00:00.000Z | 54773110 | s2ag/train | Ultrasonic studies on molecular interaction of benzaldehyde , cinnamaldehyde , 4-methoxy benzaldehyde and diethylamine in n-hexane solutions at 303 K
Ultrasonic velocities(U), Densities(ρ), Viscosities(η), are measured for three different aromatic carbonyl compounds (Benzaldehyde, Cinnamaldehyde, 4-methoxy benzaldehyde) and Diethylamine in n-hexane solutions containing equimolar concentrations (1x10M to 1x10M) at 303K. The interaction between solvent molecules and Carbonyl compounds Diethyl amine complexes are observed. Acoustical parameters such as adiabatic compressibility (κ), free length (Lf), internal pressure(πi), cohesive energy(CE), formation constant(K) values are also calculated. These values indicate complex formation and ion-solvent interaction between aromatic carbonyl compounds and diethylamine in n-hexane medium. ________________________________________________________________________________________ INTRODUCTION Carbonyl group is a functional group of seve ral biologically important molecules such as protein and hormones. Carbonyl compounds contain polar car bonyl group in which electron rich oxygen ca n function as electron donor. Basic group like amino gr oup can interact with this group to form a complex and influence the properties of such compounds [ 1 ]. Amines behave as Lewis bases since th ey contain nitrogen as the basic centre with lone pair of electrons and has hydrogen as acceptors. Aromatic amines also contain π-electrons and hence they can function as bo th n and π-electron donors. Thus donor-acceptor complexes can be formed between amines and a ldehydes. Ultrasonic investigations were carried out to detect charge-transfer complexes between certai n carbonyl compounds and chloroform, the stabi li y constants of these complexes were calculated using modif ied Bhat equation proposed by Kannappan [ 26 ]. Ultrasonic velocity measurements have been succ essfully employed to detect the nature of in teractions between certain aldehydes and amines in polar -medium like n-hexane. Calculations of adiabati c compressibility ( κ), free length (Lf), internal pressure( πi), cohesive energy(CE), formation constant(K) v alues can be used to investigate interaction of th ese aromatic carbonyl compounds-diethylamine com plexes. EXPERIMENTAL SECTION Analar grade samples of aromatic carbonyl comp ounds such as benzaldehyde, cinnamaldehyde, 4-m ethoxy benzaldehyde and aliphatic amine like diethyl amine were used. All solutions were prepared in distilled nhexane. The ultrasonic velocities of aqueous solutions were measured using ultrasonic inter ferometer (model F81) supplied by Mittal Enterprises, New Delhi operating at the frequency of 2MHZ with the accuracy of ±0.01 ms-1. The densities( ρ) of solutions were determined using specific gravity bottles of capacity 10ml. The viscosities( η) of the solutions are measured using Oswald ’s viscometer. The temperature was S. Rajesh et al J. Chem. Pharm. Res., 2013, 5(1):283-289 ______________________________________________________________________________ 284 maintained at 303 ± 0.1K during the measuremen t of ultrasonic velocity, density, and viscos ity values. The acoustical parameters are calculated from U, ρ, and η [ 7-10 ] using following relation. 1. Ultrasonic Velocity (U) The relation used to determine the ultrasonic velocity is given by, U = fλ ms Where, f Frequency of ultrasonic waves λ Wave length 2. Adiabatic compressibility (κ) The intermolecular association or dissociation leads to structural arrangement of the constit uent particles. This structural change of the molecule takes place due to the existence of electrostatic field between interacting molecules may affect the adiabatic compressibility which is defined as κ = (1/U ρ) kg -1 ms Where U – Ultrasonic velocity ρ – Density of the solution. 3. Internal pressure (πi) On the basis of statistical thermodynamics, S uryanarayana derived an expression for the det ermination of internal pressure through use of concept of free volum πi= bRT (kη/U) 1/2 (ρ /M eff) 7/6 Where T – Absolute temperature, ρDensity, and R is the gas constant, M eff – effective molecular weight. 4. Free Length (Lf) Jacobson introduced the concept of the free length in liquids. He suggested the following relation to calculate the intermolecular free length. L f = (K/U ρ ) m Where U – Ultrasonic velocity of liquid, ρ – Density of liquid, K – Jacobson temperature dependent constant defined as K = (93.875 + 0.345T) Х 10 5. Cohesive energy (CE) It is usually given as a product of interna l pressure ( πi ) and molar volume (V m). CE = πiVm kJ mol -1 6. Formation constant (K) The Formation constant is calculated using th e relation K = Y/ (b-y) 2 dmmol Where Y = (a – kb)/ (k – k); k = x/y. x = difference between U cal and Uobs at lower concentration ‘a’, y = difference be tw en Ucal and Uobs at higher concentration ‘b’ and U cal = the ultrasonic velocity of the mixture ca lculated from the mole fractions of the components using additive pr inciple. S. Rajesh et al J. Chem. Pharm. Res., 2013, 5(1):283-289 ______________________________________________________________________________ 285 This equation can be used to calculate stabi lity constant values for different combination f concentration ‘a’ and ‘b’ RESULTS AND DISCUSSION The measured ultrasonic velocities (U), densiti e (ρ), viscosities ( η) and other acoustical parameters such as adiabatic compressibility ( κ), free length (Lf), internal pressure( πi), cohesive energy(CE), formation constant(K) values at 303K is given in the table-1 to 3 . Table-1. Acoustical parameters Values for Ben zaldehyde-Diethylamine system C/10M U/ms ρ/ kgm -3 η/10 Nsm κ/10 kg ms πi atm L f , pm CE, KJ/mole K/m 1 1073.0 641.0 3.9081 1.355 2557.6 72.4 34.8 7.7 2 1053.0 638.6 3.3373 1.412 2379.7 73.9 32.5 8.1 3 1035.0 639.5 4.4560 1.459 2776.1 75.2 37.9 6.3 4 1017.0 640.6 5.0216 1.509 2976.3 76.4 40.6 7.0 5 1083.0 641.8 3.3540 1.328 2360.1 71.7 32.1 7.5 6 1040.0 634.8 3.8703 1.456 2568.0 75.1 35.3 6.7 7 1035.0 630.3 4.9409 1.481 2894.8 75.7 40.1 8.2 8 1040.0 633.4 4.4135 1.459 2738.2 75.2 37.7 8.0 9 1044.0 636.3 3.3253 1.442 2379.5 74.7 32.6 7.8 1 | v2 |
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