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Pessach, Guy. "The Legacy of Feist Revisited – A Critical Analysis of the Creativity Requirement." Israel Law Review 36, no. 1 (2002): 19–102. http://dx.doi.org/10.1017/s0021223700017891.
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One of the most significant court decisions in copyright law has been the United States Supreme Court's decision in Feist Pub., Inc. v. Rural Tel. Serv. Co., and its path-breaking approach towards the requirement of originality. The grant of copyright protection, in an intangible work, is conditioned upon the fulfillment of the prerequisite of originality. Until the Feist decision, Anglo-American copyright law had a long tradition of interpreting the requirement of originality as imposing a minimum standard of labor, skill or judgment in the production of a work that is not a copy of another work. In Feist, a watershed decision, which had international impact and influence, the United States Supreme Court first introduced the requirement of creativity into Anglo-American copyright law. According to the court's ruling, only works that entail a minimum standard of creativity could pass the threshold of originality and therefore be eligible for copyright protection.
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CARFAGNINI, MICHAEL. "Too Low a Threshold: Bilcon v Canada and the International Minimum Standard of Treatment." Canadian Yearbook of international Law/Annuaire canadien de droit international 53 (September 13, 2016): 244–77. http://dx.doi.org/10.1017/cyl.2016.17.
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AbstractTreaty obligations to afford foreign investors a minimum standard of treatment (MST) and/or fair and equitable treatment (FET) are hallmarks of international investment law. However, the relationship between such treaty-based obligations and customary international law has been the subject of considerable debate. In the North American Free Trade Agreement (NAFTA) context, the majority tribunal decision and dissenting opinion in Clayton and Bilcon of Delaware Inc. v Government of Canada (Bilcon) reflect ongoing disagreement regarding the threshold for breach of the MST under NAFTA Article 1105. This article charts NAFTA investment tribunals’ decisions regarding FET claims under Article 1105 and the development of the customary international MST on which that provision is based, in particular, the prohibition on arbitrary treatment. It argues that the majority in Bilcon applied an inappropriately low threshold in finding a breach of Article 1105, which could represent a new and unwelcome direction in NAFTA Chapter 11 jurisprudence.
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Cochran, David J., Barbara A. Silverstein, Deborah Berkowitz, Gregory A. Worrell, Thomas J. Albin, William R. Marras, Thomas J. Armstrong, and Todd R. Brown. "The Proposed OSHA Standard Related to Ergonomics." Proceedings of the Human Factors and Ergonomics Society Annual Meeting 38, no. 14 (October 1994): 841. http://dx.doi.org/10.1177/154193129403801409.
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This roundtable discussion will be devoted to the proposed OSHA Standard related to Ergonomics which is scheduled to be published the first week in October. The discussion will be timely and important. This is a very controversial topic. The participants have been selected from different backgrounds and opinions. Barbara Silverstein is the head of the standard writing team and is on leave at OSHA in Washington, D.C. from her regular employment with the State of Washington Department of Labor and Industries. Deborah Berkowitz is the Director of Safety and Health of a national labor union (United Food and Commercial Workers) and has been actively pushing for better ergonomic accommodation for workers. Gregory Worrell is the Corporate Ergonomics Director of a major meatpacking company (Monfort Inc.) and has extensive experience in establishing and conducting Ergonomics programs. Thomas Albin is a corporate level Ergonomist for 3M and is responsible for a considerable part of that company's Ergonomics effort and has extensive experience in establishing and conducting Ergonomics programs. Todd Brown is a Senior Research Engineer with the Association of American Railroads who has considerable experience in funding and conducting ergonomic research for application in the railroad environment. William Marras is a leading researcher and practitioner in the field of Ergonomics, Biomechanics, and Cumulative Trauma Disorders. Thomas Armstrong is a pioneer in the research and practice in the fields of Ergonomics and Biomechanics as they relate to Cumulative Trauma Disorders. These are talented, well respected people in their areas of expertise and will bring the latest thinking to this roundtable. This roundtable will not be a rehash of old stale ideas. The proposed standard is new and very important to the field of Ergonomics and to industry.
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Kamar, Amanda J., Meghana Doniparthi, Nhan Nhan, Ying Zhou, James A. Colton, and Eli D. Ehrenpreis. "445. Correlative Factors for State to State Differences in the Prevalence and Case Fatality Rates of SARS-CoV-2, COVID-19 Infections in the United States of America." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S290—S291. http://dx.doi.org/10.1093/ofid/ofaa439.638.
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Abstract Background Individual States of the USA have ethnic, economic, community health and education differences that influence the prevalence and outcomes of COVID-19 infection. We hypothesized that Statewide differences in the prevalence and fatality rates of COVID-19 infections are dependent on factors that may be determined by mathematical modeling. Methods Two separate statistical regression models were developed using COVID-19 case prevalence and case fatality rates functioning as dependent variables. We obtained data from the prevalence and deaths from COVID-19 cases for each state in the USA that was posted at 4 PM Central Standard Time on April 29, 2020 from the Worldometer website. Publicly available databases were utilized to obtain data for the independent variables in the model. Results Models are represented as follows: Statewide COVID-19 Prevalence Model Log (Statewide COVID_19 case prevalence) = 1.847* (100–250 individuals/mile2) +3.0025*(250+ individuals/mile2) + 1.021* (% African American population) +1.029* (% Hispanic American population +2.164 *(% adults aged 85+) Model results are shown in Table 1. Statewide COVID-19 Case Fatality Rate Model Log (Statewide COVID_19 case fatality rate) =2.194* (100–250 individuals/mile2) +2.758* (250+ individuals/mile2) +1.031* (% African American population) + 1.032* (% Hispanic American population) + 0.942 (% Native American population)+ 1.108 (% Asian American population) + 2.275 (% adults aged 85+) Model results are shown in Table 2. Table 1: COVID-19 Statewide Prevalence Model Table 2: COVID-19 Statewide Case Fatality Model Conclusion Higher State population density (See Figure 1 and Figure 2) and higher State populations of elderly persons correspond to increased prevalence and case-fatality rates of COVID-19 infections. Statewide data also shows health disparities for COVID-19 infections in Hispanic Americans, African Americans, and Asian Americans. Paradoxically, States with larger populations of Native Americans who have known poor outcomes from COVID-19 infection demonstrate a decrease in case-fatality rates, suggesting a large effect of healthcare inequality in this population. Figure 1: ANOVA one-way analysis of the association between COVID-19 prevalence and population density Figure 2: ANOVA one-way analysis of the association between COVID-19 death prevalence and population density Disclosures Eli D. Ehrenpreis, MD, FACG, AGAF, E2Bio Consultants (Board Member, Chief Executive Officer)E2Bio Life Sciences (Shareholder, Chief Executive Officer)Level Ex, Inc. (Consultant)
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Tunnell, Michael A., and Rebecca M. Brewster. "Energy and Emissions Impacts of Operating Higher-Productivity Vehicles." Transportation Research Record: Journal of the Transportation Research Board 1941, no. 1 (January 2005): 107–14. http://dx.doi.org/10.1177/0361198105194100113.
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The American Transportation Research Institute and Cummins, Inc. teamed up to investigate the energy and emissions impacts from operating commercial vehicles at weights equal to or greater than existing federal limits. Six vehicle configurations and four gross vehicle weights (GVWs) were modeled over a representative route to estimate fuel usage and corresponding tailpipe emissions. The results provide a comparative estimate of the potential energy and emission impacts from operating different vehicle configurations at various weights. When six configurations were modeled over a representative route with the Cummins, Inc., vehicle mission simulation model and a simplified algorithm to estimate emissions, fuel consumption and emissions generally decreased for each ton-mile of freight transported when compared with two standard configuration vehicles at 80,000 lb GVW. With the exception of one configuration, decreases in fuel consumption and emissions per ton-mile were 4% to 19% at 100,000 lb GVW, 15% to 22% at 120,000 lb GVW, and 27% at 140,000 lb GVW. The lone exception was for the heaviest vehicle, which experienced an increase in fuel consumption and emissions per ton-mile at a GVW of 100,000 lb when compared with the two standard configurations. At this weight, the added payload weight was insufficient to offset the additional fuel consumption demands of the heavier vehicle. Other than this exception, operating higher-productivity vehicles to accommodate higher GVWs can be expected to decrease fuel consumption and emissions on a ton-mile basis when compared with standard configuration vehicles at 80,000 lb GVW.
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Bilder, Robert M., Karen S. Postal, Mark Barisa, Darrin M. Aase, C. Munro Cullum, Stephen R. Gillaspy, Lana Harder, et al. "Inter Organizational Practice Committee Recommendations/Guidance for Teleneuropsychology in Response to the COVID-19 Pandemic†." Archives of Clinical Neuropsychology 35, no. 6 (July 15, 2020): 647–59. http://dx.doi.org/10.1093/arclin/acaa046.
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Abstract Objective The Inter Organizational Practice Committee convened a workgroup to provide rapid guidance about teleneuropsychology (TeleNP) in response to the COVID-19 pandemic. Method A collaborative panel of experts from major professional organizations developed provisional guidance for neuropsychological practice during the pandemic. The stakeholders included the American Academy of Clinical Neuropsychology/American Board of Clinical Neuropsychology, the National Academy of Neuropsychology, Division 40 of the American Psychological Association, the American Board of Professional Neuropsychology, and the American Psychological Association Services, Inc. The group reviewed literature; collated federal, regional, and state regulations and information from insurers; and surveyed practitioners to identify best practices. Results Literature indicates that TeleNP may offer reliable and valid assessments, but clinicians need to consider limitations, develop new informed consent procedures, report modifications of standard procedures, and state limitations to diagnostic conclusions and recommendations. Specific limitations affect TeleNP assessments of older adults, younger children, individuals with limited access to technology, and individuals with other individual, cultural, and/or linguistic differences. TeleNP may be contraindicated or infeasible given specific patient characteristics, circumstances, and referral questions. Considerations for billing TeleNP services are offered with reservations that clinicians must verify procedures independently. Guidance about technical issues and “tips” for TeleNP procedures are provided. Conclusion This document provides provisional guidance with links to resources and established guidelines for telepsychology. Specific recommendations extend these practices to TeleNP. These recommendations may be revised as circumstances evolve, with updates posted continuously at IOPC.online.
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Kurian, A. W., N. M. Chun, M. A. Mills, A. D. Staton, B. A. Crawford, Y. Ridge, S. S. Donlon, G. D. Gong, D. W. West, and J. M. Ford. "BRCA1/2 mutations and cancer risk in Asian-Americans." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 10512. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10512.
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10512 Background: There are significant differences in breast cancer epidemiology between Caucasian and Asian-Americans and even between different Asian groups. These cancer risks and associated BRCA1/2 mutation prevalence have not been well defined in Asians; BRCA1/2 mutation penetrance might differ due to different risk modifiers. We report on a case-control study of BRCA1/2 mutation prevalence and cancer risk in Asian-American women. Methods: Clinical Data Collection: Chart review from cancer genetics services of 4 North American centers with highest Asian volume. BRCA1/2 Mutation Risk Assessment: BRCAPRO and Myriad II models, CancerGene version 4.3 (University of Texas). BRCA1/2 Mutation Testing: Full sequencing and large rearrangement panel (Myriad Genetics Inc.). Endpoints: BRCA1/2 mutation prevalence and predictive model accuracy (observed versus predicted mutations). Results: 43 of 181 Asians (23.8%) had a BRCA1/2 mutation; 36 (19.9%) had a variant of uncertain significance. The observed prevalence of BRCA1/2 mutations was 23.8% of women, which differs significantly from the predicted prevalence of 12.9% using BRCAPRO (p = 5.6 × 10-9), and the predicted prevalence of 12.6% using Myriad II. This 2-fold difference existed for Chinese, Japanese, and Filipina women (the ethnic sub-groups with enough cases available for comparisons), even though the percent with observed and predicted mutations varied for these three groups. Conclusions: One in 4 clinically tested Asian-Americans has a BRCA1/2 mutation. Standard models significantly under-predict mutations in Asians; consequently, Asians are likely under-tested for BRCA1/2 mutations. These results may reflect lower BRCA1/2-associated cancer risk in Asians compared to Caucasians. Comparison to Caucasian controls and to Asians in Hong Kong is underway, to investigate potential genetic and lifestyle modifiers of BRCA1/2-associated cancer risk. [Table: see text] No significant financial relationships to disclose.
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Dörr, Marcus, Stefan Richter, Siegfried Eckert, Marc-Alexander Ohlow, Fabian Hammer, Astrid Hummel, Vivien Dornberger, Elisabeth Genzel, and Johannes Baulmann. "Invasive Validation of Antares, a New Algorithm to Calculate Central Blood Pressure from Oscillometric Upper Arm Pulse Waves." Journal of Clinical Medicine 8, no. 7 (July 22, 2019): 1073. http://dx.doi.org/10.3390/jcm8071073.
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Background: Antares is an algorithm for pulse wave analysis (PWA) by oscillometric blood pressure (BP) monitors in order to estimate central (aortic) blood pressure (cBP). Antares aims to enable brachial cuff-based BP monitors to be type II-devices, determining absolute cBP values independently of potential peripheral BP inaccuracies. The present study is an invasive validation of the Antares algorithm in the custo screen 400. Methods: We followed entirely the 2017 ARTERY protocol for validation of non-invasive cBP devices, the 2013 American National Standards Institute, Inc./Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060-2 and 2018 AAMI/European Society of Hypertension (ESH)/ISO validation standard protocols. In total, 191 patients undergoing cardiac catheterization were included, of which 145 patients entered analysis. Invasive cBP recordings were compared to simultaneous non-invasive cBP estimations using the Antares algorithm, integrated into an oscillometric BP monitor. Results: Mean difference between invasive and non-invasively estimated systolic cBP was 0.71 mmHg with standard deviation of 5.95 mmHg, fulfilling highest validation criteria. Conclusion: Antares is the first algorithm for estimation of cBP that entirely fulfills the 2017 ARTERY and AAMI/ESH/ISO validation protocols. The Antares algorithm turns the custo screen 400 BP monitor into a type II-device. Integration of Antares into commercially available BP monitors could make it possible to measure PWA parameters in virtually every practice in future.
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Spyropoulos, Alex C., Ron Preblick, Jackie Kwong, Melissa Lingohr-Smith, and Jay Lin. "Is Adherence to the American College of Chest Physicians Recommended Anticoagulation Treatment Duration Associated with Different Outcomes Among Patients with Venous Thromboembolism?" Blood 126, no. 23 (December 3, 2015): 1126. http://dx.doi.org/10.1182/blood.v126.23.1126.1126.
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Abstract Introduction: Venous thromboembolism (VTE) represents a major clinical and economic burden. The American College of Chest Physicians (ACCP) Guideline 9th Edition on the treatment of VTE recommends a minimum duration of anticoagulation (AC) therapy depending on patient risk profiles. The objectives of this study were to evaluate the clinical and economic outcomes associated with adherence to the AC treatment duration recommendation among VTE patients in the real world setting. Methods: Adult patients (≥18 years of age) with at least 1 inpatient diagnosis or 2 outpatient diagnoses on two different dates of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), based on ICD-9-CM codes, were identified from the IMS Pharmetrics Plus database during 1/1/2009 through 3/31/2013. The first VTE diagnosis was defined as the index event. Study patients were required to have continuous insurance coverage during the 12 months before (baseline) and after (follow-up) the index event and no prior VTE diagnosis in the baseline period. They were also required to have received at least one outpatient anticoagulant treatment within 30 days of the initial VTE diagnosis with a minimum medication days of supply of 30 days. ACCP recommend that patients with provoked VTE or unprovoked VTE and high bleeding risks receive AC treatment for at least 3 months and that patients with unprovoked VTE and low or moderate bleeding risks or patients with cancer receive AC treatment for at least 6 months. Patient records in the database including ICD-9-CM codes and RIETE bleeding risk scores were used to group patients into 2 cohorts, one comprised of patients who received AC treatment for a duration as recommended by the ACCP (adherent group, AD) and the other comprised of patients who received AC treatment for a duration less than that recommended by the ACCP (non-adherent group, non-AD). Patient demographics and clinical characteristic were evaluated during the baseline period. Healthcare resource utilization, including hospital admissions, outpatient medical services, and prescription drug usage, were measured during the baseline and follow-up periods. VTE recurrence, defined as hospitalization or ER visit with a VTE diagnosis code, was also measured during the follow-up period. Multivariate regression analysis was utilized to compare clinical and economic outcomes of study cohorts while controlling for key patient characteristics. Results: The study population included 81,827 patients with a mean age (standard deviation) of 55.3 (13.8) years. For the index VTE event, 61% had DVT only, 26% had PE only, and 13% had DVT/PE. Of the study population, the minimum ACCP recommended AC treatment durations were 3 and 6 months for 27% (n=22,157) and 73% (n=59,670) of patients, respectively. Among all patients, 74% (n=60,550) received AC therapy for the ACCP recommended duration. The proportion of patients with VTE risks, including recent hospitalization (17% vs. 9%, p<0.001), recent surgery (9% vs. 6%, p<0.001), index diagnosis of PE only (28% vs. 20%, p<0.001), and index diagnosis of DVT/PE (15% vs. 8%, p<0.001) was greater in the AD cohort than in the non-AD cohort. Furthermore, mean Charlson Comorbidity Index score (1.67 vs. 1.59, p<0.001) and RIETE bleeding risk score (RIETE ≥1: 66% vs. 55%, p<0.001) were higher for the AD cohort compared to the non-AD cohort. The most prevalent anticoagulants used for treatment were warfarin (89% vs. 96%, p<0.001) and low molecular weight heparin (58% vs. 59%, p<0.01). After controlling for key patient characteristics, risks for all-cause hospitalization (Odds ratio (OR): 0.80, confidence interval (CI): 0.77-0.83, p<0.001) and VTE recurrence (OR=0.91, CI: 0.86-0.95, p<0.001) were lower among VTE patients in the AD cohort vs. the non-AD cohort, as were differences in all-cause total healthcare payments (-$3,416, p<0.001) and VTE-related healthcare payments (-$2,139, p<0.001) during the follow-up period. Conclusions: Approximately a quarter of the study population with VTE did not receive treatment with AC therapy for the minimum duration as recommended by the ACCP guideline. Patients who did not receive outpatient AC therapy for the recommended duration had more VTE recurrences, utilized more inpatient services, and had higher healthcare costs than patients who received AC therapy for the ACCP recommended duration. Disclosures Spyropoulos: Daiichi Sankyo, Inc.: Consultancy. Preblick:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Kwong:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Lingohr-Smith:Chimerix, Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Daiichi Sankyo, Inc: Consultancy; Novosys Health: Employment. Lin:Chimerix, Inc.: Consultancy; Daiichi Sankyo, Inc: Consultancy; Bristol-Myers Squibb: Consultancy; Novosys Health: Employment.
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Houghton, Raymond L., Yvonne Y. Stevens, Kathryn Hjerrild, Jeff Guderian, Masahiko Okamoto, Mazbahul Kabir, Steven G. Reed, et al. "Lateral Flow Immunoassay for Diagnosis of Trypanosoma cruzi Infection with High Correlation to the Radioimmunoprecipitation Assay." Clinical and Vaccine Immunology 16, no. 4 (February 11, 2009): 515–20. http://dx.doi.org/10.1128/cvi.00383-08.
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ABSTRACT The incidence of blood donors seropositive for Trypanosoma cruzi in North America has increased with population migration and more rigorous surveillance. The United States, considered nonendemic for T. cruzi, could therefore be at risk to exposure to parasite transmission through blood or organ donations. Current tests show variable reactivity, especially with Central American sera. Here we describe the development of a lateral flow immunoassay for the rapid detection of T. cruzi infection that has a strong correlation to the radioimmunoprecipitation assay (RIPA) “gold standard” in the United States. Such a test could have utility in small blood banks for prescreening donors, as well as in cardiac transplantation evaluation. T. cruzi consensus and/or RIPA-positive sera from Central and South America were evaluated in enzyme immunoassays (EIAs). These included commercial panels from Boston Biomedica, Inc. (BBI) (n = 14), and HemaBio (n = 21). Other sources included RIPA-positive sera from the American Red Cross (ARC) (n = 42), as well as from Chile. Sera were tested with the multiepitope recombinant TcF. All but one of the BBI samples were positive and 7 of 21 HemaBio samples and 6 of 42 ARC samples were low positive or negative. This observation indicated the need for additional antigens. To complement TcF reactivity, we tested the sera with peptides 30, 36, SAPA, and 1.1, 1.2, and 1.3 His fragments of 85-kDa trans-sialidase. We identified a promising combination of the tested antigens and constructed a single recombinant protein, ITC6, that enhanced the relative sensitivity in U.S. blood donor sera compared to that of TcF. The data on its evaluation using RIPA-confirmed positive sera in EIA and lateral flow immunoassay studies are presented, along with an additional recombinant protein, ITC8.2, with two additional sequences for peptide 1 and Kmp-11. The latter, when evaluated in a dipstick assay with consensus positive sera, had a sensitivity of 99.2% and a specificity of 99.1%.
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Garcia Kutzbach, A., P. Camilo Estrella, V. Khoury, H. Alonzo, C. S. Pastelín, G. Guerra Batista, and A. Ogdie. "AB0506 PREVALENCE AND CLINICAL CHARACTERISTICS OF SPONDYLOARTHRITIS IN CENTRAL AMERICA AND CARIBBEAN (PRECAES)." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1280.2–1281. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2775.
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Background:Spondyloarthritis (SpA) is a group of interrelated disorders: axial spondyloarthritis (Ankylosing Spondylitis [AS] /Non Radiographic Axial Spondyloarthritis [Nr-AxSpA]), psoriatic arthritis (PsA), reactive arthritis (ReA), inflammatory bowel disease-associated arthritis (IBD), and undifferentiated SpA (USpA).1Objectives:The objectives of this study were: a) to examine the epidemiology, disease subsets, and clinical characteristics of patients with SpA in Central America and the Caribbean region; and b) to describe the natural history of these conditions in their acute and chronic forms, to determine clinical sub-types and severity.Methods:PRECAES is a cross-sectional observational study, including patients from private rheumatology clinics in three Central American countries (Guatemala, Honduras and Panama) and one in the Caribbean (Dominican Republic).Patients were enrolled between April 25th, 2018 and July 31st, 2019. Inclusion criteria: SpA diagnosis fulfilling ASAS classification criteria, age 18 - 45 years, sign informed consent and willing to perform protocol procedures during a single visit. Exclusions: any other rheumatic diseases, malignancy or HIV.Results:Each center identified 50 consecutive patients with SpA. The main reason for exclusion from this analysis was not meeting the age requirement (N=94). Therefore, we analyzed 25 from Dominican Republic (DR), 25 from Guatemala, 32 from Honduras and 24 from Panama.When applying ASAS axial and peripheral SpA definitions, all countries had high number of AS Patients. Subclinical classification by country showed the most frequent diagnosis was AS (64.1%), followed by PsA (16%), ReA (9.4%), Undifferentiated SpA (7.5%), IBD associated arthritis (1.9%) and Nr-AxSpA (0.9%) (p<0.001); characteristics of patient population and sub-clinical classification by country, Table 1. When clinical manifestations were classified as axial or peripheral SpA, 70.7% were axial in the four countries.Table 1.Patient population characteristics and Sub-clinical classification by CountrySD or ± = Standard DeviationUndifferentiated SpA (USpA), Reactive Arthritis (ReA), Nonradiographic Axial SpA (Nr-AxSpa), (AS), Inflammatory Bowel Disease-Associated Arthritis (IBD), Psoriatic Arthritis (PsA)Time from onset symptoms to diagnosis ranged in years, from 3.15 (Guatemala) to 8.2 (Honduras), among the four countries. BASMI scores were higher in Honduras (mean 5.15) and lowest in Panama (mean 1.61). Of note, the time from symptom onset to diagnosis was also longest in Honduras.NSAIDs and DMARDs were used in most countries. Glucocorticoids were rarely used in this population. Biologics are mainly used in Panama (16%), and Honduras (11%); only 8% of the enrolled patients in Dominican Republic and 2% in Guatemala.Conclusion:The most prevalent SpA diagnosis in the region is Ankylosing Spondylitis. Patient diagnosis is delayed up to 8.2 years and only 2 to 16% of the patients receive a proper treatment with a biologic therapy.This data invites to further investigation and brings opportunity to improve patients care.References:[1]Rudwaleit, M. et al. The assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann. Rheum. Dis. 2011. 70, 25-31Acknowledgements:Dr. Helga Garcia Ferrer for her thorough review of the abstract throughout the study.Disclosure of Interests:Abraham Garcia Kutzbach Grant/research support from: Novartis Pharmaceutical Inc. for this PRECAES IIT study (CAIN457FGT01T)., Pablo Camilo Estrella Grant/research support from: Novartis Pharmaceutical Inc. for this PRECAES IIT study (CAIN457FGT01T)., Vianna Khoury Grant/research support from: Novartis Pharmaceutical Inc. for this PRECAES IIT study (CAIN457FGT01T)., Hugo Alonzo Grant/research support from: Novartis Pharmaceutical Inc. for this PRECAES IIT study (CAIN457FGT01T)., Carlos Santiago Pastelín Grant/research support from: Novartis Pharmaceutical Inc. for this PRECAES IIT study (CAIN457FGT01T)., Generoso Guerra Batista Grant/research support from: Novartis Pharmaceutical Inc. for this PRECAES IIT study (CAIN457FGT01T)., Alexis Ogdie Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Eli Lilly, Janssen, Novartis, Pfizer, Takeda Pharmaceutical Company and UCB, Grant/research support from: AbbVie, BMS, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer ans USB.
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Srour, Samer A., Qaiser Bashir, Denái R. Milton, Yago Nieto, Rohtesh S. Mehta, Neeraj Saini, Ruby Delgado, et al. "Long-Term Survival for Myeloma after Autologous Stem Cell Transplantation." Blood 136, Supplement 1 (November 5, 2020): 23–24. http://dx.doi.org/10.1182/blood-2020-143053.
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Introduction: Multiple myeloma (MM) remains incurable with only a small proportion of patients surviving over 10 years (long-term survivors) from diagnosis. It has been more than 3 decades since the first autologous stem cell transplantation (ASCT) was performed for MM at our institution. In this study, we sought to determine baseline patient and disease characteristics that are associated with long-term survival after the ASCT. Methods: We included all consecutive patients who received their first ASCT between January 1988 and December 2015. The primary objective was to identify the variables associated with long-term overall survival (>10 years). The control group were patients who survived less than 10 years from their diagnosis data (short-term survivors). Logistic regression models were used to evaluate the association between predictive factors and overall survival of > 10 years. Results: Among 2176 patients who underwent their first ASCT during the study period, 1409 patients met the eligibility criteria. Overall, 392 (28%) patients were long-term survivors (>10 years) and 1017 (72%) were short-term survivors (<10 years). Table 1 shows baseline patient and disease characteristics. Only 24% and 42% of patients in the long-term and short-term survivor groups, respectively, received proteasome inhibitor-based induction therapies. Maintenance therapy was received by 49% and 45% in the short- and long-term survivor groups, respectively (p=0.19). The long-term survivor group was characterized by having higher percentage of patients younger than age 65 (86%) years, and having higher proportions of ISS Stage I (47%), standard-risk cytogenetics (96%), normal LDH (88%) and with serum creatinine <2 mg/d (87%). With a median follow-up of 13 years (range, 10-30 years), the 15-year PFS and OS survival rates in the long-term survivors were 19% (95% CI: 14% - 23%) and 62% (95%: CI 56% - 68%) (Figure 1A). The cumulative incidence rates of relapse at 1, 3, and 5 years in the short-term survival group were 9%, 63%, and 82%, respectively, compared to 2%, 20%, and 40%, respectively, in the long-term survivor group (p<0.001) (Figure 1B). All variables listed in Table 1 were assessed in univariate analysis. Seventy-six percent of patients were relapse-free at 24 months in the long-term survival group, compared to only 32% in the short-term survival group. On multivariable analysis, age, cytogenetic-risk status, race-ethnicity, and duration of remission after ASCT were significant predictors for surviving > 10 years (Table 2). ISS Stage III (vs. Stage I: OR 0.45, 95% CI 0.19-1.09; p=0.08) showed a trend towards surviving ≤ 10 years. Conclusions: ASCT is associated with durable responses and prolonged survival in a subgroup of MM patients irrespective of type of induction therapy and/or use of maintenance therapy. Duration of remission after transplant is the strongest predictor for long-term survival. Age <65 years, being African-American, and standard-risk cytogenetics were also associated with surviving more than 10 years. Disclosures Bashir: Acrotech: Research Funding; StemLine: Research Funding; Celgene: Research Funding; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; KITE: Other: Advisory Board. Nieto:Affimed: Consultancy, Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Secura Bio: Other: Grant Support. Mehta:CSL Behring: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Ciurea:Kiadis Pharma: Current equity holder in publicly-traded company, Research Funding. Popat:Bayer: Research Funding; Novartis: Research Funding. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Kebriaei:Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Jazz: Consultancy; Kite: Other: Served on advisory board; Amgen: Other: Research Support. Manasanch:GSK: Honoraria; Adaptive Biotechnologies: Honoraria; Merck: Research Funding; Quest Diagnostics: Research Funding; Takeda: Honoraria; BMS: Honoraria; Sanofi: Research Funding; Novartis: Research Funding; Sanofi: Honoraria; JW Pharma: Research Funding. Hosing:NKARTA Inc.: Consultancy. Patel:Janssen: Consultancy, Research Funding; Nektar: Consultancy, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Oncopeptides: Consultancy; Precision Biosciences: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Lee:Regeneron: Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Genentech: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding. Shpall:Zelluna: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing Agreement; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Orlowski:Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. Champlin:Omeros: Consultancy; Cytonus: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy; Genzyme: Speakers Bureau; Takeda: Patents & Royalties; DKMS America: Membership on an entity's Board of Directors or advisory committees. Qazilbash:Bioclinica: Consultancy; Amgen: Research Funding; Janssen: Research Funding; Angiocrine: Research Funding; Bioline: Research Funding.
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Robinson, Patricia A., Michaela L. Tsai, Shelly S. Lo, June Lee, Matei P. Socoteanu, Heather Kling, Michelle Bolner, Lisa Eileen Blumencranz, and William Audeh. "Genomic risk classification by the 70-gene signature and 21-gene assay in African American early-stage breast cancer patients." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e12568-e12568. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e12568.
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e12568 Background: Genomic risk of recurrence assays provide prognostic information that aids treatment recommendations for patients with early breast cancer (EBC). The 70-gene signature (MammaPrint/MP) and the 21-gene assay (Oncotype DX/ODX) were both validated by large prospective, randomized clinical trials. Previous studies have directly compared the performance of these assays, with moderate discordance widely observed. Recent work showed poor prognostic performance of the ODX in African American (AA) EBC patients (Hoskins et al., 2021). Here, we compare the concordance of two genomic tests in an AA cohort. Methods: This retrospective analysis included a subset of self-reported AA patients from the prospective, observational PROMIS (n = 66, NCT01617954) and FLEX (n = 29, NCT03053193) registry trials, for whom both MP and ODX RS results were available. Patients were enrolled from 2012 to present. The PROMIS trial enrolled patients with intermediate ODX RS (18-30). MP results were obtained from standard testing performed centrally by Agendia, Inc. (Irvine, CA); ODX testing was performed by Genomic Health, Inc. (Redwood City, CA) and results were collected from patient case report forms. Results: AA patients (n = 95) included in this sub-analysis were 77% post-menopausal with a median age of 60 years. 28% of patients were aged ≤ 50 years. Of patients with metabolic data (n = 49), 63% were obese by body mass index (BMI > 30), and 23% had type 2 diabetes mellitus (T2DM). Tumors were predominantly invasive ductal carcinoma (82%), T1 (73%), grade 2 (53%), ER+ (99%), HER2-negative (94%), lymph node-negative (86%), and MP High Risk (66%). By ODX clinical RS, 17% of tumors classified as low (0-17), 80% intermediate (18-30), and 3% high (31-100) risk. As expected, the large intermediate RS group reflects the inclusion of PROMIS patients. By TAILORx RS ranges, 76% of tumors were low risk (≤25). Of these, 61% (n = 44/72) classified as MP High Risk. Notably, 62% (n = 41/66) of tumors with TAILORx intermediate RS (11-25) were MP High Risk. Conclusions: The overall discordance between MP and ODX was 51% in these AA patients. Discordance was more frequent (61%) in ODX low risk (RS≤25) cases. Notably, of tumors with TAILORx intermediate RS (11-25), the majority (62%) classified as MP High Risk. Combined with previously published data in AA patients (Nunes et al., 2016), this results in a total of 57% (n = 52/91) of ODX low RS (≤25) tumors classified as MP High Risk. Recent data indicate that AA patients who receive a low (≤10 or ≤25) or intermediate RS (11-25) have higher recurrence rates and lower survival than White/Caucasian EBC patients with the same RS. In the current study, clinical outcomes are forthcoming; however, these data suggest the majority of AA patients are more likely to receive a MP High Risk result, which may capture the diversity of pathways driving tumor metastasis. Clinical trial information: NCT01617954, NCT03053193.
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Stapleton, Michelle, Jeffery Bub, and Suzette Chance. "A Ristocetin-Independent ELISA for the Measurement of VWF Activity." Blood 116, no. 21 (November 19, 2010): 1411. http://dx.doi.org/10.1182/blood.v116.21.1411.1411.
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Abstract Abstract 1411 Von Willebrand Disease (VWD) is a relatively common bleeding disorder characterized by both quantitative and qualitative deficiencies in von Willebrand Factor. The correct diagnosis and classification of VWD is made on the basis of a personal and family bleeding history and the results of a panel of laboratory tests. Evaluations of both VWF antigen level and function are required. Most commonly VWF function is evaluated based on VWF binding to platelets through the platelet surface glycoprotein GPIba in a platelet aggregation assay (VWF:RCo). The VWF:RCo assay requires the use of the antibiotic ristocetin to induce a conformational change in VWF which allows VWF to bind to GPIba on the surface of fresh or fixed platelets in the absence of VWF denaturation. When evaluating 172 normal controls, Flood et. al. (Blood, 2010) elegantly demonstrated that 63% of African-American controls and 17% of Caucasian controls had a single nucleotide polymorphism, D1472H, which altered the ability of these individuals to bind ristocetin and resulted in abnormal VWF:RCo results in the absence of any bleeding abnormalities. GTI Diagnostics, Inc. (Waukesha, Wisconsin) has developed a ristocetin-independent fluorescent ELISA for the quantitative measurement of VWF activity in plasma, specifically VWF binding to immobilized GPIba. This VWF activity ELISA, referred to as the GTI IbCo Assay, uses microwells coated with recombinant GPIba containing two “gain-of-function” mutations. The mutant GPIba is capable of spontaneous binding to VWF in the absence of ristocetin or VWF denaturation (Flood et. al, Blood, 2010). A brief description of the assay follows. In the absence of ristocetin, calibrators, controls, and samples are added to the microwells and VWF binding to GPIba is allowed to take place. Unbound material is washed from the wells and a biotinylated anti-VWF detection antibody is added to the wells. The microwells are washed to remove any unbound detection antibody. A streptavidin-labeled horseradish peroxidase conjugate is added to the microwells and incubated. After a final wash step, a fluorescent peroxidase substrate is added to the wells. The reaction is quenched after 30 minutes and the fluorescence is read using an excitation wavelength between 315 and 340 nm and an emission wavelength between 370 and 470 nm. The reportable result (U/dL) of VWF binding to GPIba is determined from the standard curve. All assay incubation steps are 30 minutes and conducted at room temperature, therefore the assay can be completed in < 3 hours. A small scale method comparison study was conducted on 11 plasma samples purchased from George King Bio-Medical, Inc. The plasma samples are Factor Assay ConTrol (FACT) samples and extensively characterized by George King Bio-Medical, Inc for 25 different coagulation parameters including VWF:RCo using a Chrono-Log platelet aggregometer and Helena Laboratories lyophilized platelets. The 11 samples were tested in the GTI IbCo Assay and the results obtained were compared to those obtained with the comparative method, in this case the VWF:RCo values provided by the supplier. For standardization of the GTI IbCo Assay, a IbCo value of 100 U/dL was assigned to the ISTH Secondary Coagulation Standard Lot #3. As illustrated in the table below, the samples tested included samples with varying levels VWF:RCo activity. When the results were compared, there was good correlation and agreement between the two methods. Larger method comparison studies will be conducted. Based on this limited data set the GTI IbCo Assay demonstrated good correlation and agreement with the “gold standard” Ristocetin Cofactor Assay by platelet aggregation. The GTI IbCo Assay is able to measure the functional activity of VWF, specifically in regards to VWF binding to GPIba in the absence of ristocetin in a simple ELISA format. The GTI IbCo Assay removes the need for fresh or lyophilized platelets from the traditional assay and also eliminates the ristocetin dependence from the VWF activity measurement. By removing any dependence on ristocetin to induce the VWF to GPIba interaction we have also removed any possible assay discrepancies based on a patient's inability to interact with ristocetin. Disclosures: Stapleton: GTI Diagnostics: Employment. Bub:GTI Diagnostics: Employment. Chance:GTI Diagnostics, Inc: Employment.
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Galaznik, Aaron, Jill A. Bell, Meredith M. Hoog, Michael E. Stokes, Anna W. Steenrod, Kevin B. Knopf, Brian Seal, and Yaping Shou. "Systematic Review of Therapy Used in Relapsed or Refractory Diffuse Large B-Cell Lymphoma." Blood 128, no. 22 (December 2, 2016): 3562. http://dx.doi.org/10.1182/blood.v128.22.3562.3562.
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Abstract INTRODUCTION: Non-Hodgkin's lymphoma is a heterogeneous group of diseases originating in the lymphoid system. The most common subtype, constituting up to 40% of all cases globally, is diffuse large B cell lymphoma (DLBCL).1 Approximately one-third of DLBCL patients treated with standard therapy (since 1998, a combination of chemotherapy plus immunotherapy with the CD20-directed humanized monoclonal antibody rituximab [RCHOP]) at diagnosis will develop relapsed or refractory (R/R) disease.1 Relapsed or refractory disease is defined as those whose disease does not respond to therapy (refractory) or whose disease returns after achieving remission (relapse), requiring secondary therapies. In this systematic review we examine outcomes associated with therapies used to treat R/R DLBCL including autologous (auto) stem cell transplant (SCT) and allogeneic SCT (alloSCT), plus various chemotherapy regimens in patients not eligible for SCT. METHODS: Literature databases (Medline and EMBASE) were searched for the past five years (from January 1, 2012-May 11, 2016) to identify studies reporting treatment outcomes in R/R DLBCL (including patients who had failed at least one prior treatment line). The searches applied terms to targeted publications on relapsed/refractory DLBCL and were limited to studies conducted in humans and articles published in English, including an abstract. To ensure the latest information available was included, the database searches were supplemented by reviewing American Society of Hematology (ASH) conference abstracts from the last two years. Only studies clearly (as denoted in the abstract) enrolling R/R patients with a sample size of at least 50 were included to ensure the evidence collected was well powered to detect meaningful findings. Furthermore, the review was limited by geographic location to studies primarily conducted in the European Union 5 (EU5), United States (US), and Japan. RESULTS: Of the 590 abstracts identified through Medline and EMBASE and the 325 ASH abstracts, 21 studies met the inclusion criteria after reviewing the full-text articles. Those studies meeting the criteria clearly presented clinical results for at least 50 patients with R/R DLBCL. The evidence was primarily available in observational (16/21) study designs; most of the data was presented in ASH abstracts (13/21) from the past two years. Of the clinical trials (four Phase II, one Phase II/III), many evaluated chemotherapy in patients ineligible for SCT or high dose salvage regimens. Among the studies included, 8 enrolled patients from the EU, 7 from the US, 4 from Japan, and 2 with sites in both the US and EU. Of the identified studies, there were 7 real-world observational studies evaluating SCT in R/R DLBCL. The majority (71%) investigated alloSCT with reported overall survival (OS) rates ranging from 18-52%. Among the three studies examining autoSCT, OS ranged from 54-71% (Table 1). Only one study (Rigacci, 2012) reported data on response after transplant (overall response [OR] 49%; complete response [CR] 43%). For post-SCT or SCT-ineligible patients, various chemotherapy regimens were used. Three articles were identified examining chemotherapy regimens in this setting, two of which were Phase II clinical trials. OR rates ranged widely from 3% to 62.7% for trials investigating fostamatinib and rituximab + bendamustine, respectively (Table 2). Limited data on survival were available, with only Arcari, 2015 reporting median survival of 10.8 months for patients receiving rituximab + bendamustine. CONCLUSIONS: In the past five years, only limited clinical evidence has been reported specifically for patients with R/R DLBCL. Among studies examining DLBCL, treatment courses ranged from SCT to combination chemotherapy. Survival outcomes were more often reported in studies evaluating patients treated with SCT (auto or allo) than in studies evaluating those post-SCT or SCT-ineligible. Rates of survival at three or four years varied widely from 18% to nearly two-thirds to three-quarters of patients treated with SCT; survival was higher in patients treated with autoSCT. Response rates in those ineligible for SCT were also highly variable. Studies examining SCT that were included in the review had only limited information on response. 1 World Cancer Report 2014. International Agency for Research on Cancer. (2014) Accessed July 2014. Disclosures Galaznik: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Bell:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Hoog:Evidera Inc.: Employment. Stokes:Evidera Inc.: Employment. Steenrod:Evidera Inc.: Employment. Knopf:Sutter Health Care: Employment; Exeltis: Speakers Bureau; Evidera Inc.: Consultancy. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Shou:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.
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LeBlanc, Thomas W., Roland B. Walter, Loriana Hernandez-Aldama, Kate Sully, Timothy J. Bell, Chloe Johnson, Francois Peloquin, et al. "Treatment Decision Making in AML: Factors of Importance to Clinicians, AML Patients and Their Family." Blood 134, Supplement_1 (November 13, 2019): 3498. http://dx.doi.org/10.1182/blood-2019-124660.
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INTRODUCTION: Acute myeloid leukemia (AML) is a rare hematologic cancer primarily affecting older people, with a median age at diagnosis of 67 years old (Almeida & Ramos, 2016). Heterogeneity in the presentation, functional status and presence of comorbidities among AML patients presents unique challenges for treatment. Intensive chemotherapy (IC), although the best option for prolonging survival, carries a risk of early death and other trade-offs, including significant time spent in the hospital. The toxicity of IC treatment and the requirement for prolonged hospitalizations may negatively affect patients' physical functioning and health-related quality of life (HRQoL). Novel, low-intensity treatments can be administered in the clinic and may pose less risk of immediate toxicities but may be associated with reduced efficacy. Each patient and family will approach these trade-offs differently, yet few studies examine the process of shared decision-making in AML. We aimed to better understand this process by eliciting patient/family and physician narratives about expectations and attitudes towards AML treatments. METHODS: Ten physicians in the US (n=4), UK (n=3) and Canada (n=3) and 12 AML patients (all US) and a member of their family took part in an individual, 60-minute qualitative telephone interview. Further interviews are scheduled and any additional data at the time of presentation will also be reported. The interviews followed a semi-structured guide comprising open-ended questions. The overarching aim of the interviews was to understand the value of living longer for AML patients who are not candidates for standard IC and to explore the treatment decision process from the patient, family and physician perspective. During the interviews, each participant (patient, family member or physician) completed a rating exercise in which they were asked to rate a list of pre-defined factors (9-10 factors) on a scale of 0 (not at all important) to 3 (very important) to determine their importance in AML treatment decisions. As well as providing a numerical rating for each factor, each participant was asked why they selected their rating and which three factors they would consider the most important. RESULTS: Across all three groups, relief in AML symptoms (namely fatigue and pain), longer survival and better QoL were equally considered the three most important factors when making a treatment decision. All three groups described the interaction between QoL and longer survival, explaining that any increase in survival would be important, but only if QoL (time spent with family, maintaining hobbies/interests) was maintained or improved. Physician's advice was also important to AML patients when making decisions regarding treatment. Other treatment-related factors within the rating task were rated as very important for at least a subset of patients, with no factors widely considered to be of limited importance. All participants noted that while relief of AML symptoms, longer survival and quality of life were all important, these had to be considered in light of treatment side effects and risk of infection. Likelihood of being hospitalized was important to family members, as they wanted to spend quality time at home with their loved ones, while patients and physicians considered hospitalization as an inevitable consequence of the disease and treatment. All participants reported that AML patients would consider taking any form of treatment if suitable and effective, regardless of the mode of administration. However, it was acknowledged that oral treatments would be more convenient and less invasive. The relative importance of location of care/treatment delivery was influenced by proximity to resources and whether the participant was based in an urban or rural setting. The ability to receive treatment at home was considered beneficial. CONCLUSIONS: The results from this rating exercise and qualitative interviews showed convergence across all stakeholders, indicating that AML patients, family and physicians have similar priorities regarding treatment decisions, prioritizing symptom relief, survival, and quality of life. The predominant treatment pathways in AML each require trade-offs in these factors, demonstrating the importance of shared decision making in ensuring the most appropriate treatment is selected for a given individual, in accordance with their values, goals, and preferences. Figure Disclosures LeBlanc: Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Heron: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Flatiron: Consultancy; NINR/NIH: Research Funding; Duke University: Research Funding; Astra Zeneca: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Medtronic: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Celgene: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy; American Cancer Society: Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CareVive: Consultancy. Walter:Seattle Genetics: Research Funding; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy. Hernandez-Aldama:Pfizer Inc: Consultancy. Sully:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership. Johnson:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Peloquin:Pfizer Inc: Employment, Equity Ownership. Gater:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Welch:Pfizer Inc: Employment, Equity Ownership. O'Hara:Adelphi Values Ltd: Employment; Pfizer Inc: Consultancy. Russell:Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau. Horikoshi:Pfizer Inc: Consultancy. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Naseri, Estephania, Fernanda Surita, Anderson Borovac-Pinheiro, Marília Santos, Simone Appenzeller, and Lilian Costallat. "Systemic Lupus Erythematosus and Pregnancy: A Single-Center Observational Study of 69 Pregnancies." Revista Brasileira de Ginecologia e Obstetrícia / RBGO Gynecology and Obstetrics 40, no. 10 (October 2018): 587–92. http://dx.doi.org/10.1055/s-0038-1672136.
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Objective To evaluate the effects of pregnancy in systemic lupus erythematosus (SLE) patients. Methods The present article is a retrospective cohort study. Data were collected from medical records of pregnant women with SLE from January 2002 to December 2012 at Universidade Estadual de Campinas, in the city of Campinas, state of São Paulo, Brazil. Systemic lupus erythematosus and disease activity were defined according to the American College of Rheumatology and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) criteria respectively. The means, standard deviations (SDs), percentages and correlations were performed using the SAS software, version 9.4 (SAS Institute Inc., Cary, NC, US). Results We obtained data from 69 pregnancies in 58 women. During pregnancy, a new flare was observed in 39.2% (n = 27). The manifestations were most common in patients with prior kidney disease, and mainly occurred during the third quarter and the puerperium. Renal activity occurred in 24.6% (n = 17), and serious activity, in 16% (n = 11). Of all deliveries, 75% (n = 48) were by cesarean section. Two maternal deaths occurred (3%). Preterm birth was the main complication in the newborns. The abortion rate was 8.7%. Severe SLEDAI during pregnancy was associated with prematurity (100%) and perinatal death (54%). Conclusion The maternal-fetal outcome is worse in SLE when the women experience a flare during pregnancy. The best maternal-fetal outcomes occur when the disease is in remission for at least 6 months before the pregnancy.
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Slichter, Sherrill J., Larry J. Dumont, Jose A. Cancelas, Terry Gernsheimer, Zbigniew Szczepiorkowski, Nancy M. Dunbar, Stephen Medlin, et al. "Treatment of Bleeding in Severely Thrombocytopenic Patients with Transfusion of Dimethyl Sulfoxide (DMSO) Cryopreserved Platelets (CPP) Is Safe - Report of a Phase 1 Dose Escalation Safety Trial." Blood 128, no. 22 (December 2, 2016): 1030. http://dx.doi.org/10.1182/blood.v128.22.1030.1030.
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Abstract Availability of platelets (plts) is severely limited by shelf life in some military as well as civilian settings. Additionally, some bleeding, thrombocytopenic patients do not have a therapeutic response to a standard plt transfusion. Methods for cryopreservation of apheresis plts for up to two years in 6% DMSO at <-65°C (CPP) have been developed and evaluated by in vitro assays and by in vivo infusions in non-human primates, in a few controlled human trials, and in field military operations. However, FDA has not yet approved CPP for routine use. Autologous radiolabeled CPP in healthy volunteers (n=32) had average plt recoveries of 33 ± 10% and survivals of 7.5 ± 1.2 days, and these results were 52 ± 12% and 89 ± 15%, respectively, of the same volunteers' fresh radiolabeled plts. The in vitro phenotype of CPP showed higher granule secretion, phosphotidylserine expression, and plt microparticles and poorer responses to common plt agonists compared to standard room temperature stored plts. These data suggest that transfused CPP might lead to an accelerated and enhanced clotting process in vivo. Our objective was to evaluate the safety of transfused CPP in a Phase-1 dose escalation trial. Eligibility criteria were hospitalized thrombocytopenic hematology/oncology patients with active World Health Organization (WHO) Grade 2 or greater bleeding that was, in most patients, uncontrolled by standard plts, no history of unprovoked thrombotic events, and no indication of active DIC. Fifty-nine patients consented and 28 were transfused with ½ CPP unit (n=5), one CPP unit (n=7), two CPP units (n=6), and three CPP units (n=6). One thawed single apheresis CPP unit contained 2.5 x 1011 ± 4.2 x 1010 plts in 50 ± 4 ml. In addition, one standard apheresis plt unit was randomly given to patients enrolled in each cohort (n=4). The study conformed to the Declaration of Helsinki and was listed on clinical trials.gov (NCT02078284). Patients were monitored for six days post-transfusion for adverse events (AEs) including clinical assessments for signs or symptoms of thrombosis and specific laboratory assays: prothrombin time (PT), partial thromboplastin time (aPTT), D-dimer, fibrinogen, prothrombin fragments 1 + 2 (F1+2), antithrombin, thrombin antithrombin (TAT), thrombin generation (TGT), and thromboelastography (TEG). All safety data were reviewed by an independent data safety monitoring committee prior to escalation to the next higher dose cohort. No thrombotic events occurred after transfusion of CPP units. Five serious AEs were reported, and none were associated with the CPP transfusion but, rather, were related to worsening of the patients' underlying medical conditions. Of 38 AEs, 5 were, at least, possibly related to a CPP transfusion and included DMSO skin odor following a ½ CPP unit and three CPP units (n=2), mild fever and chills in the same patient after one CPP unit (n=2), and moderate headache the next day following transfusion of three CPP units (n=1). As expected in this clinically-ill patient population, D-dimer, fibrinogen, F1+2, aPTT, and TAT averaged higher than the upper limit of normal prior to transfusion and remained similar following transfusion. TGT and TEG were suppressed pre-transfusion and were improved towards normal levels following transfusion of either CPP or standard plts. There was no induction of a post-transfusion hypercoagulable state in any patient based on laboratory results. Modest increases in corrected plts count increments (x 103/mm3) were observed following CPP transfusion (one CPP unit gave CCI's of 2.3 ± 3.5; two CPP units 4.2 ± 2.8; and three CPP units 5.6 ± 2.3) compared with 21.1 ± 3.6 after one unit of standard apheresis plts. Notably, all patients had stabilization or improvement of their bleeding following a CPP transfusion including one patient with Grade 4 CNS bleeding who had resolution of neurologic symptoms with no further plt transfusions, and four patients (17%) had WHO bleeding downgraded. In conclusion, the infusion of up to three sequential units of CPP in patients with severe thrombocytopenia and active bleeding was safe without any evidence of thrombotic complications despite CPP having a procoagulant phenotype resulting from the cryopreservation process. CPP may be efficacious to stop bleeding in thrombocytopenic patients as suggested by stabilization or downgrading of WHO bleeding grades. Phase 2/3 efficacy clinical trials are now indicated. Disclosures Slichter: NHLBI / NIH: Research Funding; Genentech: Research Funding; Cerus Corporation: Research Funding; Terumo BCT: Research Funding; Cellphire: Research Funding; Department of Defense / US Army Medical Research and Material Command: Research Funding; Megakaryon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Stock options. Dumont:US Army Medical Research and Material Command (Award W81XWH-15-C-0047) / Department of Defense: Research Funding. Cancelas:New Health Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; US Army Medical Research and Material Command (Award W81XWH-15-C-0047) / Department of Defense: Research Funding; National Institutes of Health: Research Funding; Terumo BCT: Research Funding; Cerus Corporation: Research Funding; Haemonetics, Inc.: Research Funding; Citra Labs, Inc.: Research Funding; Cellphire, Inc.: Membership on an entity's Board of Directors or advisory committees; William & Lawrence Hughes Foundation: Research Funding; Leukemia & Lymphoma Society of North America: Research Funding. Gernsheimer:Department of Defense: Research Funding; NHLBI / NIH: Research Funding. Szczepiorkowski:Fresenius Kabi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Grifols: Consultancy, Research Funding; Terumo BCT: Consultancy; Cerus Corporation: Research Funding; Erydel: Research Funding; Citra Labs: Research Funding; US Army Medical Research and Material Command (Award W81XWH-15-C-0047) / Department of Defense: Research Funding; American Association of Blood Banks: Other: President-Elect. Dunbar:Verax Biomedical: Membership on an entity's Board of Directors or advisory committees; US Army Medical Research and Material Command (Award W81XWH-15-C-0047) / Department of Defense: Research Funding. Jones:US Army Medical Research and Material Command (Award W81XWH-15-C-0047) / Department of Defense: Research Funding. Rugg:US Army Medical Research and Material Command (Award W81XWH-15-C-0047) / Department of Defense: Research Funding. Prakash:US Army Medical Research and Material Command (Award W81XWH-15-C-0047) / Department of Defense: Research Funding. Hmel:US Army Medical Research and Material Command (Award W81XWH-15-C-0047) / Department of Defense: Research Funding. Ransom:US Army Medical Research and Material Command (Award W81XWH-15-C-0047) / Department of Defense: Research Funding.
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Lust, John A., Saad Z. Usmani, Mehdi Hamadani, Charles Barranco, Martha Q. Lacy, Angela Dispenzieri, Morie A. Gertz, et al. "Phase 1b/2a Open-Label, Multiple-Dose, Dose-Escalation Study to Evaluate the Safety and Tolerability of SNS01-T Administered by Intravenous Infusion in Patients with Relapsed or Refractory Multiple Myeloma." Blood 120, no. 21 (November 16, 2012): 2973. http://dx.doi.org/10.1182/blood.v120.21.2973.2973.
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Abstract Abstract 2973 Eukaryotic translation initiation Factor 5A (eIF5A) has been implicated in the regulation of apoptosis and is the only known protein to be modified by hypusination. Hypusinated eIF5A is the predominant form of eIF5A in cancer cells. However, in its unhypusinated form, eIF5A is pro-apoptotic. SNS01-T, designed to treat B-cell cancers, consists of two active components: a plasmid DNA expressing eIF5AK50R (human eIF5A containing a lysine to arginine substitution at position 50) which remains pro-apoptotic because it cannot be hypusinated, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced delivery to tissues. The eIF5AK50R transgene is under the control of the B29 promoter and enhancer, which restricts expression to B cells. The mode of action of SNS01-T is to use an eIF5A-specific siRNA to deplete the pool of hypusinated eIF5A in myeloma cells while simultaneously adding pro-apoptotic eIF5AK50R. In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach. Eligible patients are enrolled sequentially into four cohorts of increasingly higher doses. Each cohort will receive SNS01-T by intravenous infusion twice weekly for 6 consecutive weeks and then be observed every 4 weeks during a 24-week follow-up period. Eligible patients must have been diagnosed with multiple myeloma according to IMWG criteria, have measurable disease, have relapsed disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple ascending doses of SNS01-T. Secondary objectives include pharmacokinetics, immunogenicity studies, proinflammatory cytokine quantitation, and therapeutic efficacy. The required number of 3 patients completed the dosing schedule in Cohort 1 from a total of 6 patients enrolled. Two of three patients had not progressed on treatment, based on standard response criteria including the monoclonal protein, and were considered stable at week 3 and week 6 the end of the dosing regimen. Three patients were withdrawn from the study by their physicians due to disease progression before completing treatment. One of the responding patients has continued to have stable disease at week 10, a month after the end of treatment with SNS01-T. The first group of patients received 0.0125 mg/kg, approximately 1 mg per patient by intravenous infusion. The planned dose levels for the second, third and fourth groups are 0.05, 0.2 and 0.375 mg/kg, respectively. The results to date of this first in man clinical trial indicate that SNS01-T was safely administered without dose-limiting toxicities in the first group of multiple myeloma patients. The MTD has not yet been reached. (Clinical Trials.gov Identifier: NCT01435720.) Disclosures: Hamadani: Celgene Corp: Speakers Bureau; American Cancer Society 116837-IRG-09–061–01: Research Funding; ASBMT & Millennium New Investigator Award: Research Funding; Conquer Cancer Foundation of ASCO: Research Funding. Barranco:Senesco Technologies: Employment. Thompson:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Taylor:Senesco Technologies Inc.: stock options Other. Dondero:Senesco Technologies Inc.: Employment.
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Amin, Alpesh N., Nicole Princic, Jay Lin, Stephen Thompson, and Stephen Johnston. "Real-World Analysis of the Duration of Risk of Venous Thromboembolism In US Surgical Patients." Blood 116, no. 21 (November 19, 2010): 479. http://dx.doi.org/10.1182/blood.v116.21.479.479.
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Abstract Abstract 479 Background: Patients hospitalized for major surgery are at significant risk of developing venous thromboembolism (VTE). In the US, the length of acute hospitalization for surgery has been decreasing. Given the decreased length of hospital stays, the time during which surgical patients are at risk for VTE is not well-understood in real-world clinical practice. Such information could provide insights into whether current recommendations regarding VTE prophylaxis reflect the real world needs. This retrospective, observational study assessed the incidence and time course of VTE events following admission to the hospital for major surgery in a large, real-world patient population. Methods: This study employs administrative claims data derived from the Thomson Reuters MarketScan®Inpatient Drug Link File, which comprises longitudinal patient-level inpatient and outpatient medical and pharmaceutical claims data for individuals with employer-sponsored primary or Medicare supplemental health insurance. Patients at risk for VTE due to a hospital admission between January 1, 2005, and December 31, 2008, for either abdominal or orthopedic surgery were included in this study (obtained through charge codes for types of surgical procedures that reflect the American College of Chest Physicians guideline risk groups for VTE). Patients were included if they had been continuously enrolled for at least 12 months prior to admission and at least 180 days after admission. Additionally, patients included in the analysis were required to have received some form of pharmacological prophylaxis during their hospitalization. Appropriateness of prophylaxis was not determined. The cumulative risk and hazard of VTE were established across an evaluation period of 180 days. The distribution of cumulative risk was described by the Kaplan Meier product limit method of survival analysis. The distribution of the hazard of VTE was described by a locally weighted regression procedure. The hazard function is measured as the number of VTE events per 1,000 person-days by number of days after hospital admission date to the first occurrence of VTE. Results: The study cohort consisted of 6,445 surgical patients who received prophylaxis, of whom 3,726 (57.8%) were admitted for orthopedic surgery and 2,719 (42.2%) for abdominal surgery. Patients had a mean (standard deviation [SD]) age of 64.0 (13.6) years and 63.8% were female. The mean (SD) length of stay in hospital was 5.4 (6.1) days, during which all patients received prophylaxis for VTE (criteria for inclusion) with a mean (SD) duration of 4.7 (4.3) days. 30% of patients received anticoagulation therapy within the period extending from discharge to 35 days after discharge. A total of 243 VTE events (171 DVT and 96 PE) occurred during the 180-day evaluation period. 104 (43%) VTE events occurred during the index hospitalization, and 139 (57%) VTE events occurred post-discharge. The time course of VTE events showed that the highest number of events occurred during the first 9 days (66 events, 80% in-hospital; proportion of 180-day cumulative risk ∼22%) and during days 10–19 (55 events, 58% in-hospital; proportion of 180-day cumulative risk ∼50%) following admission for the index hospitalization. VTE hazard peaked at approximately 1.4 per 1,000 person-days on the 9th day following admission for the index hospitalization. By the 21st day following index admission 50% of the cumulative 180-day risk had been incurred. The frequency of VTE then further decreased during days 20–29 (21 events, 38% in-hospital; proportion of 180-day cumulative risk ∼58%) and gradually declined thereafter, fluctuating at a background level of 1–7 events during each 10-day interval from 70–79 days up to 170–180 days. Conclusions: Over a 180-day period after admission to the hospital 243 (3.8%) out of 6,455 at-risk surgery patients receiving pharmacological prophylaxis experienced an incident VTE event. Of these VTE events, 43% occurred during the index hospitalization, while 57% occurred post-discharge. Of all VTE events that occurred within the 180-day period, a quarter occurred within 10 days and half within 3 weeks. Results from this study show that the risk of VTE was highest within the first 19 days after admission to the index hospitalization. During this high-risk period, 30% of VTE events occurred after discharge, suggesting that a non-trivial risk of VTE extends into the period after discharge. Disclosures: Amin: sanofi-aventis US Inc.: Acknowledgment: This study was funded by sanofi-aventis U.S., Inc. The authors received editorial/writing support provided by Tessa Hartog, PhD of Excerpta Medica, in the preparation of this poster funded by sanofi-aventis U.S., Inc., Honoraria, Speakers Bureau. Princic:sanofi-aventis US Inc.: Research Funding. Lin:sanofi-aventis US Inc.: Employment, Research Funding. Thompson:sanofi-aventis US Inc.: Employment. Johnston:sanofi-aventis US Inc.: Research Funding.
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Nongbua, T., A. Utta, N. Am-In, J. Suwimonteerabutr, A. Johannisson, and J. Morrell. "54 SINGLE LAYER CENTRIFUGATION BEFORE CRYOPRESERVATION IMPROVES BULL SPERM QUALITY." Reproduction, Fertility and Development 29, no. 1 (2017): 134. http://dx.doi.org/10.1071/rdv29n1ab54.
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Single layer centrifugation (SLC) with Bovicoll is a technique to enhance sperm quality. The purpose of this study was to investigate the effect of SLC before cryopreservation on bull sperm quality after thawing. Semen was collected from 8 bulls (American Brahman, n = 5 and Sahiwal, n = 3) at the North Eastern Bull Centre (KhonKaen, Thailand). The ejaculate was split: one part was prepared following the standard procedure at the bull centre (n = 88) as control. The other part was used for SLC with Bovicoll-B (Johannisson et al. 2016 Theriogenology 86, 140). The SLC-selected sperm samples were frozen using the same protocol as control (n = 88). After thawing at 37°C for 12 s, motility analysis was performed using the CEROS II® (Hamilton Thorne, Beverly, MA, USA); sperm chromatin structure, mitochondrial membrane potential, and sperm viability were assessed using a FC500 flow cytometer (Beckman Coulter, Brea, CA, USA). Treatment means were compared using the linear mixed model (Proc MIXED, SAS®, 9.3, SAS Institute Inc., Cary, NC, USA). Results are reported as least-squares means ± standard error. The sperm kinematics for SLC samples were higher than controls for progressive motility (26.37 ± 1.59%, 19.56 ± 1.59%), Linearity (LIN) (52.80 ± 0.87%, 44.94 ± 0.87%), Straightness (STR) (83.06% ± 0.59, 76.20 ± 0.59%), beat cross frequency (BCF) (29.25 ± 0.50 Hz, 24.35 ± 0.50 Hz) and wobble (WOB) (61.78 ± 0.63%, 57.40 ± 0.63%) (all P < 0.0001) respectively, whereas SLC-selected samples were lower than controls for slow motility (13.61 ± 0.71%, 15.56 ± 0.71%; P < 0.05), Amplitude of lateral head displacement (ALH) (4.88 ± 0.18 μm, 6.67 ± 0.18 μm), velocity average path, (VAP) (61.17 ± 1.93μ/s, 67.88 ± 1.93μ/s), and curvilinear velocity (VCL) (99.78 ± 3.77 μ/s, 122.91 ± 3.77 μ/s) (all P < 0.0001), respectively. Other parameters of sperm quality were not different between treatments, although there was considerable variation among individual bulls in sperm chromatin structure assay, mitochondrial membrane potential, and sperm viability. These results suggest that SLC can be used before cryopreservation to improve the kinematics of thawed bull sperm samples without adversely affecting other parameters of sperm quality.
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Olofsson, Christina, Torbjörn Ahl, Torsten Johansson, Sune Larsson, Per Nellgård, Sari Ponzer, Bengt Fagrell, et al. "A Multicenter Clinical Study of the Safety and Activity of Maleimide-Polyethylene Glycol–modified Hemoglobin (Hemospan®) in Patients Undergoing Major Orthopedic Surgery." Anesthesiology 105, no. 6 (December 1, 2006): 1153–63. http://dx.doi.org/10.1097/00000542-200612000-00015.
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Background Hemospan (Sangart Inc., San Diego, CA), a polyethylene glycol-modified hemoglobin with unique oxygen transport properties, has successfully completed a phase I trial in healthy volunteers. Because adverse events are expected to increase with age, the authors conducted a phase II safety study of Hemospan in elderly patients undergoing elective hip arthroplasty during spinal anesthesia. Methods Ninety male and female patients, American Society of Anesthesiologists physical status I-III, aged 50-89 yr, in six Swedish academic hospitals were randomly assigned to receive either 250 or 500 ml Hemospan or Ringer's acetate (30 patients/group) before induction of spinal anesthesia. Safety assessment included vital signs and Holter monitoring from infusion to 24 h, evaluation of laboratory values, and fluid balance. The hypothesis to be tested was that the incidence of adverse events would be no more frequent in patients who received Hemospan compared with standard of care (Ringer's acetate). Results Three serious adverse events were noted, none of which was deemed related to study treatment. Liver enzymes, amylase, and lipase increased transiently in patients in all three groups. There were no significant differences in electrocardiogram or Holter parameters, but there was a suggestion of more bradycardic events in the treated groups. Hypotension was less frequent in the treated patients compared with controls. Conclusions In comparison with Ringer's acetate, Hemospan mildly elevates hepatic enzymes and lipase and is associated with less hypotension and more bradycardic events. The absence of a high frequency of serious adverse events suggests that further clinical trials should be undertaken.
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Stoian, Dana, Bogdan Timar, Mihnea Derban, Stelian Pantea, Florian Varcus, Marius Craina, and Mihaela Craciunescu. "Thyroid Imaging Reporting and Data System (TI-RADS): the impact of Quantitative Strain Elastography for better stratification of cancer risks." Medical Ultrasonography 17, no. 3 (September 1, 2015): 327. http://dx.doi.org/10.11152/mu.2013.2066.173.dst.
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Aims: Due to the elevated prevalence of the solid thyroid nodules in a general population, an appropriate selection of cases referred to surgery is of paramount importance. The main aim of our study was to evaluate the performance of the Thyroid Imaging Reporting and Data System (TI-RADS) as a differential diagnosis tool for thyroid nodules. Material and methods: We evaluated 174 nodules using TI-RADS risk stratification model, using conventional ultrasound and real time elastography parameters and linear multifrequency probe (Hitachi Preirus Machine, Hitachi Inc., Japan). All the nodules were classified using the TI-RADS system according to echogenicity, margins, shapes, calcification, lymph nodes, and increased strain ra- tion. The results were compared with the pathology exam, which was considered the golden standard diagnosis. Results: The prevalence of malignant nodules was 16.7% (29 cases). The differential diagnosis performance regarding the malignant tumor for TI-RADS is appropriate for clinical use, obtaining an area under ROC curve of 0.95761 [0.8424-0.989] 95% confidence interval. Combining TI-RADS 2, 3 and 4A as probably benign and TI-RADS 4B and 5 as probably malignant, the sensitiv- ity, specificity, positive predictive value, and negative predictive value were 97.93%, 86.20%, 97.26% and 89.28% respec- tively. The overall accuracy of the method was 95.97%.According to the American Association of Clinical Endocrinologists Guidelines, 169 cases required FNAB examination; by applying the TI-RADS scoring system, the necessity for FNAB would decrease to 74 cases. Conclusion: Quantitative strain elastography, as the 6th parameter of TI-RADS system, adds diagnostic power to the risk stratification model.
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Pandey, Manu, Mahesh Swaminathan, Elizabeth A. Griffiths, James E. Thompson, Amanda Przespolewski, Swapna Thota, Jeffrey Baron, Tara L. Cronin, and Eunice S. Wang. "Outcomes of Venetoclax-Based Regimens Compared with Hypomethylating Agents (HMA) Alone or 7+3 in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia (AML): A Single Center Retrospective Analysis." Blood 134, Supplement_1 (November 13, 2019): 3866. http://dx.doi.org/10.1182/blood-2019-132123.
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In the past year, there has been a paradigm shift in the treatment of elderly and/or unfit patients with newly diagnosed acute myeloid leukemia (AML) with the approval of venetoclax (Ven) plus hypomethylating agents (HMA) or low dose Ara-C (LDAC). Ven/ HMA has shown an impressive complete response + complete response with incomplete count recovery (CR+ CRi) rate of 67% and a median overall survival (OS) of 17.5 months in older patients (pts) (median age 74 years) with intermediate and poor risk cytogenetics (Dinardo C et. Blood 2019). Similarly, Ven/LDAC resulted in a CR+ CRi rate of 54% with a median overall survival of 10.1 mos (Wei A et al JClinOnc 2019). However, to date, it is not known how the outcomes of Ven/HMA and Ven/LDAC compare with HMA or intensive chemotherapy in newly diagnosed AML pts. Methods To address this issue, we conducted a retrospective analysis of newly diagnosed AML adult pts treated with Ven-based regimens at our institution. All data was collected under an IRB approved protocol. Demographics, disease characteristics (including cytogenetics and molecular profiles), treatment details (drugs, duration, mortality and causes of death), and clinical outcomes including response and OS were analyzed. Results were compared to a historical cohort of elderly pts treated with HMA alone or intensive (7+3 based) induction chemotherapy as previously reported1. Results 31 newly diagnosed AML patients treated at our single academic institution between 2017-2019 were identified. The median age of the group was 75 years (51-90; 29 patients ≥ 60 years) with 20/31 (64.5%) males and 11/31(35.5%) females. 13/31(41.9%) patients had de-novo AML whereas 18/31 (58.1%) had high risk AML (AML with prior hematological abnormality, t-AML). By ELN 2017 risk stratification 2(6.4%),12(38.7%),17(54.8%) were favorable, intermediate, adverse risk respectively. Molecular profiling results was available for 23/31(74.2%) patients, TET2 and TP53 were the most common mutations present in 9 (29.0%) and 8 (25.8%) patients, respectively. 3/31(9.6%) patients subsequently received an allogeneic-HSCT as of August 1, 2019. The median follow-up was 112 days (9-600 days). Median number of cycles received were 2 (1-21). 15/31 (48%) pts were considered responders (CR, CRi, MLFS), 9 of 31(29%) were non-evaluable (N/E). Of these 7/9 patients died before repeat biopsy, 2/9 patient did not have a repeat biopsy. 2/31(6.4%) experienced partial response, 2/31(6.4%) had stable disease and 3/31(9.6%) had refractory disease. 30-day and 60-day mortality was 2/31(6.4%) and 6/31(19.3%) respectively. Two thirds of treated patients (20/31, 64.5%) are alive. Of the 11 patients who died 5 (45.5%) died due to pneumonia/sepsis, 3 (27.3%) died due to progressive disease, 2 (18.2%) withdrew therapy due to poor performance status and 1(9.1%) CNS bleed. There was no statistical difference in de-novo vs high risk AML, ELN 2017 risk stratification (favorable + intermediate vs adverse) when compared for response (responders vs others) or status (alive vs dead). We then compared our Ven/chemotherapy outcomes with prior data from our institution of newly diagnosed elderly pts treated with HMA or intensive chemotherapy (IC)1. There was a statistically significant difference for response favoring Ven based regimen vs HMA (48.3% vs 25.6% p=0.02); however, no significant difference was seen when comparing Ven/chemo with IC (48.3% vs 50%, p=0.87) (table 1). Similarly, no significant difference was observed in 60-day mortality when IC and HMA based therapy was compared with Ven based regimen (p=0.85 and 0.87 respectively) (table 2). Longer follow up in the Ven/chemotherapy arm is required to make any meaningful conclusion for differences in OS if any (figure A). Conclusion In our single institution retrospective review, we found higher rates of 60-day mortality than reported in a prior phase 1 multi-institute clinical trial (DiNardo et al. Blood 2019). However, response rates with Ven/chemo were significantly better than HMA alone and were equivalent to those of IC in similar elderly AML pts at our institute. We conclude that induction chemotherapy with Ven/based regimens could result in similar responses as IC in older AML pts. References 1-Gupta, Neha, et al. "Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients≥ 60 years old." American journal of hematology90.7 (2015): 639-646. Disclosures Griffiths: Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Genentech, Inc.: Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Persimmune: Consultancy; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Partner Therapeutics: Consultancy; Celgene, Inc: Consultancy, Research Funding; Novartis Inc.: Consultancy; Abbvie, Inc.: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial. Thota:Incyte, Inc.: Speakers Bureau. Wang:Jazz: Other: Advisory role; Kite: Other: Advisory role; Abbvie: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role.
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Davis, David D., Stephen Dick, Stephen Wilk, MaryClara Jones, and Yuqing Zeng. "Review of Track Inspection and Maintenance Standards for Transit." Transportation Research Record: Journal of the Transportation Research Board 2673, no. 12 (August 2, 2019): 538–47. http://dx.doi.org/10.1177/0361198118825463.
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Transportation Technology Center, Inc (TTCI) reviewed rail transit track inspection and maintenance standards in North America. These agency standards were benchmarked against similar protocols existing in other parts of the world. In addition, transit agencies were surveyed to document inspection, maintenance, and operating practices to understand variations in inspection and maintenance standards. Approximately 30 agencies participated in the survey which establishes a significant representative sample of North American transit operations. An analysis of track-related accidents was conducted to determine where changes might be required to existing standards and/or where potential gaps may exist. From this analysis, a prioritized list of recommendations was developed. The list consists of items that can be implemented immediately and also items requiring additional research and development. This research is part of the Federal Transit Administration (FTA) and Center for Urban Transportation Research (CUTR) standards development program. The program is intended to improve the safety and efficiency of rail transit operations.
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SAKHNO, T. V., P. V. PISARENKO, I. V. KOROTKOVA, O. M. OMELIAN, and N. N. BARASHKOV. "THE APPLICATION OF STATISTICAL METHODS OF QUALITY MANAGEMENT BY GMP+ STANDARDS USING FERROMAGNETIC MICROTRACERS." Grain Products and Mixed Fodder’s 18, no. 3 (October 25, 2018): 39–44. http://dx.doi.org/10.15673/gpmf.v18i3.1078.
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The GMP+FSA Feed Certification scheme is considered and analyzed which was developed in 1992 by the Dutch feed industry in response to various incidents involving contamination in feed materials. Currently it is an international scheme that is managed by GMP+ International in collaboration with stakeholders from numerous European countries. One of the most important and responsible steps in the feed production is mixing - creating a completely homogeneous mixture. In this paper, a statistical quality assessment of mixing of multicomponent feeds using the distribution of added particles – microtracers was performed. The testing procedure of the homogeneity of feeds and premixes using microtracers is presented in the Standard GMP+ BA2 ―Control of residues‖. The ferromagnetic variety of microtracers manufactured by American Company Micro-Tracers, Inc (San Francisco, California) are elementary iron particles or particles of stainless steel which are coated with a FD&C dye of different colors. The most common microtracers are Microtracer F that consists near 25000 of iron particles with a size distribution of 150 – 300 μm. These microtracers are used in the feed industry to ensure the quality of mixing feeds for animals and poultry during the last 20-30 years. The additional areas of use of microtracers include the marking of vitamins, mineral additive or medicament which introduced into premixes, which allows to mark the presence of the premix in the finished feeds. In quantitative analysis, MicrotracersTM can be used not only to document efficacy of mixing, but also to assess the adequacy of batch to batch ―cleanout‖ of mixers and other feed manufacturing equipment. In the present article the analytical results of evaluation of the mixer performance are interpreted in the terms of a Poisson statistics and chi-squared distribution. The value of probability by Poisson (p) was chosen as criteria for evaluation of homogeneity. Treating a series of counts as a Poisson distribution, the mix is judged complete if p>5% and judged incomplete if p<1%. The mix is judged ―probably incomplete‖ (marginal) if the probability value is in the range of 1%<p<5%.
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Wang, Eunice S., Elizabeth A. Griffiths, Roland B. Walter, Martin S. Tallman, Aaron D. Goldberg, Boo Messahel, and Richard M. Stone. "Tolerability and Efficacy of Crenolanib and Cytarabine/Anthracycline Chemotherapy in Older Patients (Aged 61 to 75) with Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML)." Blood 134, Supplement_1 (November 13, 2019): 3829. http://dx.doi.org/10.1182/blood-2019-130536.
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Background: Older AML patients often present with comorbidities and may have a compromised ability to tolerate intensive chemotherapy. These patients are more likely to have AML secondary to MDS/MPN and are considered to have a biologically distinct disease compared to their younger counterparts, with more frequent occurrence of adverse-risk cytogenetic abnormalities and mutations in genes regulating epigenetic modifications. In addition, the heterogeneity of driver mutations within a single patient contributes to limited responses to standard induction chemotherapy. While FLT3 mutations occur in this population, they are often subclonal, adding to the challenge of eradicating AML in older adult patients. Studies combining sorafenib or midostaurin with standard induction chemotherapy have shown relatively modest improvements in response rates and survival, and relapses, both early and late, remain a major concern. There is a major unmet need for optimizing chemotherapy and TKI treatment in this medically fragile population. We here report the safety and efficacy results in newly diagnosed older patients with FLT3 mutant AML treated with crenolanib, a type I FLT3 inhibitor, in combination with intensive induction and consolidation chemotherapy (NCT02283177). Methods: Fifteen consecutively treated patients, aged 61-75 (median age: 68), at four academic cancer centers were included in this analysis. Patients received 7+3 induction with cytarabine 100 mg/m2 for 7 days and either daunorubicin 60 mg/m2 or idarubicin 12 mg/m2 for 3 days. Crenolanib 100 mg TID was administered continuously starting 24 hours after chemotherapy until 72 hours prior to the next chemotherapy cycle. Consolidation consisted of up to 4 cycles of high-dose cytarabine (HiDAC: 1 g/m2) q12h on days 1, 3, and 5 with crenolanib starting 24 hours after the final HiDAC dose. Eligible patients proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Maintenance with crenolanib at 100mg TID was started after HiDAC or 30-90 days after HSCT for up to 12 cycles. Results: Fourteen patients completed induction chemotherapy (one patient withdrew consent at day 19). Crenolanib could be safely combined with either daunorubicin or idarubicin based induction chemotherapy. The most common adverse events (grade ≥3) were diarrhea, nausea, and febrile neutropenia. Ten of 14 patients were able to receive full doses of crenolanib during induction. The major reason for dose reduction was edema in 3 patients and GI bleeding in 1 patient. There was one treatment-related death, with 93% survival at 30 and 60 days and 87% survival at 100 days. Complete remissions with full count recovery (CR) were achieved in 10 of 15 patients after just one cycle of induction chemotherapy. Two patients achieved a complete remission after reinduction for an overall CR rate of 86%. Of the 12 patients who achieved CR, 10 patients received HiDAC consolidation, with two patients unable to receive consolidation therapy on study. Three patients received crenolanib maintenance after multiple cycles of HiDAC consolidation. Six patients underwent HSCT and 3 received crenolanib maintenance. As of July 2019, median OS for the intent to treat population is 20.2 months. One-year survival was 67% and 5 patients remain alive and in remission. All 5 long term survivors were ≤70 years old. All surviving patients received either multiple cycles of HiDAC or HiDAC plus transplant, and 4/5 underwent crenolanib maintenance. The patient who did not receive transplant completed 3 cycles of HiDAC consolidation and a full year of crenolanib maintenance. Summary/Conclusion: This safety study shows that crenolanib can be combined at full doses (100mg TID) for the duration of 7+3 induction, consolidation, and maintenance in older patients with FLT3 mutant AML. Therapy was relatively well tolerated, with less than one third of patients requiring dose reductions. Long-term survival rates are encouraging in this high-risk population, but additional studies are needed to confirm the efficacy of this combination older adults. Figure 1 Disclosures Wang: Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Griffiths:Abbvie, Inc.: Consultancy; Genentech, Inc.: Research Funding; Celgene, Inc: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Genentech, Inc.: Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy. Walter:Jazz Pharmaceuticals: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Boston Biomedical: Consultancy; Covagen: Consultancy; BiVictriX: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy. Tallman:Hematology Oncology of Indiana: Honoraria; Salzberg Weill Cornall MSKCC Seminar in Hematologic Malignancies: Honoraria; University of Oklahoma Medical Center: Honoraria; Bioline: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Nohla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Cellerant Therapeutics: Research Funding; Orsenix: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Mayo Clinic: Honoraria; New Orleans Summer Cancer Conference: Honoraria; Indy Hematology Review: Honoraria; Amgen: Consultancy; 14th Annual Miami Cancer Meeting: Honoraria; Danbury Hospital Tumor Board: Honoraria; International Conference in Leukemia: Honoraria. Goldberg:ADC Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; American Society of Clinical Oncology: Research Funding; American Society of Hematology: Research Funding; Celgene: Consultancy; Abbvie: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; DAVA Oncology: Honoraria. Messahel:Arog Pharmaceuticals: Employment. Stone:Pfizer: Consultancy; Stemline: Consultancy; Astra-Zeneca: Consultancy; Argenix: Other: DSMB; Otsuka: Consultancy; Astellas: Consultancy; Argenix: Other: DSMB; Celgene: Consultancy, Other: DSMB; Stemline: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Biolinerx: Consultancy; Biosight: Consultancy; Trovagene: Consultancy; Arog: Consultancy, Research Funding; Takeda: Other: DSMB; Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Celgene: Consultancy, Other: DSMB; Abbvie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Takeda: Other: DSMB; Biolinerx: Consultancy; Daiichi-Sankyo: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Jazz: Consultancy; Trovagene: Consultancy; Astra-Zeneca: Consultancy; Novartis: Consultancy, Research Funding; Roche: Consultancy; Macrogenics: Consultancy; Agios: Consultancy, Research Funding; Biosight: Consultancy; Abbvie: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Pfizer: Consultancy; Trovagene: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Macrogenics: Consultancy; Otsuka: Consultancy; Argenix: Other: DSMB; Astellas: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Biolinerx: Consultancy.
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Lee, Jong Yoon, Donghyun Kim, Stefanida Blake, Lakshmi Kalluri, Jessica Walter, Charles Davies, Phyllis Zee, Shuai Xu, and Thomas Power. "403 Comparative Study of Wireless Sensors Versus Type III Home Sleep Apnea Test for Home-based Diagnosis of Obstructive Sleep Apnea." Sleep 44, Supplement_2 (May 1, 2021): A160. http://dx.doi.org/10.1093/sleep/zsab072.402.
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Abstract Introduction More than 22 million Americans are estimated to have obstructive sleep apnea (OSA), though this disease remains perpetually underdiagnosed. Undiagnosed OSA contributes to poor clinical outcomes, large healthcare costs and an economic burden in excess of $150 billion dollars annually. While polysomnography (PSG) is considered the gold standard to diagnose OSA home sleep apnea testing (HSAT) is now used for most patient cohorts. Wireless sensors may offer a lower cost and less burdensome approach to home testing than traditional HSAT. Methods We performed a fully remote, national, single-arm, open-label, prospective clinical study to evaluate the performance of a wireless, two sensor experimental system (ANNETM One, Sibel Health) against a Type III HST system. A total of 154 individuals completed screening with 62 screening in as high risk for OSA using the STOP-BANG questionnaire. Ultimately 60 participants were enrolled, and 46 completed a successful home testing night wearing both the commercially available HSAT (Philips Alice NightOne Home Sleep, Koninklijke Philips N.V) and the wireless experimental system. A board-certified sleep medicine physician determined the apnea-hypopnea index (AHI) for the HSAT defined by American Academy of Sleep Medicine v2.6 guidelines. Two study investigators, blinded to the HSAT results, scored the experimental system to determine AHI based on similar guidelines. An independent study investigator conducted the final analysis of comparative performance. Participants completed a psychometric survey of their preferences, experience, and usability of the two testing systems. Results We demonstrated a high level of agreement between the HSAT and experimental system for AHI (r2=0.81, p<0.0001). The sensitivity and specificity of the experimental system to diagnose moderate and severe OSA (AHI>15) was 85% and 95%, respectively. The experimental system had a significantly higher Systems Usability Scale score compared to HSAT (61 vs 48, p<0.0001) and more than 85% of participants preferred the experimental system. Conclusion This study provides compelling evidence that the experimental system was highly acceptable and comparable to a currently used HSAT. Continued innovation in reliable, cost-effective, low profile technologies will be critical to address the unmet needs of sleep diagnostic testing. Support (if any) Anthem and Sibel Inc.
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Galsky, Matt D., Andrea Necchi, Srikala S. Sridhar, Osamu Ogawa, Natasha Angra, Stephan Hois, Philip He, Dana C. Ghiorghiu, and Joaquim Bellmunt. "A phase III, randomized, open label, multicenter, global study of first-line (1L) durvalumab in combination with standard of care (SOC) chemotherapy and durvalumab in combination with tremelimumab and SOC chemotherapy versus SOC chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (UC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS4590. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps4590.
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TPS4590 Background: Despite high response rates to 1L SoC for locally advanced or metastatic UC chemotherapy (gemcitabine + cisplatin or gemcitabine + carboplatin for patients who are cisplatin-ineligible [poor performance status, impaired renal function, comorbidities]), most patients experience disease progression. Novel strategies such as combining chemotherapy and immunotherapy offer hope for improving clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a human IgG2 mAb directed against CTLA-4. The mechanisms of action of PD-1 and CTLA-4 are nonredundant, so targeting both checkpoint pathways may have additive or synergistic efficacy compared with monotherapy. Studies of platinum-based chemotherapy combined with checkpoint blockade in other tumor types have yielded improved efficacy with acceptable safety and support exploration of this approach for 1L locally advanced or metastatic UC. Methods: NILE (NCT03682068) is a randomized, open-label, multicenter, global trial that will enroll approximately 1265 patients with histologically or cytologically documented, unresectable, locally advanced, or metastatic transitional cell carcinoma of the urothelium. Patients will be randomized (1:1:1) to durvalumab + SoC chemotherapy, durvalumab + tremelimumab + SoC chemotherapy, or SoC chemotherapy as 1L therapy. Primary endpoints are progression-free survival using blinded independent central review assessments per RECIST 1.1 and overall survival (OS). Secondary endpoints include objective response rate, OS at 24 months, proportion of patients alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, and health-related quality of life. Safety, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. The study opened for enrollment in September 2018. 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 Genitourinary Cancers Symposium. Clinical trial information: NCT03682068.
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Maxwell, Kristi, Eric A. Severson, Meagan Montesion, Ingrid Marino, Rachel Anhorn, and Bethany Sawchyn. "CGE19-064: Patient Access to Comprehensive Genomic Profiling for Hematologic Malignancies: Analysis of the Payer Coverage Landscape and Results of Testing in 3,600 Patients." Journal of the National Comprehensive Cancer Network 17, no. 3.5 (March 8, 2019): CGE19–064. http://dx.doi.org/10.6004/jnccn.2018.7255.
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Comprehensive genomic profiling (CGP) for patients with advanced solid tumors is on the trajectory of becoming standard of care through incorporation into clinical practice, professional society guidelines, availability of an FDA-approved assay, and a national coverage determination from Medicare. For hematologic malignancies, the clinical utility of CGP can be diagnostic, prognostic, or predictive depending on the type of malignancy. Molecular testing has been standard of care for many years for hematologic malignancies, and payer coverage of the CGP approach must now be considered to keep pace with advances in the field of hematology-oncology. Based on American Medical Association CPT coding definitions, molecular testing for hematologic malignancies is categorized as testing for individual genes and gene panels of 5–50 genes or >50 genes. Our review of payer coverage policies from the Policy Reporter database in October 2018 demonstrated that payer coverage for >50 genes in hematologic malignancies is limited. As an example of coverage limitations, a recently updated Medicare Local Coverage Determination limits coverage to 50 genes or less. Coverage decisions such as these are being made during a time of increasing demand for an expanded approach. Data from the Foundation Medicine, Inc. database shows that as of April 2018, over 3,600 patients with AML, MDS, and MPN have undergone clinical testing with FoundationOne Heme, a CGP assay for hematologic malignancies. In an analysis of over 1,300 AML cases tested with FoundationOne Heme, 62% had an alteration that is included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), and 91% had a clinically relevant alteration identified that could inform diagnosis, prognosis, or treatment selection. In an analysis of over 1,300 MDS cases tested, 70% had at least one clinically relevant alteration identified. In an analysis of over 200 MPN cases tested, 48% were triple negative for CALR, JAK2, and MPL, and of those triple negative cases, 55% had another clinically relevant alteration. These data demonstrate that FoundationOne Heme is a clinically important assay for patients with hematologic malignancies including AML, MDS, and MPN, and stakeholders within the system must now come together to further refine the clinical utility, improve payer coverage, and ensure patient access to this impactful testing as the field advances.
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Foran, James M., Zhuoxin Sun, Elisabeth Paietta, Janis Racevskis, David F. Claxton, Hillard M. Lazarus, Daniel A. Arber, et al. "FLT3-ITD Mutations Are Prevalent and Significantly Impact Outcome after Intensive Therapy in Elderly Adults with Acute Myeloid Leukemia (AML): Analysis of the North American Intergroup E2906 Phase III Trial in Patients Age ≥60 Years." Blood 132, Supplement 1 (November 29, 2018): 3995. http://dx.doi.org/10.1182/blood-2018-99-117838.
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Abstract Background Activating mutations in FLT3 - and in particular FLT3-ITD (internal tandem duplication) - are common in younger patients with AML, and are associated with relapse and with inferior overall survival (OS), however their prevalence and impact in older adults remains uncertain. We performed an analysis of FLT3-ITD mutations in patients age ≥60 yrs in the large prospective multicenter ECOG-ACRIN (E-A) E2906 Phase III trial. Methods Eligible patients (pts) age ≥60 yrs (n=727) were randomized to 'Standard' therapy with 7&3 (Dauno 60mg/m2) induction, and 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70yrs) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). As previously reported (Foran et al, ASH #217a, 2015), there was superior overall survival (OS) with standard therapy. AML diagnostic samples collected prospectively in the central E-A Leukemia Translational Research Lab (LTL) were used to detect mutations in the FLT3 gene by PCR using cDNA from total RNA. LTL investigators were blinded to treatment assignment. Patients with no RNA available or blast count <10% (threshold of sensitivity for the PCR assay) on the submitted sample were excluded. Statistical analysis was performed using X2 (categories) and Wilcoxon rank sum (continuous) tests to compare baseline patient and disease characteristics. Log-rank tests and multivariate Cox models stratified by treatment arm and adjusted for patient and disease variable (including WBC, cytogenetics, sex, performance status, secondary AML) were used to examine FLT3-ITD effect on OS and disease-free survival [DFS; relapse or death after complete remission (CR)/CRi (CR with incomplete CBC recovery)]. Results In the first 231 pts tested, FLT3-ITD mutations were identified in 43 (18.6%) pts, and the remainder were FLT3-ITD-negative (i.e. non-ITD). The proportion with FLT3-ITD was the same for patients age 60-69 yrs (18.8%) vs. ≥70 yrs (18.3%). In comparison to non-ITD, FLT3-ITD+ pts had significantly higher WBC (median 18.1 vs. 6.3, p=0.002) and BM blasts (80% vs. 51.5%, p=0.0004) at AML diagnosis, and were more likely to have intermediate risk (79.1% vs. 59%) vs. unfavorable risk (7.0 % vs. 31.4%) cytogenetics (p=0.002). There was no difference in CR/CRi rate overall (p=0.40), however standard (Arm A) pts with FLT3-ITD had a significantly higher CR/CRi rate (78.9% vs. non-ITD 51.5%, p=0.04). With median follow-up 53.5 months, FLT3-ITD patients tended to have worse OS (HR 1.24, 95%CI 0.85-1.81) but this was not statistically significant (Figure 1, p=0.26), and results were similar for both Arms A/B. DFS similarly tended to be worse overall for FLT3-ITD (HR 1.44, 95%CI 0.65-2.43) (p=0.17), and DFS was significantly worse for FLT3-ITD+ Arm A/Standard pts (Figure 2, p=0.033), while Arm B/CLO pts had a worse DFS regardless of FLT3 mutation status (Arm B, FLT3-ITD vs. non-ITD, p=0.93). More patients with FLT3-ITD underwent allogeneic transplantation (25.6% vs. non-ITD 19.7%), although this was not significant (p=0.41). Conclusions FLT3-ITD mutations are prevalent in older and elderly (age ≥70 yrs) patients with AML, and while they occur at somewhat lower rates than reported for younger adults, FLT3-ITD+ AML in this population has a leukemia phenotype similar to that reported in younger patients. Despite significantly higher CR/CRi rates with Standard therapy, older pts with FLT3-ITD also have significantly worse DFS following intensified Ara-C consolidation therapy than non-ITD pts. These results support routine assessment of FLT3-ITD status in older AML patients, and the incorporation of novel post-remission treatment strategies to improve outcome in FLT3-ITD+ pts ≥60 yrs. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Lazarus:Pluristem Ltd.: Consultancy. Tallman:BioSight: Other: Advisory board; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding.
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Myers, Daryl R., Keith Emery, and C. Gueymard. "Revising and Validating Spectral Irradiance Reference Standards for Photovoltaic Performance Evaluation." Journal of Solar Energy Engineering 126, no. 1 (February 1, 2004): 567–74. http://dx.doi.org/10.1115/1.1638784.
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In 1982, the American Society for Testing and Materials (ASTM) adopted consensus standards for direct-normal and hemispherical (“global”) tilted solar terrestrial spectra (ASTM E891/E892/G159). These standard spectra were intended to evaluate photovoltaic (PV) device performance and other solar-related applications. The International Standards Organization (ISO) and International Electrotechnical Commission (IEC) adopted these spectra as spectral standards ISO 9845-1 and IEC 60904-3. Additional information and more accurately representative spectra are needed by today’s PV community. Modern terrestrial spectral radiation models, knowledge of atmospheric physics, and measured radiometric quantities are applied to develop new reference spectra under consideration by ASTM.
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Kubina, Milan, Dominika Šulyová, and Josef Vodák. "Comparison of Smart City Standards, Implementation and Cluster Models of Cities in North America and Europe." Sustainability 13, no. 6 (March 12, 2021): 3120. http://dx.doi.org/10.3390/su13063120.
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Sustainability in Smart Cities is a current and trendy topic in a global sense. The primary impetus for writing this article was to create a general implementation model for the smart governance of European Smart Cities based on the American best practice. The ambition is to be able to modify the generally created model to meet the local conditions of all countries. The aim of the article is to point out the essential elements and differences between the implementation standards, models and clusters in the cities of North America and Europe, including their benefits and limitations. This article compared standards, implementation and cluster models for Smart Cities in North America and Europe through a secondary analysis from Arcadis and IDC consultants, standards agencies, and relevant sources. In addition, comparisons and summaries of the results were used. The results of this article point out the fundamental differences between the American and European approaches to building Smart Cities. American models are more centrist-oriented to people and complex in their simplicity, thus achieving a higher degree of reputation. Europeans are less consistent and top-down oriented. The new model will make European Smart Cities more focused on the needs and expectations of all stakeholders. The main results of this article are the answers to the research questions and the general implementation model, the verification of which will take place in practice in the future.
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Gregory, G. D. "North American and IEC standards for circuit breakers." IEEE Industry Applications Magazine 7, no. 1 (2001): 64–71. http://dx.doi.org/10.1109/2943.893366.
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Wachs, Joy E. "The American Association of Occupational Health Nurses: Seventy-Five Years of Education, Practice, and Research." Workplace Health & Safety 65, no. 4 (April 2017): 148–53. http://dx.doi.org/10.1177/2165079917701139.
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For the past 75 years, the American Association of Industrial Nurses, and later the American Association of Occupational Health Nurses, has advocated for occupational and environmental health nurses by supporting quality undergraduate and graduate education in the specialty and certification through the American Board of Occupational Health Nurses, Inc., and providing funding for and dissemination of occupational health nursing research as well as by developing occupational health nursing practice standards, competencies, and code of ethics.
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Everson, R. B., D. Bangsi, L. L. Darga, M. R. Bell, V. P. Pidlaoan, and D. Kanakapalli. "High throughput, highly multiplexed transcriptional profiling of cytologic preparations from buccal mucosa." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14104. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14104.
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14104 Background: Alterations in gene expression can be sensitive and informative indicators that a biologically effective exposure occurred. For example, serial specimens could provide evidence that a dose with a biological effect was reached in Phase I testing. Sampling buccal mucosal can provide epithelial cell specimens rapidly with little discomfort. However, ribonucleases in saliva rapidly degrade epithelial cell RNA, prohibiting analysis by standard array techniques. Using buccal cells, we conducted a pilot study to optimize procedures for RNA isolation and analysis and determined influences of gender, race, and cigarette smoking on gene expression. Methods: Buccal cells were collected by scraping the inner cheek with a previously described standardized plastic tool (BioTechniques. 2004;36:484–487) made available Avrum Spira of Boston University. Preliminary experiments compared RNA extraction procedures, including methods based on trizol (Invitrogen, Carlsbad, CA), RNeasy columns (Qiagen, Valencia, CA), and the High Pure RNA Paraffin Kit (Roche, Indiana, USA). After standardization of the method, specimens were obtained from 64 subjects using a blocked design sampling equal numbers of subjects by gender, African American and white race, and smoking status. Gene expression levels were determined using the cDNA-mediated annealing, selection, extension, and ligation assay (Illumina, Inc.), which measures expression of over 500 genes per analysis. Results: The Roche extraction method provided the highest yield of RNA and was used for subsequent assays. Technical replicates were highly reproducible. Preliminary analyses revealed that using P=0.05, 38 genes were expressed differentially by gender, 20 by race, and 10 by smoking status. The genes most differentially expressed by gender included IRF1, MET, STAT1, RAP1GDS1; race CD9, CCNA2, CEACAM1, FVT1; smoking CD44, NQO1, SKI, SRC. Conclusions: Highly multiplexed gene expression analysis of buccal cells are feasible. Demographic characteristics of study subjects can be important, but they do not heavily influence levels for many genes. Results indicate the assays could be provide useful information in cross-sectional or serial studies of the impact of molecular therapeutics. No significant financial relationships to disclose.
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Wang, Ling, Benjamin Zuchelkowski, Derek Sinchar, Minying Yang, Sebastien Gingras, Tamir Kanias, Janet S. Lee, Daniel Kim-Shapiro, Grier Page, and Mark T. Gladwin. "Evaluation of the Functional Effects of an African American Glucose-6-Phosphate Dehydrogenase (G6PD) Polymorphism (Val68Met) on RBC Hemolytic Propensity and Post-Transfusion Recovery in a Humanized Mouse Model." Blood 134, Supplement_1 (November 13, 2019): 102. http://dx.doi.org/10.1182/blood-2019-124926.
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Background: Growing evidence suggest that donor genetic variation is associated with RBCs storage integrity and post-transfusion recovery. In collaboration with the REDS III program, we performed a large-scale genome-wide association study (GWAS) study in ~13,000 healthy human blood donors, which demonstrated that RBCs with an African American G6PD-deficient A- variant (rs1050828, Val68Met) was associated with higher oxidative hemolysis after cold storage in normal volunteers. Despite a high prevalence of X-linked G6PD mutation in African American population (> 10%), blood donors are not routinely checked for G6PD deficiency and its importance in transfusion medicine is relatively understudied. We hypothesize that G6PD V68M SNP is associated with G6PD deficiency and modulates RBCs in vitro hemolytic propensity and in vivo post-transfusion recovery. Methods and Results: CRISPR-Cas9 technology was used to create non-synonymous human G6PD X-linked SNP (Val68Met) in C57B6 mice, and the desired genotypes were isolated by strategic back-crossing and sequential genotyping to ensure passage of SNP. G6PD enzymatic activity in erythrocytes was measured in fresh collected blood using a colorimetric assay kit. The predisposition of fresh and stored RBCs (after 11 days cold storage) to hemolysis was evaluated by subjecting washed mouse RBCs to selected stress assays, including osmotic fragility, mechanical fragility, and oxidative hemolysis using AAPH, diamide or H2O2. Hemolysis was measured by detection of supernatant cell-free hemoglobin using Drabkin's assay. Hematological values were measured using a Hemavet® 950 Hematology Analyzer System. Reticulocyte count was obtained using thiazole orange staining and analyzed by flow cytometry. We found severe disruption of G6PD enzymatic activity in erythrocytes from G6PD V68M SNP mice compared to WT mice (~5% residual activity in hemizygous male and ~60% in heterozygous female mice). Significant increased oxidative hemolysis was observed in both fresh and stored mouse RBCs with G6PD SNP, consistent with the GWAS study in human. G6PD V68M SNP hemizygous male mice had higher mean corpuscular volume (MCV) and lower mean corpuscular hemoglobin concentration (MCHC) compared to WT mice. However, no difference was observed in storage hemolysis, osmotic fragility, mechanical fragility and reticulocyte counts. Transfusion experiments with stored red blood cells from G6PD hemizygote males into GFP positive recipients will evaluate red blood cell recovery and half-life after standard cold storage and transfusion. Conclusions: We successfully generated a novel mouse strain carrying a "humanized" African American G6PD V68M variant which resembles the phenotype of humans with G6PD deficiency and increased oxidative hemolysis. Studies are undertaken to further investigate the effects of G6PD V68M SNP on RBCs structure, functions and in vivo post-transfusion recovery. Disclosures Gladwin: Bayer Pharmaceuticals: Other: Co-investigator; United Therapeutics: Patents & Royalties: Co-inventor on an NIH government patent for the use of nitrite salts in cardiovascular diseases ; Globin Solutions, Inc: Patents & Royalties: Provisional patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning.
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Pemmaraju, Naveen, Andrew A. Lane, Kendra L. Sweet, Anthony S. Stein, Sumithira Vasu, William Blum, David A. Rizzieri, et al. "Results of Pivotal Phase 2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)." Blood 132, Supplement 1 (November 29, 2018): 765. http://dx.doi.org/10.1182/blood-2018-99-118966.
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Abstract Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematologic malignancy with a historical overall survival (OS) of ~8-14 months from diagnosis and no approved therapies or standard of care. Tagraxofusp (Elzonris™; SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on BPDCN and other malignancies. Tagraxofusp was granted Breakthrough Therapy Designation for the treatment of patients with BPDCN, and a rolling Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) was completed in June 2018. Detailed results from the pivotal trial of tagraxofusp in BPDCN will be presented. Methods: This pivotal Phase 2 clinical trial is a multicenter, open label, non-randomized, single-arm trial designed to determine safety and efficacy of tagraxofusp in patients with BPDCN. In Stage 1 (lead-in), first line (1L) and relapsed/refractory (r/r) patients with BPDCN received tagraxofusp as a daily IV infusion at 7, 9, or 12 mcg/kg/day on days 1-5 of a 21-day cycle. Patients with BPDCN enrolled in subsequent stages received tagraxofusp at the dose determined in Stage 1 (12 mcg/kg). Stage 2 (expansion) enrolled 1L and r/r patients, and Stage 3 (pivotal, confirmatory) enrolled only 1L patients. Results: 45 patients with BPDCN (Stages 1 and 2, n=32; Stage 3, n=13) were enrolled at 7 sites in the US, including 32 (71%) patients as 1L. Median age was 70 years (range, 22-84); 82% male. Median follow-up for all 1L patients treated at 12 mcg/kg (n=29) was 13.8 months (range 0.2-37.4+). The most common treatment-related adverse events (TRAEs) at 12 mcg/kg in 148 patients treated in four clinical trials with tagraxofusp were transaminitis (44%), hypoalbuminemia (44%), and thrombocytopenia (26%). Capillary leak syndrome (CLS), all grades, occurred in 17% of patients across all indications at 12 mcg/kg; 0.7% (1/148) and 1.6% (3/182) of cases resulted in death across all indications at 12 mcg/kg and all doses, respectively. The Stage 3 pivotal cohort met its primary endpoint with a 54% (7/13) rate of CR+CRc (95% CI: 25.1, 80.8). Across Stages 1, 2 and 3, in 1L patients dosed at 12 mcg/kg (n=29), ORR was 90% (26/29) with a 72% (21/29) rate of CR+CRc+CRi (ORR=overall response rate; CR=complete response; CRc=clinical CR: absence of gross disease with minimal residual skin abnormality; CRi=CR with incomplete hematologic recovery). 45% (13/29) of first-line patients treated with 12 mcg/kg were bridged to stem cell transplant (SCT) (10 allo+3 auto). In r/r patients, ORR was 69% (9/13) with a 38% (5/13) rate of CR+CRc+CRi. Additional patient follow-up will be provided. Conclusions: The pivotal trial of tagraxofusp was the largest prospectively designed, multi-center trial specifically dedicated to patients with BPDCN. This study has met its primary endpoint, and also demonstrated high response rates that were generally achieved early in the course of treatment and maintained over multiple cycles of therapy. Safety profile demonstrated most common toxicities of transaminitis, hypoalbuminemia, and thrombocytopenia; occurrence of CLS was the most serious TRAE, which was overall manageable in this population. Patients with BPDCN are being enrolled in an additional cohort, Stage 4, to ensure ongoing access. Tagraxofusp is also being evaluated in other trials including in patients with chronic myelomonocytic leukemia (CMML) and myelofibrosis (MF). Disclosures Pemmaraju: celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding; stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; abbvie: Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding. Lane:N-of-one: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Agios: Consultancy; Jazz: Speakers Bureau; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Astellas: Consultancy; BMS: Honoraria; Phizer: Consultancy; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; Phizer: Consultancy. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Vasu:Boehringer Ingelheim Inc: Membership on an entity's Board of Directors or advisory committees. Blum:Tolero: Research Funding; Forma: Research Funding; Astellas: Consultancy; Xencor: Research Funding; Boehringer Ingelheim: Research Funding; Pfizer: Consultancy. Rizzieri:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: 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; Novartis: Consultancy; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Duvic:Guidepoint Global: Consultancy; Eisai: Research Funding; Allos: Research Funding; Clinical Care Options: Consultancy; Array Biopharma: Consultancy, Honoraria; Spatz Foundation: Research Funding; Defined Health: Consultancy; Medivir AB: Membership on an entity's Board of Directors or advisory committees; MiRagen Therapeutics: Consultancy; MEDACorp: Consultancy; Taiwan Liposome Company LTD: Consultancy; Medscape: Other: Speaker/Preceptor; Concert Pharmaceuticals, Inc.: Consultancy; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huya Bioscience Int'l: Consultancy; Shape: Research Funding; Kiniksa Pharmaceuticals: Consultancy; Soligenix, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Dr. Reddy's Laboratories (A.K.A. Promius Pharma): Consultancy; Huron Consulting Group: Consultancy; Aclaris Therapeutics Int'l Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; UT MD Anderson Cancer Center: Employment; The Lynx Group: Consultancy; Evidera, Inc.: Consultancy; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogics: Research Funding; Precision Oncology, LLC: Membership on an entity's Board of Directors or advisory committees; Oncoceuticals: Research Funding; Jonathan Wood & Associates: Other: Speaker; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen Pharma: Research Funding. Spence:Stemline Therapeutics: Consultancy. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Bergstein:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Sloan:Stemline Therapeutics: Consultancy. Konopleva:Stemline Therapeutics: Research Funding.
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Nasonov, E., R. Stoilov, T. Tyabut, and M. C. Genovese. "OP0021 OLOKIZUMAB, MONOCLONAL ANTIBODY AGAINST IL6, IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE RHEUMATOID ARTHRITIS INADEQUATELY CONTROLLED BY METHOTREXATE: EFFICACY AND SAFETY RESULTS OF PHASE III CREDO-1 STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 16.1–17. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1688.
Full textAbstract:
Background:Olokizumab (OKZ) is a new humanized monoclonal antibody targeting IL-61, 2. Here we present the results of the first phase III study of OKZ in patients with Rheumatoid Arthritis (RA).Objectives:The primary objective was to evaluate the safety and efficacy of OKZ administered subcutaneously (SC) every 2 weeks (q2w) and 64mg SC every 4 weeks (q4w) vs placebo in the treatment moderate-to-severe RA.Methods:In this randomized, double-blind, placebo-controlled, multicenter study in patients with moderately to severely active RA despite methotrexate (MTX) (ClinicalTrials.gov IdentifierNCT02760368, CREDO-1) patients received SC injections of OKZ 64 mg q2w, OKZ 64 mg q4w and PBO q2w for 24 weeks. Starting at Week (Wk) 14, non-responders were rescued. After Wk 24, subjects were eligible for an open-label study extension.The primary endpoint was American College of Rheumatology 20% (ACR20) response at Wk 12.Secondary endpoints included: percentage of subjects with low disease activity, improvement of physical ability. Safety outcomes, including treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs) and laboratory abnormalities (via central lab) were assessed.Results:428 patients were randomized to OKZ 64mg q2w (n=143), OKZ 64mg q4w (n=142), and PBO (n=143). Baseline characteristics were comparable between treatment arms: mean (SD) age was 51.3 (12.0) years, 82.7% of patients were female, disease duration 8.14 (7.6) and all patients were on MTX. Mean (SD) baseline DAS28-CRP was 6.0 (0.76) and HAQ-DI was 1.72 (0.49).130 (90.9%) patients in q2w, 134 (94.4%) in q4w and 132 (92.3%) in PBO arms completed the study.Both regimens of OKZ were significantly better than PBO in all primary and secondary endpoints (Table 1).Table 1.Key efficacy results (intent-to-treat population) NRI1OKZ q2wOKZ q4wPBONumber of Subjects143142143ACR20 Response, n (%) Wk 12 (primary endpoint)91(63.6)***100(70.4)***37(25.9)DAS28<3.2 Response, n (%) Wk 1248(33.6)***55(38.7)***5(3.5)HAQ-DI Wk 12 LSM (SE)-0.54(0.041)-0.56(0.042)-0.20(0.042)Treatment Comparison vs PBO LSM Difference (SE)-0.34***(0.059)-0.36***(0.059)97.5% CI for LSM Difference-0.47, -0.21-0.49, -0.23ACR50 Response, n (%) Wk 2461(42.7)***69(48.6)***11(7.7)CDAI ≤2.8 Response, n (%) Wk 2412(8.4)**11(7.7)**01– NRI, Non-Responder Imputation; LSM, Least Squares Mean; **p-value difference from PBO <0.001; ***p-value difference from PBO <0.0001; SE, Standard ErrorThe key efficacy outcomes were maintained throughout the 24-week.Overall incidence of TEAEs was 58.0% in OKZ q2w arm; 57.0% in OKZ q4w arm and 43.7% in PBO, TEAEs leading to study treatment discontinuation were reported in 4.9%, 3.5% and 0.7% patients, respectively.At least one TESAE (subcutaneous abscess, pulmonary tuberculosis, staphylococcal sepsis, toxic shock syndrome, cervix carcinoma, obstructive pancreatitis, diabetic vascular disorder) was reported in 8 (5.6%) of OKZ groups, numerically higher than 4(2.8%) in PBO. There was one death due to septic shock in the OKZ q2w arm.Conclusion:Treatment with OKZ over a 24-week period was associated with significant improvements in the signs, symptoms and physical function of RA, with a safety profile consistent with Phase II data for OKZ and with the data for the agents with similar mechanism of action.There were no discernible differences between the two regimens of OKZ in efficacy or safety outcomes.References:[1]Genovese MC et al. Ann Rheum Dis. 2014 Sep; 73:1607; 2. Takeuchi T, et al. Mod Rheumatol. 2016; 26:1Acknowledgments:Investigators and patients of CREDO-1 study.Disclosure of Interests:Evgeny Nasonov Speakers bureau: Lilly, AbbVie, Pfizer, Biocad, R-Pharm, Rumen Stoilov Grant/research support from: R-Pharm, Tamara Tyabut: None declared, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme
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Atrash, Shebli, Evelyn M. Flahavan, Tao Xu, Esprit Ma, Sudeep Karve, Wan-Jen Hong, Gilbert Jirau-Lucca, Michael Nixon, and Sikander Ailawadhi. "Treatment Patterns and Outcomes of Multiple Myeloma (MM) with Chromosome Translocation (11;14) in United States (US) Routine Clinical Practice." Blood 136, Supplement 1 (November 5, 2020): 40–43. http://dx.doi.org/10.1182/blood-2020-134703.
Full textAbstract:
Introduction: MM is an incurable disease with risk categorizations by cytogenetic abnormalities. Prognostic implications of chromosome translocation t(11;14)+ are important to inform development of biomarker-targeted therapies such as the B-cell lymphoma-2 (BCL-2) pathway inhibitors. This study aims to evaluate MM treatment (Tx) patterns and outcomes of t(11;14)+ compared with other cytogenetic cohorts in US routine clinical practice. Methods: A retrospective observational cohort study of the Flatiron Health database, which comprises de-identified electronic health record-derived patient (pt)-level data from over 280 community and academic cancer clinics in the US. Pts aged ≥18 years who received a first-line (1L) induction Tx within ≤60 days of MM diagnosis from 1/1/2011 to 1/31/2020, and were not enrolled in a clinical trial were identified at the start of each Tx line (index date) and followed up (f/u) until 1/31/2020. Only cytogenetic results by fluorescence in situ hybridization (FISH) were used to stratify the cohort into: t(11;14)+; standard risk, excluding t(11;14)+ (SR); and high risk, (HR; del 17p, t(4;14), t(14;16), t(14;20), chromosome 1 abnormalities as a proxy for 1q gain; and t(11;14) where it co-occurs). Descriptive analyses of pt characteristics and Tx were conducted. Kaplan-Meier analyses were used to evaluate median time to next treatment (TTNT) and overall survival (OS) with log-rank test for significance. The cohort was stratified by age ≤70/>70 years (yrs) as a proxy for transplant eligibility. Results: Of 10,703 pts with MM in the database, 5982, 3059 and 1595 pts were eligible for 1L, second-line (2L), and third-line (3L) analysis, of which 76%, 84%, and 86%, respectively, had FISH test results before Tx initiation. 14% of pts with FISH test results were t(11;14)+, ~55% SR and ~35% HR. Included pts were predominately male (55%), ~90% treated in the community setting and ~16% African-American. Pts in the 3L cohort were younger at diagnosis with a median age (interquartile range) of 67 (59 ̶ 74) yrs compared with 69 (61 ̶ 76) yrs in both 1L and 2L. The 1L Tx pattern was consistent across cytogenetic cohorts with bortezomib (V), lenalidomide (R), dexamethasone (d) as the most common Tx (>42%). Together, VRd, Rd, Vd, and cyclophosphamide (Cy) in combination with Vd represented ≥90% of 1L Tx (Figure 1). Across 2L cytogenetic cohorts, the most common Tx regimens (≥25%) were VRd and Rd. The use of regimens containing carfilzomib (K) and daratumumab (D) was emerging in 2L: KRd in 8% of t(11;14)+ and HR and 5% in SR; Kd 5% in all groups; DRd in 4% of t(11;14)+ and 3% in SR and HR (Figure 1). 3L Tx pattern was fragmented with different Tx regimens. Rd was the most common 3L Tx option: 9% in t(11;14)+, 10% in SR and 7% in HR (Figure 1). Across all lines of Tx, t(11;14)+ had similar Tx outcomes to SR, and HR had poorest outcomes (Table 1). Pts TTNT shortened as they advanced to later lines of Tx (Table 1). Although TTNT did not differ by age across lines of Tx, OS was superior in pts <70 yrs across all 3 cytogenetic risk cohorts, especially in 1L where transplant in those ≤70 yrs vs >70 yrs at diagnosis was 44% vs 11% for t(11;14)+, 47% vs 10% for SR and 49% vs 9% for HR. Conclusions: This study identified cytogenetic subgroups across 1L to 3L in a predominately community setting in the US. MM t(11;14)+ pts had similar 1L and 2L Tx patterns to SR and HR. Across all lines of Tx, the outcomes of t(11;14)+ and SR pts were comparable and better than HR pts. TTNT was reduced as pts advanced to later lines of Tx. Pts continuing to 3L Tx were younger at diagnosis, but there was not a clear-cut standard of care. While TTNT did not differ by age across lines of Tx, OS was superior in pts <70 yrs across all 3 cytogenetic risk cohorts. This study sets the benchmark for novel treatment options, such as BCL-2 pathway inhibitors, primarily wherever available biomarker-driven therapy is considered appropriate. Disclosures Atrash: Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; BMS, Jansen oncology, Sanofi: Speakers Bureau; Amgen, GSK, Karyopharm.: Research Funding. Flahavan:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Roche Products Ltd.: Current Employment. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Karve:AbbVie: Current Employment, Current equity holder in publicly-traded company. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Jirau-Lucca:Genentech, Inc.: Current Employment; AbbVie: Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company; Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Nixon:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Ailawadhi:Takeda: Honoraria; Pharmacyclics: Research Funding; Cellectar: Research Funding; BMS: Research Funding; Medimmune: Research Funding; Phosplatin: Research Funding; Amgen: Research Funding; Celgene: Honoraria; Janssen: Research Funding.
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Smolen, J. S., F. Behrens, S. Liu Leage, C. Sapin, I. De La Torre, G. Meszaros, G. Schett, et al. "AB0841 TARGET OUTCOMES IN PsA: SIMULTANEOUS ACHIEVEMENT of ACR50-PASI100 AND BEYOND: INSIGHTS FROM SPIRIT-H2H AT WEEK 24." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1726.2–1727. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2884.
Full textAbstract:
Background:Psoriatic Arthritis (PsA) treatment should aim to achieve robust improvement of arthritis as well as control of extra-articular manifestations like the skin. SPIRIT-H2H evaluated the efficacy of ixekizumab (IXE) and adalimumab (ADA) in patients with active PsA and psoriasis, and naïve to biologic Disease-Modifying Anti-Rheumatic Drugs (bDMARDs). At week 24 (W24), IXE showed superiority to ADA in simultaneous achievement of ACR50 and PASI100 as well as significant improvement of treat-to-target and other extra-articular outcomes.Objectives:To examine and to compare PsA efficacy outcomes in patients beyond achievement of the primary endpoint of the SPIRIT-H2H trial at W24, irrespective of treatment allocation.Methods:All patients recruited had active PsA (defined as tender joint count ≥3/68, swollen joint count ≥3/66 and body surface area [BSA] ≥3%), and inadequate response to conventional synthetic (cs)-DMARDs. Patients were randomised 1:1 to open-label, assessor-blinded IXE or ADA. We conducted post-hoc analysis of SPIRIT-H2H (NCT03151551), categorizing patients into four independent groups based on the achievement of the primary outcome (ACR50 & PASI100), ACR50 only, PASI100 only or none of them after 24 weeks of treatment. Statistical analyses consisted of mixed model for repeated measurement and logistic regression models using non-response imputation.Results:At week 24, patients reaching simultaneously ACR50 and PASI100 had a statistically significant higher response in most treat-to-target endpoints than those meeting ACR50 only (p<0.05). In this latter group, a high response rate was observed in ACR70, MDA, DAPSA remission and PASI90 response (48.9%, 60.6%, 35.1%, 36.2%, respectively). In patients that did not achieve either ACR50 or PASI100, up to 1/3 of the patients did achieve ACR20, DAPSA score ≤14, or no physical impairment.Table.Efficacy Endpoints at W24ACR50 & PASI100ACR50 onlyPASI100 onlyNeither ACR50 nor PASI100n=181n=94n=121n=170ACR20100.0b,c100.053.734.7ACR7064.6a,b,c48.90.00.0MDA75.7a,b,c60.623.112.4VLDA32.6a,b,c13.83.31.8DAPSA LDA or Remission (≤14)92.3a,b,c81.943.028.8DAPSA Remission (≤4)44.8b,c35.16.62.4HAQ-DI score ≤0.575.7b,c64.930.627.4PASI75100.0a,c60.6100.037.1PASI90100.0a,c36.2100.014.7SF-36 PCS change from baseline§12.3±0.53b,c12.3±0.745.4±0.664.0±0.55Data are presented as %;§mean±standard error.ap<0.05 vs. ACR50 only;bp<0.05 vs. PASI100only;cp<0.05 vs. Neither ACR50 nor PASI100.ACR, American College of Rheumatology; DAPSA, Disease Activity in Psoriatic Arthritis; HAQ-DI, Health Assessment Questionnaire Disability Index; LDA, Low Disease Activity; MDA, Minimal Disease Activity; PASI, Psoriasis Area Severity Index; VLDA, Very Low Disease Activity.Nine patients with active PsO and BSA≥3% were assessed as PASI=0 at baseline, a medical inconsistency that was resolved using medical judgement. These patients were considered PASI100 responders if PASI=0 and BSA=0 at post baseline visits.Conclusion:Reflecting the complexity of PsA, different degrees of improvement were observed across all treat-to-target outcomes with greater improvements in patients that met ACR50 response regardless of skin resolution. These findings at week 24 need to be confirmed with a longer duration of treatment.Disclosure of Interests:Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai, Soyi Liu Leage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Christophe Sapin Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Inmaculada De La Torre Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Gabriella Meszaros Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB, Andrew Ostor Consultant of: MSD, Pfizer, Lilly, Abbvie, Novartis, Roche, Gilead and BMS, Speakers bureau: MSD, Pfizer, Lilly, Abbvie, Novartis, Roche, Gilead and BMS, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Filip van den Bosch Consultant of: AbbVie, Celgene Corporation, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene Corporation, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB
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Bagot, Martine, Stéphane Dalle, Lubomir Sokol, Athanasios Tsianakas, Amy Musiek, Pablo Ortiz-Romero, Brian Poligone, et al. "Long-Term Clinical Benefit to Anti-CCR4 Mogamulizumab: Results from the Phase 3 Mavoric Study in Previously Treated Cutaneous T-Cell Lymphoma (CTCL)." Blood 132, Supplement 1 (November 29, 2018): 2901. http://dx.doi.org/10.1182/blood-2018-99-118473.
Full textAbstract:
Abstract Background: CTCL represents a rare group of non-Hodgkin lymphomas with substantial negative impact on patient (pt) quality of life and mortality in advanced-stage disease. Mycosis fungoides (MF), the most common subtype of CTCL, and the rarer leukemic variant Sézary syndrome (SS) are distinct subtypes of CTCL. Mogamulizumab is a first-in-class, defucosylated monoclonal antibody directed against C-C chemokine receptor 4 (CCR4), which is highly expressed on malignant T-cells in CTCL. Primary results from the MAVORIC study (data cut-off December 2016), a phase 3 trial comparing mogamulizumab to FDA-approved vorinostat in adults with relapsed/refractory MF/SS, showed mogamulizumab significantly prolonged median progression-free survival compared with vorinostat (7.7 vs 3.1 months, P<0.0001), with a confirmed overall global response rate (comprised of all disease compartments) of 28% and an expected and generally manageable safety profile. This follow-up analysis assessed the safety and efficacy of mogamulizumab based on treatment exposure in order to characterize pts with MF/SS who were able to achieve long-term clinical benefit with mogamulizumab. Methods: This was an open-label, randomized, international, phase 3 study (NCT01728805). Pts with MF/SS who were treated with ≥1 prior systemic therapy were randomized 1:1 to receive mogamulizumab (1.0 mg/kg, administered once weekly for the first 28-day cycle, then on Days 1 and 15 of subsequent cycles) or oral vorinostat (400 mg daily). In this follow-up analysis (data cut-off September 2017), exposure quartiles were determined, and baseline demographics, confirmed global response rate, and safety were analyzed by exposure group. To detect linear trends across exposure quartiles, frequencies were analyzed using Chi-square test and continuous data were assessed by analysis of variance. Results: A total of 184 pts randomized to mogamulizumab were included in this analysis. Mean time of mogamulizumab exposure was 275 days (d; standard deviation [SD]: 292 d; range: 1-1617). Based on quartile assessment, >351 d was defined as cut-off for long-term exposure. Baseline characteristics across exposure groups are shown in the Table. Significant trends were observed for baseline Eastern Cooperative Oncology Group performance status (ECOG PS; P=0.04), disease type (P=0.03), and blood involvement (defined as ≥B1 per Olsen et al J Clin Oncol 2011; P<0.001), with long-term pts more likely to have an ECOG PS grade of 0, SS, and/or blood involvement. Confirmed global response rates increased with increasing exposure to mogamulizumab in pts with MF and SS (Figure; trend P<0.001 for MF, SS, or MF+SS). Of all randomized pts exposed to mogamulizumab for >351 d, 76% had a confirmed global response (ie, either complete or partial response). The percentage of pts reporting a treatment-emergent adverse event (AE) or serious AE did not vary with increasing exposure to mogamulizumab (<72 d exposure: 26% of pts with TEAEs and 6% with SAEs; 72-170 d: 18% and 3%, respectively; 171-350 d: 23% and 6%, respectively; >351 d: 21% and 4%, respectively). The most common treatment-related AEs reported by pts after >351 d of exposure to mogamulizumab were drug eruption (9/45 [20%]), thrombocytopenia (5/45 [11%]), stomatitis (4/45 [9%]), and anemia (4/45 [9%]). Conclusions: This follow-up analysis of the phase 3 MAVORIC study demonstrated mogamulizumab treatment of pts with MF/SS for approximately 1 year was not associated with an increased safety risk. Significant long-term clinical benefit was observed in pts with blood involvement at baseline, regardless of CCR4 expression status. A higher proportion of pts who had long-term (>351 days) exposure attained confirmed global response versus those who had less exposure. Disclosures Bagot: Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees. Dalle:Kyowa Hakko Kirin Pharmaceutical: Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Tsianakas:Kyowa Kirin: Research Funding. Musiek:Seattle Genetics: Honoraria; Kyowa Kirin: Honoraria; Actelion: Other: Scientific Advisory Committee . Ortiz-Romero:Innate Pharma: Consultancy; Takeda: Consultancy; MEDA: Research Funding; Actelion: Consultancy; 4SC: Consultancy. Poligone:Johnson and Johnson: Research Funding; Kyowa Hakko Kirin: Research Funding; Soligenix: Research Funding; Mallinckrodt: Speakers Bureau; Stemline Therapeutics: Honoraria; Seattle Genetics: Honoraria. Duvic:Clinical Care Options: Consultancy; Soligenix, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huron Consulting Group: Consultancy; Taiwan Liposome Company LTD: Consultancy; Rhizen Pharma: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Oncology, LLC: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; UT MD Anderson Cancer Center: Employment; Dr. Reddy's Laboratories (A.K.A. Promius Pharma): Consultancy; Defined Health: Consultancy; Medivir AB: Membership on an entity's Board of Directors or advisory committees; Medscape: Other: Speaker/Preceptor; Guidepoint Global: Consultancy; Jonathan Wood & Associates: Other: Speaker; Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Evidera, Inc.: Consultancy; Kiniksa Pharmaceuticals: Consultancy; MEDACorp: Consultancy; The Lynx Group: Consultancy; Spatz Foundation: Research Funding; Forty Seven, Inc.: Membership on an entity's Board of Directors or advisory committees; Shape: Research Funding; Aclaris Therapeutics Int'l Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Allos: Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity's Board of Directors or advisory committees; Concert Pharmaceuticals, Inc.: Consultancy; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy; Array Biopharma: Consultancy, Honoraria; Oncoceuticals: Research Funding; Tetralogics: Research Funding. Elmets:NCI: Research Funding; Veterans Administration: Research Funding; California Wine Grape Association: Research Funding; Soligenix: Research Funding; Elorac: Research Funding; Leo Pharma: Other: Data and Safety Monitoring Board. Leoni:Kyowa Kirin: Employment. Dwyer:Kyowa Kirin: Employment. Sun:Kyowa Kirin: Employment. Nikonova:Kyowa Kirin: Employment. Kim:miRagen: Research Funding; Forty Seven Inc: Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Merck: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding.
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Kranendonk, Henry. "Sound Off!: Can We Make High School More Relevant?" Mathematics Teacher 103, no. 6 (February 2010): 392–93. http://dx.doi.org/10.5951/mt.103.6.0392.
Full textAbstract:
In “Standards for High School Mathematics: Why, What, How?” in the December 2008/January 2009 issue of Mathematics Teacher, Eric W. Hart and W. Gary Martin summarized a perplexing problem in the U.S. education system—namely, the challenge of reforming high school mathematics. The article referenced a 2007 conference sponsored by the Center for the Study of Mathematics Curriculum that addressed two important questions concerning mathematics achievement: What should students learn, and when should they learn it? Presenters from Achieve, Inc., the American Statistical Association, the College Board, the Mathematics Association of America (MAA), and NCTM openly discussed and debated the topic questions. The conference provided an excellent format for dialogue about the nuts and bolts of what students should be taught and when these topics should be taught in the K–12 timeline. Several participants acknowledged, however, that additional factors complicate our challenges with high school students.
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Kranendonk, Henry. "Sound Off!: Can We Make High School More Relevant?" Mathematics Teacher 103, no. 6 (February 2010): 392–93. http://dx.doi.org/10.5951/mt.103.6.0392.
Full textAbstract:
In “Standards for High School Mathematics: Why, What, How?” in the December 2008/January 2009 issue of Mathematics Teacher, Eric W. Hart and W. Gary Martin summarized a perplexing problem in the U.S. education system—namely, the challenge of reforming high school mathematics. The article referenced a 2007 conference sponsored by the Center for the Study of Mathematics Curriculum that addressed two important questions concerning mathematics achievement: What should students learn, and when should they learn it? Presenters from Achieve, Inc., the American Statistical Association, the College Board, the Mathematics Association of America (MAA), and NCTM openly discussed and debated the topic questions. The conference provided an excellent format for dialogue about the nuts and bolts of what students should be taught and when these topics should be taught in the K–12 timeline. Several participants acknowledged, however, that additional factors complicate our challenges with high school students.
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Doner, Kevin, Ian W. Flinn, Brian K. Ulrich, Stephen J. Noga, Naveed M. Chowhan, Steven W. Papish, Tallat Mahmood, et al. "Rapid Prospective Identification of Non-Germinal Center B Cell-Like (GCB) Diffuse Large B-Cell Lymphoma (DLBCL) Patients for Targeted Trials: Early Results From PYRAMID, A Phase 2 Randomized Study of R-CHOP ± Bortezomib In Newly Diagnosed Non-GCB DLBCL." Blood 116, no. 21 (November 19, 2010): 1792. http://dx.doi.org/10.1182/blood.v116.21.1792.1792.
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Abstract Abstract 1792 Background: With increasing knowledge of cancer pathogenesis and availability of target-specific novel agents, it is expected that therapy will be increasingly tailored to individual biology. This is particularly true in lymphoma because translational research has characterized the molecular basis of the clinical heterogeneity in major lymphoma types, and many new agents are in development. However, a major challenge for clinical studies of specific lymphoma patient subgroups is the real-time testing of patient material in a way that enables prospective targeted clinical trials. Here we describe early patient selection results from a phase 2 trial of newly diagnosed DLBCL that prospectively identifies and enrolls only patients with the non-GCB subtype for randomization to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with or without the proteasome inhibitor bortezomib (VELCADE®). The non-GCB subtype exhibits inferior outcome compared to the GCB subtype after therapy with either CHOP or R-CHOP. Both preclinical and clinical data suggest that inhibition by bortezomib of the nuclear factor-κB pathway, which is frequently activated in non-GCB tumors, specifically benefits these patients (Dunleavy K et al, Blood 2009). Methods: This multicenter phase 2 study is enrolling patients at academic centers (n=10), major hospitals (n=13), and community practices (n=32), providing insight that may be broadly informative with respect to both patient outcomes and future targeted trial design. Obstacles to non-GCB-specific patient selection in this setting include change in standard treatment practice for DLBCL, as well as the challenges of collecting a tumor sample, running the assay, and reporting the subtype in a timely manner. All clinical centers in this study have agreed to release diagnostic pathology blocks to a College of American Pathologists/Clinical Laboratory Improvement Amendments-certified pathology lab for centralized subtyping. The pathology samples are subject to non-GCB testing via a 3-marker immunohistochemistry panel (CD10, bcl-6, mum-1; Hans CP et al, Blood 2004), and the results are reported directly to the clinical site. Results: To date, 45 patients have provided consent and have been subtyped. The mean turnaround time from receipt of sample to reporting of subtype was 1.2 business days (range 1–2 business days). All pathology blocks have been returned to the clinical sites; the mean time elapsed was 4.6 business days (range 4–6 business days). Rapid return of these samples was cited by clinical centers as an important aspect of the study design. There is no indication that pathology block release and central laboratory subtyping has led to delays in patient treatment. Of the 42 patients with results available to date, 5 samples were inevaluable, primarily due to limited tumor cells in the biopsy. Of the 37 samples successfully subtyped, 22 were GCB (59.5%) and 15 were non-GCB (40.5%); this is generally consistent with the ∼50% prevalence of the non-GCB subtype reported in retrospective studies of DLBCL. Fourteen patients have been randomized to therapy. Conclusions: Updates to turnaround time, patient subtype frequency, and enrollment will be presented. These data indicate that many centers are interested in targeted trials that offer new and potentially tailored therapies for their DLBCL patients. These centers can overcome their reluctance to release diagnostic pathology samples and actively enroll patients to randomized studies of frontline therapy. Overall, these results suggest that with careful trial design and attention to key logistical issues, prospective enrichment of specific patient subtypes is feasible in lymphoma. The PYRAMID trial (Clinicaltrials.gov: NCT00931918) continues to enroll patients. Disclosures: Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Flinn:Millennium Pharmaceuticals, Inc: Research Funding. Noga:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Takeda: 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; Cephalon: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho-Centicor: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Papish:Genentech: Consultancy, Honoraria, Speakers Bureau; Sanofi Aventis: Consultancy; MD Advantage: Consultancy; Genomic Health: Speakers Bureau. Reeves:Celgene: Equity Ownership. Parasuraman:Millennium: Employment, Equity Ownership. Corvez:Millennium: Employment, Equity Ownership. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Leonard:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria.
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Fay, Rebecca, John A. Brozovsky, and Patricia G. Lobingier. "Ruckman, Inc.: Converting from U.S. GAAP to IFRS." Issues in Accounting Education 26, no. 2 (May 1, 2011): 341–60. http://dx.doi.org/10.2308/iace-10020.
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ABSTRACT This case is designed as a comprehensive review of significant differences between accounting principles generally accepted in the United States of America (U.S. GAAP) and International Financial Reporting Standards (IFRS) for specific topics covered during most Intermediate Accounting courses. The task requires you to analyze and evaluate a company's significant accounting policies for compliance with IFRS as you plan and conduct the conversion of a firm's financial statements from U.S. GAAP to IFRS. The skills developed throughout this case are currently in high demand as IFRS is quickly becoming the global norm in accounting standards and many multinational companies based in the U.S. are already affected by these standards. The Securities and Exchange Commission (SEC) has developed a roadmap that may require U.S. companies to begin adopting IFRS in 2015. You will be tested on your knowledge of IFRS on the CPA exam. The case is presented in two phases, allowing you to experience the conversion process from planning to execution.
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Abdelaal, Mahmoud A. Z., Dyala Abdelrahman, Mahir Cengiz, Hakan Yavuzer, Serap Yavuzer, Ivy Bien, Preeti Bhuva, et al. "Actions of L-Glutamine vs. COVID-19 Suggest Additional Benefit in Sickle Cell Disease." Blood 136, Supplement 1 (November 5, 2020): 11–12. http://dx.doi.org/10.1182/blood-2020-135903.
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Background:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection associated with coronavirus disease 2019 (COVID-19) causes a 3- to 9-fold higher age-adjusted mortality in African American and Hispanic populations, the major US racial groups affected by sickle cell disease (SCD). The Centers for Disease Control designates SCD as a condition at increased risk for severe COVID-19. An urgent need for repurposing of available and safe therapeutics has been cited for such high-risk populations until vaccines are widely available. L-glutamine (GLN) ameliorates clinical pathology of SCD related to elements of COVID-19. Multiple systemic complications of COVID-19 are increasingly attributed to oxidative damage, a target which GLN regulates. Prescription-grade L-glutamine (PGLG) (Endari®, Emmaus Medical) decreases oxidative stress by increasing the ratio of reduced nicotinamide adenine dinucleotide (NAD) to total NAD, which may increase availability of reduced glutathione. PGLG also decreases red cell endothelial adhesion in patients with SCD. Of note, additional analysis of the phase 3 trial demonstrated a 63% lower occurrence of acute chest syndrome (ACS) in PGLG-treated SCD patients compared to control, which has important relevance in the pandemic. A recent report of two computational screens of FDA-approved therapeutics, directed to protein and chemistry targets and to gene expression changes induced by SARS-CoV-2, predicts glutathione and GLN are highly likely to confer benefit in COVID-19 (Kim, J Translat Med, 2020). Methods:We therefore reviewed reports of multi-system effects of GLN in experimental respiratory distress animal models and in ICU and COVID-19 patients. We focused on contributors to cytokine storm and acute respiratory distress syndrome (ARDS), the leading causes of mortality in COVID-19 (Huang, Lancet, 2020). We also conducted a clinical trial in hospitalized COVID-19 patients on ESPEN-recommended nutrition +/- GLN. Results:In experimental ARDS, sepsis, and endotoxin-induced lung injury, GLN decreases consolidation, pulmonary edema, and neutrophil infiltration and increases lung compliance, oxygen saturation, heat shock protein activation, and survival by 2.5-fold over saline controls (Perng WC, Clin Exp Pharmacol Physiol, 2010; Singleton, Crit Care Med, 2005). Patients with severe COVID-19 have increased proinflammatory cytokines; interleukin 6 (IL-6) levels predict and contribute to severity of COVID-19 (Yuki, Clin Immunol, 2020). GLN modulates inflammatory responses by suppressing C-reactive protein, IL-6, and TNF-α release; it also reduces IL-6 in murine studies (37% decrease,p< 0.05; Chuang, BMC Pulm Med, 2014), which could benefit COVID-19 patients. Myocardial injury occurs in up to 12% of COVID-19 patients directly with viral entry through ACE-2 receptors, microvascular damage, endothelial shedding, and inflammation-mediated damage, which GLN protects against (Shi, Eur Heart J, 2020; Shi, JAMA Cardiol, 2020; Shao, Pak J Med Sci, 2015). Inflammatory states lead to GLN consumption and negative GLN balance (Santos, Amino Acids, 2019). Deficient plasma GLN (< 420 µmol/L) is a defined risk for higher mortality in ICU and COVID-19 patients (Shen, Cell, 2020). Glutathione deficiency contributes to SARS-CoV-2 oxidative lung damage and severe disease (Polonikov, ACS Infect Dis, 2020). In a recent clinical trial, patients were confirmed to have SARS-CoV-2 by RT-PCR, had positive CT scans, and were admitted from a COVID-19 clinic. Both arms received ESPEN-recommended nutrition for COVID-19 alone or with GLN (10 grams, 3 times/day; see Table). Conclusions:GLN and glutathione deficiency contribute to COVID-19 severity, and GLN has salutary biologic actions on reducing lung pathology, mediators of cytokine storm, and myocardial injury in animal models, SCD, and ICU patients. GLN reduces severity in standard risk COVID-19 patientsafterinfection has occurred. These findings, combined with computational prediction of GLN benefit vs. COVID-19, support the hypothesis that PGLG treatmentprior toSARS-CoV-2 infection mayreducethe development of severe COVID-19 in SCD and perhaps other high-risk populations. The data as a whole provides a strong rationale for a controlled clinical trial of PGLG toreducesevere COVID-19 in high-risk SCD patients and improve outcomes if infection occurs. Disclosures Cengiz: Biruni University Medical Faculty:Current Employment;Istanbul University-Cerrahpasa Medical Faculty:Ended employment in the past 24 months.Yavuzer:Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine, Department of Internal Medicine, Division of Geriatrics:Current Employment.Yavuzer:Biruni University Medical Faculty:Current Employment;Istanbul University-Cerrahpasa Mediacl Faculty:Ended employment in the past 24 months.Tang:Kaiser Permanente:Current Employment.Ward:Emmaus Medical, Inc.:Current Employment.Goodrow:Emmaus Medical, Inc.:Current Employment;Emmaus Life Sciences Shareholder:Current equity holder in publicly-traded company.Ludlum:Emmaus Life Sciences, Inc.:Consultancy, Current equity holder in publicly-traded company.Stark:Emmaus Life Sciences Shareholder:Current equity holder in publicly-traded company;Emmaus Medical, Inc:Current Employment.Perrine:Cetya Inc.:Membership on an entity's Board of Directors or advisory committees;Phoenicia Bioscience:Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees;Phoenicia Therapeutics:Membership on an entity's Board of Directors or advisory committees, Patents & Royalties;Boston University School of Medicine:Current Employment, Patents & Royalties;Viracta Therapeutics:Patents & Royalties.
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Tafe, Laura J., Yelena Y. Janjigian, Michael Zaidinski, Cyrus V. Hedvat, Meera R. Hameed, Laura H. Tang, James B. Hicks, Manish A. Shah, and Violetta Barbashina. "Human Epidermal Growth Factor Receptor 2 Testing in Gastroesophageal Cancer: Correlation Between Immunohistochemistry and Fluorescence In Situ Hybridization." Archives of Pathology & Laboratory Medicine 135, no. 11 (November 1, 2011): 1460–65. http://dx.doi.org/10.5858/arpa.2010-0541-oa.
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Context.—Patients with advanced gastroesophageal cancer have poor survival with current therapy. Human epidermal growth factor receptor 2 (HER2) represents a promising therapeutic target, but the optimal HER2 testing strategy is not yet defined. Objectives.—To evaluate the concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) and to determine if the American Society of Clinical Oncology/College of American Pathologists HER2 scoring system is applicable to gastroesophageal carcinomas. Design.—Formalin-fixed paraffin-embedded tumor samples from patients with advanced stage gastroesophageal cancer were tested by IHC and FISH and scored according to the American Society of Clinical Oncology/College of American Pathologists criteria for breast cancer. Concordance between IHC and FISH was evaluated. A subset of cases was subjected to array comparative genomic hybridization to verify the positive and negative HER2 results. Results.—A total of 135 cases with paired IHC and FISH results were evaluated. The majority of samples (84%) were biopsies. HER2 amplification was detected in 20 tumors (15%). Using the American Society of Clinical Oncology/College of American Pathologists scoring system, IHC-FISH concordance was 97% for IHC 0, 93% for IHC 1+, and 100% for IHC 3+. Human epidermal growth factor receptor 2 positivity was strongly associated with tumor grade (moderately differentiated > poorly differentiated, P < .001) and histologic subtype (intestinal > diffuse, P = .007). Array comparative genomic hybridization analysis was successful in 31 tumors (14 FISH+ and 17 FISH−). Fluorescence in situ hybridization and array comparative genomic hybridization results were highly concordant in both HER2-positive and HER2-negative groups (93% and 100% concordance, respectively). Conclusions.—Human epidermal growth factor receptor 2 testing in gastroesophageal cancer can be performed using standard breast cancer procedures and the American Society of Clinical Oncology/College of American Pathologists scoring criteria. Although IHC 0 and IHC 3+ provide clear stratification, reliable separation of IHC 1+ and IHC 2+ may be difficult, especially in biopsy samples. The latter 2 groups are best referred to FISH for definitive classification.
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Satturwar, Swati, Renuka Malenie, Ann Sutton, Ding Dai, and F. Zahra Aly. "Validation of immunohistochemical tests performed on cytology cell block material: Practical application of the College of American Pathologists’ guidelines." CytoJournal 16 (March 15, 2019): 6. http://dx.doi.org/10.4103/cytojournal.cytojournal_29_18.
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The advent of fiberoptic endoscopy with biopsy has revolutionized procurement of specimens from deep sites. This has translated into more cytologic specimens whereby the material is limited and best handled by cytology laboratory staff. While the diagnosis of the pathologic process is of utmost importance, there is increasing expectation that the diagnosis be specific and accurate as not to require additional biopsy for initiation of treatment. This expectation has driven demand in immunohistochemical (IHC) and molecular studies conducted specifically on material processed as cytology specimens. The Clinical Laboratory Improvement Amendments of 1988 requires laboratories in the United States of America to verify the performance of patient tests. Due to varying laboratory practices with respect to validation of IHC assays, the College of American Pathologists introduced guidelines for analytic validation of IHC tests. These guidelines address how to perform validation by recommending the number of cases in the validation set, comparator concordance, and when to revalidate. The main thrust of the guidelines is based on formalin-fixed paraffin-embedded tissue with only one expert consensus opinion referring to validation of IHC tests on cytology specimens which delegates to the medical director, the determination of number of positive and negative cases to be tested. This article will outline how an academic center approaches validation of IHC studies performed on cytology cell block specimens using the College of American Pathologists guidelines. A stepwise approach from selection of antibodies to validate followed by building the validation panel and evaluating the stain results for concordance against the gold standard of histology tissue specimen will be described. A rationale for dealing with discordant results and future innovations will conclude the report.
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Novotny, Sandra K., and Thearin R. Wendel. "A COMPARISON OF REGULATIONS RELATED TO THE OIL SPCC PROGRAM." International Oil Spill Conference Proceedings 1989, no. 1 (February 1, 1989): 23–26. http://dx.doi.org/10.7901/2169-3358-1989-1-23.
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ABSTRACT Several federal agencies regulate selected aspects of the production, refining, transportation, and storage of petroleum and petroleum products. Based on analyses of such programs, the U.S. Environmental Protection Agency (EPA) may propose modifications to the Oil Spill Prevention, Control, and Countermeasures (SPCC) program. These proposed changes would be likely to result in improved consistency with other government and industry standards. Regulatory changes may occur in two extensive and significant areas: adoption of specific and widely recognized industry and regulatory tank standards, and mandatory contingency planning at all facilities covered by the SPCC regulations. Relevant industrial, trade association, and technical standards generated by the American Petroleum Institute, the Underwriters Laboratories, Inc., the National Fire Protection Association, the American National Standards Institute, and the National Association of Corrosion Engineers have been reviewed for applicability to the SPCC regulations. Areas of concern include materials specifications, welding requirements, pressure testing prior to service, overpressure and vacuum relief requirements, design specifications, hydrostatic testing requirements, and siting specifications.