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Smith, Ian. "Double Dare Structural Engineering." Structural Engineering International 12, no. 4 (November 2002): 225. http://dx.doi.org/10.2749/101686602777965090.
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Timek, Tomasz A. "Dare to double spare?" Journal of Thoracic and Cardiovascular Surgery 153, no. 5 (May 2017): 1031–32. http://dx.doi.org/10.1016/j.jtcvs.2017.02.021.
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Batson, John. "Double Dog Dare You." JEMS: Journal of Emergency Medical Services 31, no. 2 (February 2006): 18. http://dx.doi.org/10.1016/s0197-2510(06)70314-x.
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McCalmont, Timothy H. "I double dare me." Journal of Cutaneous Pathology 39, no. 1 (December 27, 2011): 5–7. http://dx.doi.org/10.1111/j.1600-0560.2011.01846.x.
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Morrison, Hope. "Double Dog Dare (review)." Bulletin of the Center for Children's Books 65, no. 9 (2012): 456. http://dx.doi.org/10.1353/bcc.2012.0370.
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Enter, Dorien, Philip Spinhoven, and Karin Roelofs. "Dare to Approach." Clinical Psychological Science 4, no. 6 (July 7, 2016): 1073–79. http://dx.doi.org/10.1177/2167702616631499.
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Persistent fear and avoidance in patients with social anxiety disorder (SAD) has been associated with reduced testosterone levels. Because threat avoidance is a major maintaining factor in SAD, and because testosterone administration promotes social approach, we tested whether testosterone administration can directly facilitate threat approach behavior in SAD. In a double-blind, placebo-controlled study, 17 female participants with SAD received a single dose of testosterone before performing a well-established social Approach-Avoidance Task. This objective implicit measure of social motivational action tendencies requires participants to approach or avoid visually presented emotional faces. After testosterone administration, the patients showed increased approach tendencies to angry facial expressions. These results suggest that testosterone can counteract persistent automatic social avoidance tendencies in SAD. This finding advances our understanding of steroid involvement in the regulation of social motivational action in general and in SAD in particular, and may have important clinical implications, promoting testosterone’s candidacy for pharmacological treatment-enhancement studies.
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Dalessandro, Emanuele, Alice Zocchi, Anna Lisa Varri, Alessio Mucciarelli, Michele Bellazzini, Francesco R. Ferraro, Barbara Lanzoni, Emilio Lapenna, and Livia Origlia. "Three candidate double clusters in the LMC: truth or dare?" Monthly Notices of the Royal Astronomical Society 474, no. 2 (November 8, 2017): 2277–88. http://dx.doi.org/10.1093/mnras/stx2892.
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Hladky, Kathleen. "I Double-Dog Dare you in Jesus’ Name! Claiming Christian Wealth and the American Prosperity Gospel." Religion Compass 6, no. 1 (January 2012): 82–96. http://dx.doi.org/10.1111/j.1749-8171.2011.00325.x.
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Strauss, Julia C. "Of Silk Roads and Global Transformations: China's Rise and its Impact on the Developing World." China Quarterly 239 (September 2019): 804–12. http://dx.doi.org/10.1017/s030574101900105x.
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On a random Tuesday in May 2019, I found myself in Shanghai's Pudong International Airport, waiting in a fortunately short and quickly moving immigration line prior to a return flight home. Just to the right was an immigration desk with what appeared to be a new sign: a “Belt-and-Road” channel (Yidai yilu tongdao). There was no one behind the BRI desk. I was intrigued by this, but of course did not dare to take a photograph of the sign in a restricted zone. Twenty minutes later I attempted to log on from the airline lounge, and ended with failure. The relevant two-step process now involved a passport scan, the receipt of a registration number that required inputting an (overseas) mobile number and receiving SMS verification with further password. The juxtaposition of the fast-track but empty BRI immigration desk and the clunky double verification procedure to get online at all seemed to encapsulate much China's current position in the world.
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Salvador González, José María. ""Flos campi et lilium convallium". Third Interpretation of the Lily in the Iconography of The Annunciation in Italian Trecento Art from Patristic and Theological Sources." Eikon / Imago 3, no. 1 (June 10, 2014): 75–96. http://dx.doi.org/10.5209/eiko.73389.
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This paper (which complements two previous works of our authorship) proposes to interpret the bouquet of lilies in medieval images of The Annunciation in two essentially intertwined dogmatic meanings, related to Christology and Mariology. Contradicting conventional “explanations” of such flower in this Marian scene, we found our proposal in many and consistent testimony of some prestigious Church Fathers and medieval theologians, glossing the biblical sentence Ego sum flos campi et lilium convallium. Such lyrical expression is seen by those authors as a clear metaphor that identifies Christ, the incarnate Son of God, and that, as such, also refers to Mary, in whose virginal womb the Son of God's incarnation is produced. Thus, based on the solid patristic and theological tradition on this biblical sentence, we dare to interpret the bouquet of lilies in paintings of the Annunciation (illustrated here by nine paintings of the Italian Trecento) as a double metaphor, which means both the supernatural human incarnation of God the Son and the virginal divine motherhood of Mary.
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Kosiborod, Mikhail N., Russell Esterline, Remo H. M. Furtado, Jan Oscarsson, Samvel B. Gasparyan, Gary G. Koch, Felipe Martinez, et al. "Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial." Lancet Diabetes & Endocrinology 9, no. 9 (September 2021): 586–94. http://dx.doi.org/10.1016/s2213-8587(21)00180-7.
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Arunakumari, P. S. "Does HRT double the risk of dementia? NHS Centre for Reviews and Dissemination. Dare Abstract Report 29.5.2003. National Electronic Library of Medicine www.nelm.nhs.uk." Journal of Family Planning and Reproductive Health Care 29, no. 4 (October 1, 2003): 251. http://dx.doi.org/10.1783/147118903101197999.
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Brunström, Mattias, and Bo Carlberg. "Benefits and harms of lower blood pressure treatment targets: systematic review and meta-analysis of randomised placebo-controlled trials." BMJ Open 9, no. 9 (September 2019): e026686. http://dx.doi.org/10.1136/bmjopen-2018-026686.
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ObjectivesTo assess the effect of antihypertensive treatment in the 130–140 mm Hg systolic blood pressure range.DesignSystematic review and meta-analysis.Information sourcesPubMed, CDSR and DARE were searched for the systematic reviews, which were manually browsed for clinical trials. PubMed and Cochrane Central Register of Controlled Trials were searched for trials directly in February 2018.Eligibility criteriaRandomised double-blind trials with ≥1000 patient-years of follow-up, comparing any antihypertensive agent against placebo.Data extraction and risk of biasTwo reviewers extracted study-level data, and assessed risk of bias using Cochrane Collaborations risk of bias assessment tool, independently.Main outcomes and measuresPrimary outcomes were all-cause mortality, major cardiovascular events and discontinuation due to adverse events. Secondary outcomes were cardiovascular mortality, myocardial infarction, stroke, heart failure, hypotension-related adverse events and renal impairment.ResultsEighteen trials, including 92 567 participants (34% women, mean age 63 years), fulfilled the inclusion criteria. Primary preventive antihypertensive treatment was associated with a neutral effect on all-cause mortality (relative risk 1.00, 95% CI 0.95 to 1.06) and major cardiovascular events (1.01, 0.96 to 1.06), but an increased risk of discontinuation due to adverse events (1.23, 1.03 to 1.47). None of the secondary efficacy outcomes were significantly reduced, but the risk of hypotension-related adverse events increased with treatment (1.71, 1.32 to 2.22). In coronary artery disease secondary prevention, antihypertensive treatment was associated with reduced risk of all-cause mortality (0.91, 0.83 to 0.99) and major cardiovascular events (0.85, 0.77 to 0.94), but doubled the risk of adverse events leading to discontinuation (2.05, 1.62 to 2.61).ConclusionPrimary preventive blood pressure lowering in the 130–140 mm Hg systolic blood pressure range adds no cardiovascular benefit, but increases the risk of adverse events. In the secondary prevention, benefits should be weighed against harms.PROSPERO registration numberCRD42018088642.
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Pridgen, W., C. Duffy, J. F. Gendreau, and R. M. Gendreau. "POS0017 IMC-1, A FIXED DOSE COMBINATION OF FAMCICLOVIR AND CELECOXIB, IMPROVES COMMON SYMPTOMS ASSOCIATED WITH FIBROMYALGIA IN ADDITION TO PAIN: POST HOC ANALYSIS OF A PHASE 2A TRIAL." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 210.1–210. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1424.
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Background:Fibromyalgia is a chronic disease characterized by widespread pain and severe fatigue that may be triggered by reactivation of latent herpes simplex virus type 1 (HSV-1). In a Phase 2a proof of concept trial, IMC-1 (a fixed dose combination of famciclovir and celecoxib) demonstrated greater tolerability and statistically significant reduction in pain compared with placebo, as measured by change from baseline to week 16 in 24-hour recall pain intensity on an 11-point Numerical Rating Scale (NRS) and 7-day recall pain intensity on the 11-point pain item on the Revised Fibromyalgia Impact Questionnaire (FIQ-R).Objectives:In this post hoc analysis, we evaluated the effects of IMC-1 compared with placebo on other fibromyalgia symptoms, including lack of energy, stiffness, problems with sleep, problems with memory, depression, and anxiety.Methods:In the double-blind, multi-center, placebo-controlled trial, male or female patients 18–70 years of age who met diagnostic criteria for fibromyalgia and had at baseline a 24-hour recall average pain intensity score between 4 and 9 on the NRS were randomized 1:1 to 16 weeks of treatment with IMC-1 or placebo. Mean changes from baseline to week 16 in FIQ-R symptom scores were analyzed using a Mixed-Effect Model Repeated Measure (MMRM) model with treatment as the main effect, and investigative site and baseline FIQ-R symptom scores as covariates.Results:A total of 143 patients were enrolled and randomized to treatment with IMC-1 (n=69) or placebo (n=74). Baseline demographic and clinical characteristics were comparable between treatment groups; the majority of patients were Caucasian (95.8%) and female (93.7%) with a mean age of ~49 years. Compared with placebo, treatment with IMC-1 resulted in statistically significant improvements in the FIQ-R symptom scores of stiffness (least squares mean change from baseline -0.96 vs. -1.92, P=0.03), sleep quality (-0.76 vs. -1.76, P=0.039), depression (-0.44 vs. -1.33, P=0.016), and anxiety (-0.30 vs. -1.69, P<0.001), but not in energy level (-0.67 vs. -1.29, P=0.115) or memory problems (-0.71 vs. -1.24, P=0.165).Conclusion:In addition to alleviation of chronic pain, treatment with IMC-1 appears to be effective in improving many of the other symptoms often associated with fibromyalgia. Further clinical trials are warranted.References:[1]Pridgen WL, Duffy C, Gendreau JF, Gendreau RM. A famciclovir + celecoxib combination treatment is safe and efficacious in the treatment of fibromyalgia. J Pain Res. 2017;10:451-460.Disclosure of Interests:William Pridgen Consultant of: Virios Therapeutics, Carol Duffy Consultant of: Virios Therapeutics, Grant/research support from: The University of Alabama, Department of Biological Sciences has received financial research support from Innovative Med Concepts (now Virios Therapeutics) in the form of two Sponsored Research Agreements., Judy F. Gendreau Consultant of: Tonix, Dare Bioscience, Virios Therapeutics, R. Michael Gendreau Consultant of: Tonix, Teva, Swing Therapeutics, Dare Bioscience, Employee of: Virios Therapeutics.
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Yu Dong, Yu Dong, Guanglong Wang Guanglong Wang, Haiqiao Ni Haiqiao Ni, Kangming Pei Kangming Pei, Zhongtao Qiao Zhongtao Qiao, Jianhui Chen Jianhui Chen, Fengqi Gao Fengqi Gao, Baochen Li Baochen Li, and and Zhichuan Niu and Zhichuan Niu. "Short-wave infrared detector with double barrier structure and low dark current density." Chinese Optics Letters 14, no. 2 (2016): 022501–22505. http://dx.doi.org/10.3788/col201614.022501.
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Hai-tao ZHOU, 周海涛, 李瑞峰 Rui-feng LI, 戴玉鹏 Yu-peng DAI, 郭瑞翔 Rui-xiang GUO, 王丹 Dan WANG, and 杨保东 Bao-dong YANG. "基于内腔单-双暗态转换的全光开关." Acta Sinica Quantum Optica 26, no. 3 (2020): 271. http://dx.doi.org/10.3788/jqo20202603.0401.
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Monaco, Mauro Lo, and Sergio Vinciguerra. "God Save the Double!" Dance Research 24, no. 1 (April 2006): 66–69. http://dx.doi.org/10.3366/dar.2006.0005.
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Lo Monaco, Mauro, Sergio Vinciguerra, and Diana Cruickshank. "God Save the Double!" Dance Research 24, no. 1 (2006): 66–69. http://dx.doi.org/10.1353/dar.2006.0005.
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Iida, Shinsuke, Takayuki Ishikawa, Chang Ki Min, Kihyun Kim, Su Peng Yeh, Saad Z. Usmani, Maria-Victoria Mateos, et al. "Subcutaneous daratumumab in Asian patients with heavily pretreated multiple myeloma: subgroup analyses of the noninferiority, phase 3 COLUMBA study." Annals of Hematology 100, no. 4 (February 18, 2021): 1065–77. http://dx.doi.org/10.1007/s00277-021-04405-2.
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AbstractThe phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (Ctrough). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of Ctrough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the Ctrough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03–185.00%) and 148.02% (90% CI, 113.32–193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105
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Semochkin, S. V. "Treatment of double-refractory multiple myeloma." Oncohematology 16, no. 3 (September 10, 2021): 58–73. http://dx.doi.org/10.17650/1818-8346-2021-16-3-58-73.
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In most publications on relapsed and refractory multiple myeloma, the term double-refractory refers to the loss of response to lenalidomide and proteasome inhibitors. The prognosis in the case of double-refractory multiple myeloma is poor. Usually, these are severely pretreated patients who have accumulated drug toxicity after 2 or more lines of therapy, with limited reserves of bone marrow hematopoiesis and often decompensated comorbidities. A partial solution to the problem was to use certain new drugs that have demonstrated activity as monotherapy or in combination with dexamethasone in this group of patients. This review is aimed to provide a critical review of recent clinical studies addressing this issue. According to the recent European Hematology Association and European Society for Medical Oncology (EHA-ESMO) 2021 guidelines for the diagnosis and treatment of double-refractory multiple myeloma, triple combinations should be considered, including monoclonal antibodies (elotuzumab (Elo), isatuximab (Isa), daratumumab (Dara)), dexamethasone and pomalidomide (Elo-Pd, Isa-Pd, Dara-Pd) or carfilzomib (Isa-Kd, Dara-Kd). In Russia, as of March 2021, the first two regimens were approved (Elo-Pd, Isa-Pd). Elotuzumab was tested in combination with pomalidomide in the randomized phase II ELOQUENT-3 trial (Elo-Pd vs. Pd; n = 177). Median progression-free survival was 10.3 months on Elo-Pd vs. 4.7 months on Pd (hazard ratio 0.54; 95 % confidence interval 0.34–0.86; р = 0.008). Elo-Pd superiority was observed in all subgroups, including patients with double-refractory MM, high-risk cytogenetic aberrations del17p, t(4;14), t(14;16), and increased serum LDH. The Isa-Pd triplet was approved in the randomized phase III ICARIA-MM study (Isa-Pd vs. Pd; n = 307). The median progression-free survival in this protocol was 11.5 months in the Isa-Pd group vs. 6.5 months in the Pd group (hazard ratio 0.596; 95 % confidence interval 0.44–0.81; р = 0.001). Isa-Pd triplet superiority was demonstrated in all unfavorable prognostic subgroups, including lenalidomide-refractory patients, patients with high-risk cytogenetics, and doublerefractory patients. New triplets with monoclonal antibodies represent an important option for the treatment of doublerefractory multiple myeloma.
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Li, Minghua, Libin Zeng, Yifeng Chen, Lin Zhuang, Xuemeng Wang, and Hui Shen. "Realization of Colored Multicrystalline Silicon Solar Cells with SiO2/SiNx:H Double Layer Antireflection Coatings." International Journal of Photoenergy 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/352473.
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We presented a method to use SiO2/SiNx:H double layer antireflection coatings (DARC) on acid textures to fabricate colored multicrystalline silicon (mc-Si) solar cells. Firstly, we modeled the perceived colors and short-circuit current density (Jsc) as a function of SiNx:H thickness for single layer SiNx:H, and as a function of SiO2thickness for the case of SiO2/SiNx:H (DARC) with fixed SiNx:H (refractive indexn=2.1at 633 nm, and thickness = 80 nm). The simulation results show that it is possible to achieve various colors by adjusting the thickness of SiO2to avoid significant optical losses. Therefore, we carried out the experiments by using electron beam (e-beam) evaporation to deposit a layer of SiO2over the standard SiNx:H for156×156 mm2mc-Si solar cells which were fabricated by a conventional process. Semisphere reflectivity over 300 nm to 1100 nm andI-Vmeasurements were performed for grey yellow, purple, deep blue, and green cells. The efficiency of colored SiO2/SiNx:H DARC cells is comparable to that of standard SiNx:H light blue cells, which shows the potential of colored cells in industrial applications.
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Mateos, Maria-Victoria, Hareth Nahi, Wojciech Legiec, Sebastian Grosicki, Vladimir Vorobyev, Ivan Spicka, Vania TM Hungria, et al. "Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 8005. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.8005.
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8005 Background: In a phase 1b trial, a SC formulation of DARA with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE drug delivery technology, Halozyme, Inc.) had adequate PK, low rates of infusion-related reactions (IRRs) and similar efficacy to DARA IV. This phase 3 study compared the efficacy, PK, and safety of DARA SC vs IV in pts with RRMM. Methods: DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg IV) were given weekly for C1-2 (28-day cycles), every 2 weeks for C3-6, and every 4 weeks thereafter. DARA SC (15 mL) was given over 3-5 mins at alternating left/right abdominal sites. Pts (≥18 years) must have received ≥3 prior lines of therapy (LOT), including a PI and an IMiD, or were double refractory. Co-primary endpoints were ORR (analyzed by Farrington-Manning test, with non-inferiority = 60% retention of ORR) and pre-dose C3D1 DARA Ctrough (non-inferiority = lower bound of 90% CI for the ratio of the geometric means [GM] ≥80%). Results: 522 pts were randomized (n=263 SC; n=259 IV). Median age was 67 yrs. Median baseline body weight was 73 kg. Pts received a median of 4 LOT and 100% had received both PI and IMiD; 17% had high cytogenetic risk at baseline. Median follow-up was 7.5 mos. ORR was 41% for DARA SC and 37% for DARA IV. DARA SC retained at least 89% of the benefit of DARA IV (97.5% confidence). The ratio of GM of Ctrough for DARA SC over DARA IV was 108% (90% CI, 96%-122%). A significantly lower rate of IRRs was observed with DARA SC vs DARA IV (12.7% vs 34.5%; P<0.0001). Median duration of injection was 5 mins for DARA SC and median duration of infusion was 421/255/205 mins for the first/second/subsequent DARA IV infusions. Median PFS was 5.6 mos DARA SC vs 6.1 mos DARA IV (HR, 0.99; 95% CI, 0.78-1.26). Most common TEAEs (≥15%) were anemia, neutropenia, thrombocytopenia, and diarrhea. Primary reasons for treatment discontinuation included progressive disease (43% SC vs 44% IV) and AEs (7% SC vs 8% IV). Conclusions: Efficacy and PK co-primary endpoints were met, demonstrating non-inferiority of DARA SC to IV. DARA SC significantly decreased IRR rate and administration time, with a comparable safety profile to DARA IV. Clinical trial information: NCT03277105.
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Storti, Paola, Rosanna Vescovini, Valentina Marchica, Marina Bolzoni, Federica Costa, Emanuela Vicario, Denise Toscani, et al. "CD14+CD16+ Monocyte Binding to Myeloma Cells Is Required for Daratumumab Dependent Killing in Multiple Myeloma Patients." Blood 132, Supplement 1 (November 29, 2018): 3200. http://dx.doi.org/10.1182/blood-2018-99-112873.
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Abstract Recently, the introduction of anti-CD38 monoclonal antibody, Daratumumab (DARA), in multiple myeloma (MM) therapy has improved the response rate of relapsed MM patients. However only a fraction of the DARA-treated patients respond, thus further studies on DARA mechanisms of action are needed. Because the antibody dependent cellular phagocytosis (ADCP) mediated by monocyte, is one of the mechanisms through DARA exerts its anti-MM activity, an ex-vivo approach was established in order to investigate which mechanisms or patient's immunological characteristics could influence DARA-mediated killing of MM cells. Bone marrow mononuclear cells (BM-MNCs) obtained from 25 MM patients (12 newly diagnosed and 13 relapsed MM) were analyzed at time 0 (T0) by flow cytometry. We checked the % of plasma cells (PCs) (CD138+ cells), % of total monocytes (CD14+ cells) and their two subsets (CD14+CD16- or CD14+CD16+ cells), the ratio between % of CD14+ and % of CD138+ cells (CD14+:CD138+ ratio) and the median fluorescence intensity (MFI) of CD38 and of the immuno-check points CD47 on PCs and CD172a (SIRPα) on monocytes. Subsequently, BM-MNCs were treated with control IgG (10µg/ml), DARA (10µg/ml) and the F(Ab)2 portion of DARA (DARA F(Ab)2) (10µg/ml) for 48 hours and then the % variation of surviving 7AAD- CD138+ cell, the modification of the % of monocyte or subsets analyzed and the % of PCs that are attached to monocyte (identified as CD138+ cells also positive to CD14) were evaluated by flow cytometry. Firstly, we found that DARA significantly exploited its anti-MM activity (median % variation of surviving CD138+ cells: 69.05%, p=0.0007) compared to IgG control while DARA F(Ab)2 did not have any killing effect (median % variation of surviving CD138+ cells: 97.33%) compared to the control. Secondly, we detected that the % of total of monocytes and their subsets (CD14+CD16+ or CD14+CD16-) composition were not modulated by DARA or DARA F(Ab)2 treatment compared to IgG. Indeed, only in presence of DARA, we observed that a double positive population of CD138+CD14+ cell significantly increased compared to IgG control (mean %: 15.76 vs 3.14, p=<0.0001) and to DARA F(Ab)2 condition (mean %:15,76 vs 1,48, p=<0.004). Moreover, we found that monocytes involved in the double positive population CD138+CD14+ were almost completely CD14+CD16+ monocytes. Indeed, we have divided the patient' samples in high responder (HR) and low responder (LR) based on the median % of survival cell after DARA treatment (HR: <69.05% and LR:>69.05% of surviving PCs). Interestingly, in the HR group compared to LR group were significantly increased the % of double positive CD138+CD14+ (median % HR:21.59 vs LR: 7.41, p=0.035), the % of CD138+ cells bonded to CD14+CD16+ (median % HR:13.28 vs LR: 3.93, p=0.048) and the CD14+:CD138+ ratio measured at T0 (median HR:0.63 vs LR: 0.32, p=0.0158). Moreover, in 5 relapsed MM patient, we have correlated the ex-vivo response to DARA with the type of in vivo response after DARA single-agent treatment. In addition in our cohort of patients, we observed that the % of surviving CD138+ cells after DARA treatment negatively correlate with the CD14+:CD138+ ratio at T0 (r:-0.628, p=0.0023), with the % of CD138+CD14+ population (r:-0.602, p=0.0039) and with the % of CD138+CD14+CD16+ population (r:- 0.657, p=0.0238) but did not correlate with the MFI of CD38 expression on PCs and the % of CD14+CD16+ at T0. Finally, to go further inside the mechanism involved in DARA response, we have explored the role of the inhibitory axis CD47-CD172a in the ADCP DARA-induced in 5 ex-vivo samples from our cohort of MM patients. We found that the MFI of CD47 strongly positively correlated with the % of surviving CD138+ cells (r: 0.9897; p=0.010) after DARA treatment; on the other hand, we have not reported any correlation with the MFI of CD172a on monocytes. The results of these analyses are continuously updating increasing the number of samples tested. In conclusion, these data highlight that monocyte binding to PCs, in particular those CD14+CD16+, plays a central role in DARA killing effect independently of % subset composition in the pre-treatment samples, suggesting that there are mechanisms that regulate the effectiveness of the monocyte-based killing effect on malignant PCs, as the immune-suppressive axis CD47-CD172a, giving the rationale design to identify new strategies to increase the efficiency of DARA-based therapeutic regimen. Disclosures Malavasi: Takeda Pharmaceutical Co: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceutica: Membership on an entity's Board of Directors or advisory committees, Research Funding. Aversa:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Giuliani:Takeda Pharmaceutical Co: Research Funding; Celgene Italy: Other: Avisory Board, Research Funding; Janssen Pharmaceutica: Other: Avisory Board, Research Funding.
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Lonial, Sagar, Brendan M. Weiss, Saad Zafar Usmani, Seema Singhal, Ajai Chari, Nizar J. Bahlis, Andrew Belch, et al. "Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius)." Journal of Clinical Oncology 33, no. 18_suppl (June 20, 2015): LBA8512. http://dx.doi.org/10.1200/jco.2015.33.18_suppl.lba8512.
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LBA8512 Background: DARA, a human anti-CD38 IgG1κ mAb, has single agent activity and is well-tolerated in rel/ref MM (Lokhorst HM et al. ASCO 2014). This ongoing phase 2 study (NCT01985126) evaluated DARA monotherapy in the FDA breakthrough therapy designation population: MM patients with ≥ 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or double refractory to a PI and IMiD. Preliminary results are reported. Methods: MMY2002 is a 2-part, open-label, international, multicenter study. In part 1 stage 1, 34 patients were randomized to DARA 8 mg/kg (n = 18) q4w or 16 mg/kg (n = 16) qw x 8 wk, q2w x 16 wk, then q4w in a Simon-2-stage design to determine the most effective dose. Subsequently, 90 additional patients were enrolled in the 16 mg/kg DARA group. The primary endpoint was overall response rate (ORR) by independent review (IRC). Results: Data for the 16 mg/kg DARA group are presented (n = 106). Baseline characteristics: median time since diagnosis, 4.8 y; median prior treatment lines, 5; 75% ISS ≥ 2. Refractory to: last line of therapy, 96%; last PI and IMiD, 95%; pomalidomide, 63%: carfilzomib, 48%; alkylating agents, 78%. Adverse events (AE; ≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), cough (20.8%). Infusion-related reactions (IRR, 42.5%) were mainly grade 1/2 during first infusion (grade 3 4.7%; no grade 4). No patients discontinued study due to IRRs; 5 (4.7%) discontinued treatment due to AEs. None of these AEs were assessed by the investigator to be DARA-related. ORR (IRC assessed) was 29.2%, with 3 sCR, 10 VGPR, and 18 PR with a 7.4 month median duration of response. ORR was consistent across clinically relevant subgroups. Median time to progression was 3.7 months. Median overall survival has not been reached and the estimated 1-year OS rate is 65%. After a median follow up of 9.4 months 14/31 (45.2%) of responders remain on therapy. Conclusions: In a heavily pre-treated MM population (95% refractory to last PI and IMiD), DARA at 16 mg/kg showed meaningful durable single agent activity, with deep responses and a favorable safety profile. Clinical trial information: NCT01985126.
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Richardson, Paul G., William Bensinger, Katja C. Weisel, Kevin Boyd, Karthik Ramasamy, Esther Gonzalez, Linda Favre-Kontula, et al. "Durvalumab (DURVA) plus daratumumab (DARA) in patients (pts) with relapsed and refractory multiple myeloma (RRMM)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS8054. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps8054.
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TPS8054 Background: DARA, a monoclonal antibody (mAb) against CD38, is approved for RRMM. Combination treatment (Tx) with DARA + DURVA, a mAb against programmed death ligand-1 (PD-L1), may enhance host anti-MM immunity and response. DARA and PD-L1 mAbs have each demonstrated clinical activity in combination with pomalidomide (POM) + low-dose dexamethasone (LoDEX) in MM. Thus, the phase 2 MEDI4736-MM-003 trial is evaluating DURVA + DARA in RRMM, and, in an exploratory analysis, the addition of POM + LoDEX to DARA + DURVA either upon progressive disease (PD) with DARA + DURVA or as up-front Tx will be assessed. Methods: ≈ 144 pts with RRMM are being enrolled. Pts with measurable MM who received ≥ 3 prior anti-MM Txs, including a protease inhibitor and an immunomodulatory agent, or are double-refractory to these 2 agents will be included. Exclusion criteria include allogeneic stem cell transplant (SCT), autologous SCT ≤ 12 weeks, and prior DARA or other CD38 antibody therapies. Primary endpoints are overall response rate (ORR) and safety. Secondary endpoints are time to response, duration of response, progression-free survival, and pharmacokinetics. The study includes a 3 + 3 safety run-in phase to confirm the tolerability of the recommended phase 2 doses (RP2Ds) of DURVA and DARA. Dose-limiting toxicities will be evaluated during the first Tx cycle. Safety and efficacy will be assessed by a Simon 2-stage design (Table). POM + LoDEX may be added to DARA + DURVA in pts who received ≥ 2 cycles of DARA + DURVA and had confirmed PD. Based on preliminary safety and efficacy, the 4-drug regimen may be explored as up-front Tx. Tx with either the 2- or 4-drug regimens will continue until PD or unacceptable toxicity. Pts treated with POM will be followed for second primary malignancies every 6 mos until the end of the trial. To date, 6 pts have enrolled in the run-in phase. Clinical trial information: NCT02807454. [Table: see text]
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Li, Minghua, Hui Shen, Lin Zhuang, Daming Chen, and Xinghua Liang. "SiO2Antireflection Coatings Fabricated by Electron-Beam Evaporation for Black Monocrystalline Silicon Solar Cells." International Journal of Photoenergy 2014 (2014): 1–5. http://dx.doi.org/10.1155/2014/670438.
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In this work we prepared double-layer antireflection coatings (DARC) by using the SiO2/SiNx:H heterostructure design. SiO2thin films were deposited by electron-beam evaporation on the conventional solar cell with SiNx:H single-layer antireflection coatings (SARC), while to avoid the coverage of SiO2on the front side busbars, a steel mask was utilized as the shelter. The thickness of the SiNx:H as bottom layer was fixed at 80 nm, and the varied thicknesses of the SiO2as top layer were 105 nm and 122 nm. The results show that the SiO2/SiNx:H DARC have a much lower reflectance and higher external quantum efficiency (EQE) in short wavelengths compared with the SiNx:H SARC. A higher energy conversion efficiency of 17.80% was obtained for solar cells with SiO2(105 nm)/SiNx:H (80 nm) DARC, an absolute conversion efficiency increase of 0.32% compared with the conventional single SiNx:H-coated cells.
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Pesce, Dolores. "A Revised View of the Thirteenth-Century Latin Double Motet." Journal of the American Musicological Society 40, no. 3 (1987): 405–42. http://dx.doi.org/10.2307/831675.
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This paper argues that features of the Continental Latin double motet of the latter half of the thirteenth century which were previously considered "peripheral" are also found in motets linked to the Notre-Dame tradition. Furthermore, the Latin repertory as a whole reveals stylistic diversity, including the use of textures characteristic of French double motets from early through mid-century. This revised view of the repertory as stylistically multi-faceted is supported by a study of manuscript transmission, particularly in the Bamberg and Darmstadt codices.
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Plourde, Julie. "Un genre en construction : féminité et théâtre à la Congrégation Notre-Dame de Montréal." Cahiers d'histoire 32, no. 1 (November 26, 2013): 35–56. http://dx.doi.org/10.7202/1020230ar.
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Le théâtre et la construction du genre féminin, dans la Congrégation Notre-Dame (CND), semblent avoir été intrinsèquement liés. Genre littéraire pouvant s’exercer à l’oral et s’analyser à l’écrit, le théâtre présentait donc un double intérêt que cette institution éducative sut exploiter afin de former des jeunes filles en accord avec les conventions sociales de l’époque. En examinant l’esprit des fondateurs, en situant le théâtre au sein du programme scolaire et en analysant plusieurs productions écrites de jeunes filles, nous explorerons le pourquoi et le comment de l’utilisation de l’art dramatique par la Congrégation de Notre-Dame. Nous tenterons par là de cerner certaines caractéristiques du genre féminin qui sont transmises à travers cette pratique artistique.
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Atack, M. "San-Antonio et son double: l'aventure litteraire de Frederic Dard." French Studies 66, no. 1 (December 26, 2011): 112–13. http://dx.doi.org/10.1093/fs/knr186.
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Overdijk, Marije B., Sandra Verploegen, Bögels Marijn, Marjolein van Egmond, Richard W. J. Groen, Anton C. M. Martens, Jeroen Lammerts van Bueren, Wim Bleeker, and Paul W. H. I. Parren. "Phagocytosis Is A Mechanism of Action for Daratumumab." Blood 120, no. 21 (November 16, 2012): 4054. http://dx.doi.org/10.1182/blood.v120.21.4054.4054.
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Abstract Abstract 4054 Daratumumab (DARA) is a human IgG1 CD38 antibody with broad-spectrum killing activity. DARA induces killing of CD38-expressing tumor cells, including fresh cells from multiple myeloma (MM) patient samples, via diverse mechanisms. These prominently include the Fc-dependent effector mechanisms complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) (de Weers et al. J. Immunol. 2011). In this study we show that DARA is also able to induce tumor cell killing via antibody-dependent cellular phagocytosis (ADCP) as an additional Fc-dependent effector mechanism. In a first set of experiments, we studied ADCP with human macrophages as effector cells. Calcein-AM-labeled Daudi tumor cells, a Burkitt's lymphoma cell line, were mixed with human macrophages in the absence or presence of DARA. Specific DARA-induced phagocytosis was analyzed in flow cytometry by measuring the percentage of calcein-AM+/CD11b+ double-positive (DP) macrophages. Both classical GM-CSF activated and alternative M-CSF activated macrophages mediated DARA-specific ADCP of the Burkitt's lymphoma cells. To further explore the in vivo contribution of ADCP in the mechanism of action (MoA) of DARA, we studied DARA mediated phagocytosis with murine macrophages. In vitro ADCP with M-CSF-stimulated bone marrow-derived murine macrophages showed a dose-dependent DARA-specific effect on the Burkitt's lymphoma cell lines Ramos and Daudi, resulting in up to 24% and 43% DP macrophages and a 25% and 50% tumor cell reduction, respectively. Furthermore, dose-dependent DARA-specific phagocytosis was observed with patient-derived MM cell lines L363 and UM9, which were transduced with CD38 to obtain levels CD38 expression as they are generally observed in primary MM patient samples. With life-cell imaging we found that ADCP of Daudi and Ramos cells occurred very rapid and efficiently. Interestingly, our recordings document that single macrophages could engage multiple target cells and that they were able to engulf up to six tumor cells sequentially in a 30 min period. This suggests that ADCP might be a very potent MoA of DARA in vivo, which we are currently studying in a mouse xenograft model. In conclusion, in addition to CDC and ADCC, we now show that DARA can also induce killing of CD38 expressing tumor cells via phagocytosis. This very fast and potent MoA might contribute to the treatment efficacy of DARA in hematological tumors, especially at sites where high numbers of macrophages reside, such as the bone marrow. Disclosures: Overdijk: Genmab BV: Employment. Verploegen:Genmab BV: Employment. Groen:Genmab BV: Research Funding. Martens:Genmab BV: Research Funding. Lammerts van Bueren:Genmab BV: Employment. Bleeker:Genmab BV: Employment. Parren:Genmab BV: Employment.
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Voorhees, Peter M., Brendan Weiss, Saad Usmani, Huaibao Feng, Clarissa Uhlar, Imran Khan, Tahamtan Ahmadi, and Sagar Lonial. "Management of Infusion-Related Reactions Following Daratumumab Monotherapy in Patients with at Least 3 Lines of Prior Therapy or Double Refractory Multiple Myeloma (MM): 54767414MMY2002 (Sirius)." Blood 126, no. 23 (December 3, 2015): 1829. http://dx.doi.org/10.1182/blood.v126.23.1829.1829.
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Abstract Introduction : Daratumumab (DARA), a human anti-CD38 IgG1κ monoclonal antibody, showed single agent activity in a phase 1/2 study of patients (pts) with relapsed or refractory (r/r) MM (Lokhorst HM. J Clin Oncol. 2014; 32(suppl): 8513). In this study infusion-related reactions (IRRs) were generally mild. The occurrence of serious adverse events (AEs) was rare with DARA monotherapy. Similar efficacy and safety findings were reported in a preliminary analysis of an ongoing phase 2 study (NCT01985126) of DARA monotherapy in MM pts who had received ≥3 prior lines of therapy, including a PI and IMiD, or were double refractory to a PI and IMiD (Lonial S. J Clin Oncol. 2015; 33(suppl): LBA8512). This analysis examined IRR incidence and management in this phase 2 study in r/r MM. Methods : This open-label, 2-part, international, multicenter, phase 2 study was conducted to determine the optimal DARA dose and schedule. Thirty-four pts were randomized in part 1 to DARA 8 mg/kg q4w or DARA 16 mg/kg qw for 8 weeks, then q2w for 16 weeks, and q4w thereafter. An additional 25 pts were subsequently enrolled in part 1 into the 16-mg/kg cohort based on a pre-specified interim analysis. An additional 65 pts were then enrolled in the 16-mg/kg DARA group in part 2. IRRs were broadly defined to include investigator-reported events such as cough, hypersensitivity reactions, and cytokine release syndrome. To manage IRRs, pts received pre-infusion medication: methylprednisolone 100 mg (or equivalent) intravenously for the first 2 infusions and 60 mg thereafter; paracetamol (acetaminophen) 650-1000 mg orally; and diphenhydramine 25-50 mg (or equivalent). Corticosteroid post-infusion medication (20 mg methylprednisone or equivalent) was given on the 2 days following DARA infusions to prevent delayed IRRs. DARA infusion was initiated in 1,000 mL at 50 mL/hr. In the absence of IRRs/hypersensitivity, the rate increased hourly at 50-mL/hr intervals to 200 mL/hr. Second and subsequent infusions (in 500 mL) began at 50 and 100 mL/hr, respectively, and escalated to 200 mL/hr. Upon onset of IRRs, infusions were temporarily interrupted or slowed. Results: Data from the DARA 16 mg/kg (n = 106) and 8 mg/kg (n = 18) treatment groups are presented. All pts received pre-infusion medication as prescribed, consisting of analgesics (100%), antihistamines (100%), and corticosteroids (100%). All pts received post-infusion corticosteroids except 3 pts in the 16 mg/kg group. IRRs occurred in 43% and 44% of pts in the 16 mg/kg and 8 mg/kg groups, respectively. Among pts receiving 16 mg/kg (8 mg/kg), 87% (82%) of IRRs were during the first infusion; 4% (19%) and 9% (0%) of IRRs occurred during the second and all subsequent infusions, respectively. The median (range) time to onset for IRRs was 90 (1-514) minutes after the start of infusion, and the median duration of infusion was 7.0 (2-24), 4.2 (2-9), and 3.4 (1-7) hours during the first, second, and all subsequent infusions, respectively. The most frequently reported IRRs appear in Table 1. Most IRRs were grade 1 or 2. Few pts reported grade 3 IRRs, which included bronchospasm (n = 2 at 16 mg/kg), and hypertension, anemia, and dyspnea (n = 1 each at 16 mg/kg), and chills and cytokine release syndrome (both in 1 pt at 8 mg/kg), and hypertension (n = 1 at 8 mg/kg). Infusion rates were decreased for 10% and 17% of pts in the 16 mg/kg and 8 mg/kg groups, respectively. Grade 4 IRRs were not reported, and no IRRs led to treatment discontinuation. Three pts were unable to finish an infusion due to an IRR but received subsequent DARA infusions; the remaining pts who experienced an IRR continued full-dose therapy with supportive treatment. Cytokine changes (IL-6, TNFα, IFNγ, and IL-1β) from baseline to 4 hours after the first DARA infusion were variable, but did not correlate with clinical response or IRRs. Conclusions : DARA-related IRRs were manageable with temporary slowing or stopping of infusion. No pt discontinued treatment due to an IRR. IRRs were most likely to occur during the first or second infusion, were predominantly of grade 1 or 2 severity, and did not recur at a higher grade with subsequent infusions. These results highlight the favorable safety profile of DARA in r/r MM pts. Table 1. IRRs Reported in >2 Pts 16 mg/kg 8 mg/kg Adverse Event, n (%) Any Grade Any Grade Congestion 13 (12.3) 1 (5.6) Chills 6 (5.7) 5 (27.8) Cough 6 (5.7) 3 (16.7) Throat irritation 7 (6.6) 0 Dyspnea 6 (5.7) 1 (5.6) Vomiting 6 (5.7) 1 (5.6) Nausea 5 (4.7) 0 Bronchospasm 4 (3.8) 0 Disclosures Voorhees: Celgene, GlxoSmithKline, and Oncopeptides: Research Funding; Array Biopharma, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Millennium/Takeda and Novartis: Honoraria. Weiss:Janssen and Onclave: Research Funding; Janssen and Millennium: Consultancy. Usmani:Celgene Corporation: Consultancy, Honoraria; Janssen: Research Funding; Onyx: Consultancy, Honoraria, Research Funding. Feng:Janssen: Employment. Uhlar:Janssen: Employment. Khan:Janssen: Employment. Ahmadi:Janssen: Employment. Lonial:Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.
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Beers, Chris E., and Joseph M. Culp. "Plasticity in foraging behaviour of a lotic minnow (Rhinichthys cataractae) in response to different light intensities." Canadian Journal of Zoology 68, no. 1 (January 1, 1990): 101–5. http://dx.doi.org/10.1139/z90-014.
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Unlike most cyprinids, the longnose dace (Rhinichthys cataractae) forages primarily at night in streams in southern Alberta. This nocturnal strategy may result from intrinsic capabilities, like dark-adapted vision, or extrinsic constraints due to biotic interactions during the day. Our objectives were to determine, in the absence of biotic interactions such as predation and competition, (i) whether this foraging habit maximized the foraging ability of the dace in terms of search time, reaction distance, and attack efficiency; and (ii) if dace foraging behaviour was sufficiently plastic to adjust to changes in light intensity. All measures of foraging ability were superior under twilight conditions. Although search times in starlight were double those in twilight, this increase was much smaller than was predicted using a hemispherical search volume model. The daces' ability to offset small nocturnal search volumes was accomplished by changing their pattern of search behaviour. In particular, use of a benthic rooting behaviour increased, and we hypothesize that this behaviour is associated with location of prey by olfaction. Although the nocturnal foraging strategy of dace does not appear to maximize net energy gain, this strategy may be a response to other constraints, such as high predation risk during diel periods with increased illumination.
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Chari, Ajai, Maria-Victoria Mateos, Niels WCJ van de Donk, Jonathan L. Kaufman, Philippe Moreau, Albert Oriol, Torben Plesner, et al. "Subcutaneous Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: Part 2 Safety and Efficacy Update of the Open-Label, Multicenter, Phase 1b Study (PAVO)." Blood 132, Supplement 1 (November 29, 2018): 1995. http://dx.doi.org/10.1182/blood-2018-99-113590.
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Abstract Introduction: Daratumumab (DARA) is a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumor and immunomodulatory mechanism of action. DARA (16 mg/kg administered intravenously [IV]) is approved in many countries as monotherapy and in combination with standard of care (SOC) treatment regimens for patients with relapsed/refractory (RR) multiple myeloma (MM) and newly diagnosed MM. Three phase 3 studies have now demonstrated that DARA in combination with SOC treatment doubles complete response (CR) rates, triples minimal residual disease-negative rates, and reduces the risk of progression or death by at least 50% vs SOC alone. The median durations of the first, second, and subsequent DARA IV infusions are 7.0, 4.3, and 3.4 hours, respectively. To determine whether the duration of infusion can be shortened without compromising the safety or efficacy of daratumumab, an open-label, multicenter, phase 1b clinical trial (PAVO; NCT02519452) was conducted to evaluate a subcutaneous (SC) formulation of DARA with recombinant human hyaluronidase enzyme PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) in patients with RRMM. Part 1 of the study revealed that a mix-and-deliver SC administration was well tolerated, with low rates of infusion-related reactions (IRRs) and similar efficacy to DARA IV (Usmani et al. ASH 2016; abstract 1149). Here, we present updated safety and efficacy findings from Part 2 of the PAVO study, where a concentrated, pre-mixed SC co-formulation of DARA and rHuPH20 (DARA SC) was evaluated in patients with RRMM. Methods: Eligible RRMM patients had received ≥2 prior lines of therapy, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD). In Part 2 of the study, a concentrated co-formulation of DARA (1,800 mg) and rHuPH20 (30,000 U; in 15 mL) in a single, pre-mixed vial was administered over 3 to 5 minutes by manual SC injection into the abdomen. DARA SC was given QW during Cycles 1-2, Q2W during Cycles 3-6, and Q4W thereafter in 28-day cycles. Pre- and/or post infusion medications included acetaminophen, diphenhydramine, montelukast, and methylprednisolone. Co-primary endpoints were safety and Ctrough of DARA SC at the end of QW dosing. Secondary endpoints included the overall response rate (ORR) and CR rate according to the International Myeloma Working Group response criteria. Results: At the clinical cut-off date of December 13, 2017, 25 patients were enrolled in Part 2 of the study. Patients received a median of 3 (range: 2-9) prior lines of therapy, with 56% double refractory to both PI and IMiD. No treatment discontinuations occurred due to treatment-emergent adverse events (TEAEs). The most common (≥20%) TEAEs included lymphopenia (32%), thrombocytopenia (24%), fatigue, asthenia, back pain, diarrhea, nausea, headache, and viral upper respiratory tract infection (20% each). The incidence (16%) and severity of IRRs (mostly grade 1-2) with DARA SC was low, the majority of which occurred on Cycle 1 Day 1, and no discontinuations due to IRRs were observed. Transient grade 3 hypertension was reported as an IRR in 2 patients. Grade 1 injection-site TEAEs were reported with DARA SC in 3 patients (induration, erythema, injection-site discoloration, and hematoma [n = 1 each]). At 6.5 months of median follow-up, the ORR was 52% (28% very good partial response; 24% partial response). Median progression-free survival (PFS) was not reached among all-treated patients, including among patients who were double refractory. Updated data will be presented at the meeting based on longer follow-up. Conclusions: DARA SC enabled dosing in 3-5 minutes and improves patient convenience. DARA SC was well-tolerated in patients with RRMM with low rates of IRRs and no new safety signals compared with DARA IV. Over 50% of patients responded to treatment and median PFS has not been reached after median follow-up of 6.5 months. These data inform ongoing phase 3 studies of DARA SC in RRMM (including a non-inferiority study of DARA SC vs DARA IV [COLUMBA; NCT03277105]), smoldering multiple myeloma, and AL amyloidosis. Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; The Binding Site: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Kaufman:Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; BMS: Consultancy. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Plesner:Janssen: Consultancy; Celgene: Other: Independent Response Assessment Comittee. Tang:Janssen: Employment. Hellemans:Janssen Research & Development: Employment. Tromp:Janssen Research & Development: Employment. Clemens:Janssen Research & Development, LLC: Employment. Farnsworth:Janssen Research & Development: Employment. San-Miguel:Roche: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy.
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Mansilla Viedma, Pedro. "Sociología de la moda, un punto de vista privilegiadoThe Sociology of Fashion. A privileged point of view." Vínculos de Historia. Revista del Departamento de Historia de la Universidad de Castilla-La Mancha, no. 6 (May 31, 2017): 171. http://dx.doi.org/10.18239/vdh.v0i6.274.
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Como el título sugiere, el artículo pretende reflexionar sobre el punto de vista de la sociología sobre la moda, exagerando irónicamente lo específico de su punto de vista hasta elevarlo a “privilegiado”. Utilizo esa exageración para llamar la atención sobre la doble dimensión teórica de esa mirada. Una primera, fácil de entender, y quizás de aceptar, subraya la lectura sociológica de una moda ya pasada, como puede hacerlo la historia del arte, del traje o de la moda. Otra segunda, atreviéndose a reflexionar, o a invitarnos a reflexionar, sobre su otro punto de vista. Aquel que condicionaría el nacimiento mismo de la moda desde la sociología. La moda a posteriori es analizada, la moda a priori también, y aquí, donde la moda es efecto de una causa sociológica, y no al revés, es donde radicaría el verdadero interés de mi artículo. ¿Son antes los pantalones femeninos, el traje femenino, el smoking femenino –robados psicoanalíticamente al hombre durante el siglo XX– o la emancipación de la mujer? ¿Apareció siempre la minifalda después de la liberaciónsexual femenina o alguna vez, en algún país, fue al revés? ¿El movimiento hippie creó siempre una moda hippie o la imitación de la moda hippie invitó, en su onda expansiva mundial, a un estilo de vida consecuente con ese cambio de ropa? Estamos acostumbrados a que la moda sea un efecto, ¿puede ser una causa? Estamos acostumbrados a que la sociología explique un fenómeno, ¿aceptaríamos que a veces se pueda convertir en su causa?PALABRAS CLAVE: sociología, moda, causa, objeto de arte, contexto.ABSTRACTAs the title suggests, this article aims to reflect on the sociological viewpoint on fashion, ironically exaggerating the specifics of its point of view to elevate it to the point of “privilege”. I use this exaggeration to draw attention to the theoretical double dimension of that viewpoint. A first one, easy to understand and perhaps to accept, highlights the sociological reading of past fashion trends, as may History of Art, Costume or Fashion. A second one would dare to reflect, or to invite us to reflect, on this other point of view, one that would condition the very birth of Fashion from Sociology. Fashion is analyzed both a posteriori and a priori, and here, where Fashion is the effect of a sociological cause, and not the other way round, is where the true interest of my article would lie. Do women’s trousers, women’s tailored suits, women’s tuxedos –psychoanalytically robbed from men during the twentieth century– precede the emancipation of women or is it the other way around? Didthe miniskirt always appear after women’s sexual liberation, or was it the other way around in some countries? Did the hippie movement give rise to the hippie clothes style or did the hippie style, in its worldwide expansion, invite participation in a lifestyle consistent with that change in clothing? We are used to seeing Fashion as an effect. Could it be a cause? We are used to Sociology explaining a phenomenon, would we be willing to accept that it can at times be the cause of it?KEY WORDS: sociology, fashion, cause, art object, context.
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Usmani, Saad Z., Hareth Nahi, Maria-Victoria Mateos, Henk M. Lokhorst, Ajai Chari, Jonathan L. Kaufman, Philippe Moreau, et al. "Open-Label, Multicenter, Dose Escalation Phase 1b Study to Assess the Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (PAVO)." Blood 128, no. 22 (December 2, 2016): 1149. http://dx.doi.org/10.1182/blood.v128.22.1149.1149.
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Abstract Introduction : Daratumumab (DARA), a human CD38 IgG1κ monoclonal antibody, has demonstrated single agent efficacy while being highly tolerable as a monotherapy, and significant efficacy in combination with standard-of-care regimens in pts with multiple myeloma (MM) who have received ≥1 prior lines of therapy (Lokhorst HM. NEJM 2015, 373(13):1207-19; Lonial S. Lancet 2016, 387:1551-60;Palumbo A. NEJM 2016, in press; Dimopoulos MA. NEJM 2016, in press). DARA is currently administered as an intravenous (IV) infusion. Subcutaneous (SC) delivery of DARA is being tested in combination with the recombinant human hyaluronidase enzyme (rHuPH20) to facilitate systemic absorption of DARA after SC infusion into the abdominal wall. PAVO is the first study to assess the safety, pharmacokinetics, and efficacy of SC administration of DARA plus rHuPH20 (DARA-PH20) in pts with relapsed or refractory MM (RRMM). Methods : Pts had RRMM with ≥2 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Part 1 of the 2 part study enrolled sequential cohorts at 1200 mg and 1800 mg DARA dose levels to determine the recommended SC dose for Part 2. DARA-PH20 was administered in 4-week treatment cycles: QW for 8 weeks, Q2W for 16 weeks, and Q4W thereafter. DARA-PH20 was infused in 1200 mg doses in 60 mL over 20 min or 1800 mg in 90 mL over 30 min, via a syringe pump at rotating sites on the abdomen. Pre- and/or post-infusion medications included paracetamol, diphenhydramine, montelukast, and methylprednisolone. In part 2, pts will be randomized 1:1 to receive the recommended phase 2 dose (RP2D) of SC DARA-PH20 or IV DARA (16 mg/kg). The RP2D of DARA-PH20 will be selected based on a cumulative review of the pharmacokinetic and safety data obtained from part 1 and should achieve a maximum serum Ctrough during weekly dosing that is similar to or higher than that observed for the approved 16 mg/kg IV dose. Primary endpoints were Ctrough of DARA up to Cycle 3 Day 1 and safety. Secondary endpoints included overall response rate (ORR). Results : To date, 41 pts were treated in part 1 with SC DARA-PH20 at the 1200 mg (n=8) and 1800 mg (n=33) dose levels. Infusion related reactions (IRRs) were reported in 9/41 pts (22%) and were mostly grade 1/2 in severity including chills, fever, rigors, vomiting, itching, edema of the tongue, non-cardiac chest pain and wheezing. One pt developed grade 3 dyspnea and 1 pt required hospitalization due to fever and chills (both grade 2) after the first infusion. All IRRs developed during or within 6 hours of the first SC infusion and were controlled with antihistamine, corticosteroid, antiemetic, or bronchodilator treatment. No IRRs were reported with subsequent infusions. Overall, the adverse event profile of DARA-PH20 was consistent with that of IV DARA. Grade 3 or higher drug-related adverse events were reported in 5/41 (12%) pts including fatigue (2 pts), influenza, hypertension, dyspnea, and tumor lysis syndrome. SC administration of DARA-PH20 was well tolerated at the abdominal wall injection site with 3/41 (7%) pts reporting grade 1 erythema, induration, or burning sensation. Analysis showed a higher max Ctrough in the 1800 mg cohort in comparison to the max Ctrough achieved following IV DARA (16 mg/kg). In the 1200 mg cohort of 8 pts (median of 5 lines of prior therapy [range 2-10]; prior ASCT, 63%; PI refractory only, 0%; IMiD refractory only, 13%; double refractory to PI and IMiD, 63%) a 25% ORR was observed including 2 partial responses (PR). Median time to response was 14 (range 8-20) weeks. Among 17 response evaluable pts in the 1800 mg cohort with cycle 3 day 1 assessments (median of 4 prior lines of therapy [range 2-7]; prior ASCT, 76%; PI refractory only, 6%; IMiD refractory only, 12%; double refractory to PI and IMiD, 65%) a 41% ORR was observed consisting of 3 very good partial responses and 4 PRs. Median time to response was 4 (range 4-8) weeks. Conclusions : SC DARA-PH20 was well tolerated and achieved serum trough concentrations similar to or greater than IV DARA with a lower rate of IRRs compared to IV DARA over a significantly shorter infusion time. Preliminary data suggest that in this pt population SC DARA-PH20 may enable similar response rates to IV DARA monotherapy. The 1800 mg dose level of DARA-PH20 was selected as the RP2D for part 2 of the study. These early data support further study of SC DARA in clinical trials. Additional data on pts from part 1 will be presented at the meeting. Disclosures Usmani: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Mateos:Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Lokhorst:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Research Funding. Chari:Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding. Kaufman:Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy. Moreau:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hellemans:Janssen: Employment, Equity Ownership. Masterson:Janssen: Employment. Clemens:Janssen: Employment. Ahmadi:Janssen: Employment. Liu:Merck: Equity Ownership; Janssen: Employment; J&J: Equity Ownership. San-Miguel:Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.
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Ananthanarayanan, T. S., W. E. Mayo, and R. G. Rosemeier. "High Resolution Digital X-Ray Rocking Curve Topography." Advances in X-ray Analysis 30 (1986): 527–35. http://dx.doi.org/10.1154/s0376030800021698.
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AbstractThis study presents a unique and novel enhancement of the double crystal diffractometer which allows topographic mapping of X-ray diffraction rocking curve half widths at about 100-150μm spatial resolution. This technique can be very effectively utilized to map micro-lattice strain fields in crystalline materials. The current focus will be on the application of a recently developed digital implementation for the rapid characterization of defect structure and distribution in various semiconductor materials.Digital Automated Rocking Curve (DARC) topography has been successfully applied for characterizing defect structure in materials such as: GaAs, Si, AlGaAs, HgMnTe, HgCdTe, CdTe, Al, Inconnel, Steels, BaF2 PbS, PbSe, etc. The non-intrusive (non- contact & non-destructive) nature of the DARC technique allows its use in studing several phenomena such as corrosion fatigue, recrystallization, grain growth, etc., in situ. DARC topography has been used for isolating regions of non-uniform dislocation density on various materials. It is envisioned that this highly sophisticated, yet simple to operate, system will improve semiconductor-device yield significantly.The high strain sensitivity of the technique results from combination of the highly monochromated and collimated X-ray probe beani, the State of the art linear position-sensitive detector (LPSD) and the high-precision specimen goniometer.
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Njike, Valentine Yanchou, Naomi Hamburg, Mark Kellogg, Amarnath Annapureddy, and Joseph Vita. "Dose and response to cocoa (DARC): A randomized double-blind controlled trial." Clinical Trials and Regulatory Science in Cardiology 23-24 (November 2016): 9–15. http://dx.doi.org/10.1016/j.ctrsc.2016.11.001.
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Matas-Céspedes, Alba, Anna Vidal-Crespo, Vanina Rodriguez, Julio Delgado, Neus Villamor, Gael Roue, Elías Campo, et al. "Daratumumab, a Novel Anti-CD38 Monoclonal Antibody Shows Anti-Tumor Activity in CLL and hampers Leukemia-Microenvironment Interactions." Blood 124, no. 21 (December 6, 2014): 4680. http://dx.doi.org/10.1182/blood.v124.21.4680.4680.
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Abstract Daratumumab (DARA) is a anti-human CD38 antibody with Fc-mediated cell killing activity. DARA induces killing of tumor cells, mainly via complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) (de Weers M. J Immunol 2011), and antibody-dependent cellular phagocytosis (ADCP) by macrophages (mΦ), both murine and human in multiple myeloma (MM) and Burkitt lymphoma cells. DARA is currently being evaluated in phase III clinical trials in patients with MM. We have previously reported that DARA induces cytotoxic activity in vitro via ADCC in primary cells and cell lines from Chronic Lymphoctic Leukemia (CLL), and significantly prolongs overall survival of animals in a systemic CLL mouse model. Here, we present additional data on in vivo mechanism of DARA and its effect on tumor-microenvironment interactions in CLL. We first evaluated whether ADCP contributes to DARA activity both in vitro and in vivo. For in vitro ADCP, mΦ were generated from monocytes of normal PBMCs and stimulated with GM-CSF (10ng/mL, 7 days). CLL cell lines and primary cells were labeled with calcein and incubated for 4h with mΦ at an effector:target ratio of 2:1 in the presence of a fixed mAb concentration of 1 μg/mL, followed by flow cytometric analysis. The amount of remaining CLL target cells (CD19+, CD11b-) was reduced by 3-16%. ADCP defined as percentage of mφ which had phagocytosed, referred to as double positive mΦ (CD11b+, calcein+, CD19-), ranged from 3-10%. To analyze ADCP in vivo, SCID beige mice, devoid of NK cells but with active macrophages, were inoculated intraperitoneally with CLL cells (20×106) and simultaneously treated with a single dose of DARA or isotype control (20mg/kg, n=3-5 per group). Forty-eight hours later, CLL cells were recovered from the intraperitoneal cavity and counted in a flow cytometer (identified as human CD45+/CD19+/CD5+cells). In DARA-treated mice the number of CLL cells recovered was reduced by 42% (n=2, p<0.05) compared to the isotype control group. Remarkably, the decrease in cell number was already detectable 2h after DARA administration. CLL pathogenesis relies on supportive tumor-microenvironment interactions both in the bone marrow (BM) and in the lymph node (LN), and CD38 constitutes a molecular hub integrating proliferative and migratory signals for CLL (Malavasi, F. Blood 2011). We evaluated the effect of DARA on migration and adhesion. In in vitro migrations assays, we have demonstrated that DARA (10-30 μg/mL) inhibited CXCL12/SDF1α-mediated migration up to 70% (n=5). In addition, DARA reduced up to 55% (n=2) of downstream pERK activation, that peaked after 5min of CXCL12/SDF1α stimulation. We analyzed the effect of DARA on primary CLL cell migration from Peripheral Blood (PB) to BM and spleen in vivo, using NOD/SCID/gamma (NSG) null mice (lacking NK cells and effective macrophages). In this system, NSG mice were pretreated (day 0) with DARA, control IgG or anti-CXCR4 as positive control for inhibition of cell homing, prior to injection of fresh primary CLL cells (50×106 cells/per mice) on day 1. PB, BM and spleen cells were isolated on day 2 and CLL cells were identified by staining for human CD45/CD19/CD5 and counted using a flow cytometer. Cell counting showed that CLL cells mainly migrate to the spleen, and that DARA significantly reduced this migration (55% inhibition on average, p<0.05). In addition to migration, CD38 also plays a key role in cell adhesion through interaction with integrins (CD49d/CD29) and with extracellular matrix proteins. We analyzed the effect of DARA on the adhesion of CLL cells to the extracellular matrix vascular-cell adhesion molecule-1 (VCAM-1) mediated by CD49d/CD29. DARA reduced adhesion of CLL cells (n=4), to VCAM-1 by 46±13% (range 27-57) compared to isotype control. By RT-PCR we observed an up-regulation of MMP9 transcripts (average 2 fold, n=2), and DARA abrogated both constitutive MMP9 expression (90% reduction) and VCAM-derived (94% reduction) MMP9 expression. In summary, DARA shows a positive effect on ADCP-mediated anti-tumor activity on CLL cells both in vitro and in vivo. In addition DARA exhibits a strong effect on CLL cell migration and adhesion. Based on these data, we hypothesize that DARA may exert unique and substantial effects on CLL tumor cell growth and contributes to potent therapeutic efficacy in a clinical setting. Disclosures Doshi: Janssen R&D: Employment. Parren:Genmab: Employment, Equity Ownership. Lammerts van Bueren:Genmab : Employment. Pérez-Galán:Genmab: Research Funding.
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Ansar, Iqraa, Karun Neupane, Hamid Ehsan, Muhammad Yasir Anwar, Hassaan Imtiaz, Ali Younas Khan, Anum Javaid, et al. "Dartumumab in Pretreated AL Amyloidosis: A Systematic Review." Blood 136, Supplement 1 (November 5, 2020): 46–47. http://dx.doi.org/10.1182/blood-2020-138530.
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Background: Amyloidosis is characterized by the deposition of misfolded lambda or kappa light chain (AL) proteins in tissue. It commonly affects the heart, which correlates with poor prognosis. Disease-modifying therapies aim to suppress the production of abnormal light chains. Daratumumab (Dara) use is associated with a reduction in light chain protein production. Dara is a human anti-CD38 monoclonal antibody approved for the treatment of newly diagnosed and Relapsed & Refractory Multiple Myeloma. AL amyloidosis plasma cells express CD38, and therefore, Dara is an attractive alternative in this setting. This review aims to assess the efficacy and safety of daratumumab in pre-treated AL amyloidosis patients. Methods: We conducted a comprehensive literature search in PubMed, Embase, Medline using MeSH terms and keywords "AL amyloidosis," "daratumumab", and "darzalex" to incorporate the studies published up to July 2020. We included studies assessing the efficacy and safety of daratumumab alone or in combination with other therapies in pretreated AL amyloidosis. After excluding duplicates, non-relevant, and review articles, we selected four prospective and twelve retrospective studies. RESULTS: In our review, data on 482 patients were included. The ages ranged from 35-88 years. The median number of prior therapies was 3 (ranges:2-6), and the most common therapy was bortezomib in 90% of patients followed by immunomodulators in 55% and stem cell transplant in 35%. A total of 260 (54%) patients received Dara monotherapy, 126 (26%) received Dara plus Dexamethasone (d), and 96 (20%) patients received other Dara containing two or three-drug regimens. The time from the diagnosis to the start of Dara therapy varied from 1 to 137 months. 71 % of patients had cardiac, and 62 % had renal involvement. There was a greater than 30 % reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) in cardiac patients responsive to therapy. 1. Daratumumab monotherapy: Dara monotherapy achieved an overall response rate (ORR) of 76% (191/249), complete response (CR) of 30% (69/224), very good partial response (VGPR) of 41% (79/192) and partial response (PR) of 14% (19/140). The overall survival (OS) ranges from 59-100% at 10-12 months were noted. Table 1. 2. Daratumumab+ Dexamethasone: Dara plus d achieved ORR of 81% (86/106), CR of 51% (53/102), VGPR of 29% (18/62), PR of 15% (15/102), and OS of 87% at 24 months. Table 1. 3. Daratumumab with combination regimens: The use of Dara based combination regimens of Dara+pomalidomide (P)+d (36% of patients), Dara+lenalidomide (R)+d (32%) and Dara+bortezomib (V)+d (18%), reported by Abeykoon et al., showed an ORR of 88% (14/16), CR of 19 % (3/16), VGPR of 63% (10/16), PR of 6 %(1/16), OS of 89 % at 10 months and progression-free survival (PFS) of 83% at 10 months. Godara et al. reported an ORR of 100% (9/9) using a combination of Dara and birtamimab. The combination of D+cyclophosphamide (c)+V+d reported by Palladini et al. achieved an ORR of 96 % (27/28), CR of 36 % (11/28), VGPR of 29 % (8/28) and PR of 14 % (4/28).Table 1. The most reported adverse event was infusion-related reactions; grade 3-4 adverse were less than 10 % and mostly related to the heart (heart failure & atrial fibrillation). The most-reported hematological adverse effects were anemia, thrombocytopenia, neutropenia, infections, and sepsis. The most common non-hematological adverse events were heart failure, bronchitis, pneumonia, fatigue, nausea, and diarrhea. Table 2. Conclusion: Dara therapy is associated with promising efficacy with a response rate of more than 70% when used alone and more than 80% when used in combination. These regimens are well tolerated in advanced cardiac disease patients with a tolerable risk of volume overload and infusion-related complications. Additional multicenter randomized, double-blind clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
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Andriyanto, Teguh. "Sistem Peramalan Harga Emas Antam Menggunakan Double Exponential Smoothing." INTENSIF 1, no. 1 (February 1, 2017): 1. http://dx.doi.org/10.29407/intensif.v1i1.531.
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Gold is one of the long-term investment items. The price of gold at any time may change. For someone who invests in gold, of course, requires information changes in gold prices so he can determine when to buy or sell gold. Without accurate information it will be difficult to determine the value or price of gold a few months or years ahead. In this study built prototype information system forecasting gold price of Antam. Monthly historical data of Antam gold price is downloaded from the official website of Antam in excel format. Further excel files are uploaded and processed to determine the forecast price of gold some period to the fore. Forecasting information system is built using PHP programming language and MySql database. The results of forecasting error testing show the accuracy of forecasting of 87.34%. Dara 78 pricing and forecasting data obtained 60 data value tracking signal is beyond the limits of control.
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Hájek, Roman, Tomas Jelinek, Vladimir Maisnar, Ludek Pour, Ivan Spicka, Jiri Minarik, Evzen Gregora, et al. "Comparative Effectiveness of Daratumumab Monotherapy Versus a Real-World Historical Control from the Czech Republic in Heavily Pretreated and Highly Refractory Multiple Myeloma Patients." Blood 128, no. 22 (December 2, 2016): 3332. http://dx.doi.org/10.1182/blood.v128.22.3332.3332.
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Abstract BACKGROUND: The European Commission has granted conditional approval to daratumumab (DARA) as monotherapy in adult patients (pts) with relapsed or refractory multiple myeloma (MM) whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) and who have demonstrated disease progression on the last therapy. DARA was approved under an accelerated assessment based on single-arm phase 2 studies. Outcomes in these heavily pretreated pts in a real-world (RW) setting can provide evidence on the relative treatment efficacy of DARA versus physician's choice (PC). AIMS: To perform an adjusted comparison of overall survival (OS) and progression-free survival (PFS) for DARA monotherapy versus PC, as observed in a RW historical cohort of heavily pretreated and highly refractory MM pts from the Czech Republic using pt-level data. METHODS: Using RW longitudinal pt chart data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group, pts with ≥2 prior lines of therapy previously exposed to both a PI and an IMiD were identified. Pt-level data from the RMG were pooled from pivotal DARA monotherapy studies (pts treated with DARA 16 mg/kg). Pts in the RMG could contribute information to the analysis for multiple lines of therapy, with baseline defined as the date of initiation of the actual treatment line. For the definition of PFS, missing data for the date of disease progression for pts in the RMG who initiated subsequent therapy were replaced by the conservative proxy of the date of initiation of the next treatment. OS and PFS were analysed using a Kaplan-Meier analysis. To adjust for confounding variables, a multivariate Cox proportional hazards regression was developed that included age, gender, beta-2 microglobulin levels (β2M : <3.5/3.5-5.5/>5.5 g/L), albumin levels (<3.5/≥3.5 g/L), line of therapy (3-13), prior exposure to pomalidomide/carfilzomib, refractory status (none/double/triple/quadruple), andincidence of thrombocytopenia (defined as platelet counts <150.000 per µL) as covariates. Predicted PFS and OS curves for the RMG cohort were derived from the multivariate model. RESULTS: From the RMG database, we identified 971 treatment lines in 463 pts previously exposed to both a PI and an IMID (n=206 in third line, n=256 in fourth line, n=203 in fifth line, n=307 in ≥sixth line). The dates of treatment initiation for the RMG pts ranged from March 2006 to March 2015. The most frequent treatment regimens were lenalidomide (33.4%), chemotherapy (18.1%), bortezomib (13.6%), thalidomide (8.0%), and bortezomib+thalidomide (5.3%). The number of pts treated with carfilzomib (2.5%) and pomalidomide (2.4%) was limited. DARA-treated pts (N=148) differed from the RMG cohort in median age (64 vs 62 years), median prior lines of therapy (5 vs 4), prior exposure to carfilzomib (41.2% vs 0.3%) and pomalidomide (55.4% vs 0.6%), thrombocytopenia incidence (46.9% vs 18.0%), and ≥triple refractory status (64.2% vs 5.3%). Median observed PFS and OS for DARA versus PC were 4.0 and 5.6 months, respectively, for PFS and 20.1 and 11.9 months, respectively, for OS. Older age, male sex, low albumin levels, high β2M levels, thrombocytopenia incidence, and double/triple/quadruple refractory status were all independent, statistically significant risk factors for mortality. Albumin levels, β2M levels, thrombocytopenia incidence, and refractory status were also predictive of PFS. The adjusted hazard ratio (95% confidence interval) for OS and PFS for DARA versus PC was 0.35 (0.22-0.56) and 0.79 (0.56-1.12), respectively. Figure 1 represents the predicted survival curves for the RMG cohort that were derived from the multivariate model, comparing observed PFS/OS versus predicted with DARA treatment. CONCLUSIONS: This adjusted treatment comparison suggests a significant improvement in OS and a numerical improvement in PFS for DARA compared to RW historical control data in heavily pretreated/highly refractory MM pts. The lower PFS benefit estimate for DARA compared to OS may be partly explained by limitations in the availability and comparability of data regarding progressive disease in the RMG cohort compared to clinical trial data. Adjusted comparisons between trial data and historical cohorts can provide useful insights to clinicians and reimbursement decision makers on relative treatment efficacies in the absence of head-to-head comparison studies for DARA monotherapy. Disclosures Hájek: Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Spicka:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gatopoulou:Janssen Health Economics & Market Access EMEA: Employment. Vesela:Janssen Cilag s.r.o., Czech Republic: Employment. Diels:Johnson & Johnson: Employment, Equity Ownership. Besson:Janssen: Employment. Ito:Janssen: Employment, Equity Ownership.
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Spicer, B., B. Morris, H. Ugalde, H. Slavinski, and T. Skulski. "Structure of the Betts Cove Ophiolite Complex beneath the western margin of Notre Dame Bay, Newfoundland." Canadian Journal of Earth Sciences 47, no. 2 (February 2010): 181–98. http://dx.doi.org/10.1139/e09-069.
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Ophiolitic rocks emplaced following closure of the Ordovician Iapetus Ocean outcrop around the western margins of Notre Dame Bay in western Newfoundland. Previous geological and geophysical models have interpreted the Betts Cove Ophiolite Complex (BCO) as a series of imbricate thrust slices. A new three-dimensional (3-D) model indicates that locally the BCO has the form of a northeast-trending doubly plunging syncline that was later segmented by a series of normal and high-angle reverse faults. This segmentation is interpreted in terms of a Carboniferous graben structure that is responsible for the current morphology of the Notre Dame Bay. The 3-D model incorporates new high-resolution aeromagnetic, marine magnetic, and topographic imagery. In addition, newly available structural information is used to both constrain the geometry of the geological contacts in the near surface and to map contacts in the subsurface. Calibration of the computed geophysical models was achieved using newly acquired magnetic susceptibility data. The resulting 3-D model, which is compatible with all aspects of the geological and geophysical data, provides an explanation for the distribution of Ordovician ophiolites around Notre Dame Bay.
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Mateos, Maria-Victoria, Luděk Pour, Enrique M. Ocio, Pieter Sonneveld, Catarina Jansson Blixt, Kajsa Larsson, Linda Palmér, and Paul G. Richardson. "LIGHTHOUSE (OP-108): A phase 3 study of melflufen in combination with dexamethasone (dex) and daratumumab (dara) versus dara in relapsed/refractory multiple myeloma (RRMM) patients (pts)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS8051. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps8051.
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TPS8051 Background: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen + dex showed clinical efficacy and was well tolerated in pts with heavily pretreated RRMM (HORIZON; Richardson et al. J Clin Oncol. 2020 Dec 9 [Epub]). The ongoing phase 1/2 ANCHOR study (OP-104) established the optimal dose for melflufen + dex and dara, showing meaningful clinical activity and manageable safety at both melflufen doses tested in pts with RRMM (Ocio et al. ASH 2020. Oral 417). The aim of this study (OP-108; NCT04649060) is to evaluate the efficacy and safety of melflufen + dex and dara vs dara in pts with RRMM previously treated with an IMiD and a proteasome inhibitor (PI), similar to the indication for dara monotherapy. Methods: Pt enrollment has begun (N = 240 planned). Pts must be ≥ 18 y, double refractory to (or intolerant of) an IMiD and a PI or had ≥ 3 prior lines of therapy (LoTs) including an IMiD and a PI, have measurable disease, and Eastern Cooperative Oncology Group performance status ≤ 2. Pts with primary refractory disease and refractoriness to an anti-CD38 antibody are excluded. Pts will be randomized 1:1 to open-label melflufen + dex and dara (Arm A) or single-agent dara (Arm B) until progressive disease [PD] or unacceptable toxicity, stratified by prior LoT number. Pts in Arm B with PD can opt to receive Arm A triplet therapy. Arm A: melflufen 30 mg intravenously on d 1 of each 28-d cycle; dex 40 mg/wk orally (20 mg if aged ≥ 75 y); dara 1800 mg subcutaneously on d 1, 8, 15, and 22 of cycle 1 and 2, d 1 and 15 of cycles 3-6, and d 1 of cycles 7+. Arm B: dara at the same dosage as Arm A. Primary objective: superiority ( P value from the 2-sided statistical test < 0.05; upper limit of the 2-sided 95% CI for the hazard ratio < 1) of progression-free survival (PFS) in pts treated with triplet therapy vs dara. An estimated sample of 240 pts with 160 expected events (PD or death) and 15% assumed dropout rate would provide 90% power at a 2-sided log rank test at 5% significance level to detect a hazard ratio for death of 0.6. Key secondary endpoints: overall response rate (ORR; ≥ partial response [PR]), duration of response, and safety. Response will be assessed by a blinded independent review committee based on International Myeloma Working Group criteria. Other secondary endpoints: clinical benefit rate (≥ minimal response), time to response, time to progression, time to next treatment, and overall survival. Exploratory endpoints include: minimal residual disease in pts achieving ≥ very good PR, PFS following next line of treatment (PFS-2), pt-reported outcomes, pharmacokinetics, translational biomarkers, response rate in pts with extramedullary disease, and efficacy (including ORR) in Arm B pts who receive Arm A triplet therapy after PD. Clinical trial information: NCT04649060.
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Ningsih, Rita, and Arfatin Nurrahmah. "Minat Berwirausaha Mahasiswa Ditinjau Dari Self Efficacy Dan Adversity Quotient." JPEK (Jurnal Pendidikan Ekonomi dan Kewirausahaan) 4, no. 2 (December 25, 2020): 161–74. http://dx.doi.org/10.29408/jpek.v4i2.2390.
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The purpose of this research is to know the influence between self efficacy and adversity quotient on entrepreneurial interests of students, the effect of self efficacy on student entrepreneurial interests, and the effect of adversity quotient on student entrepreneurial interests. The method used is survey. Samples were obtained using simple random sampling technique as many as 105 students took entrepreneurship courses at one of the PTS in Jakarta. Data analysis is done using the help of the SPSS-16 program. Test requirements the analysis used is the test of normality, linearity test and multicolinearity test. The hypothesis test using a correlational test is followed by a double regression test. Based on the results of the research, the results that: 1) there are influence of self efficacy and adversity quotient jointly towards entrepreneurial interest. Self efficacy and adversity quotient contributions to entrepreneurial interest of 45.7% of the remaining 54.3% are donated by variables other than self efficacy and adversity quotient; 2) there is self efficacy influence on entrepreneurial interest, and 3) there is adversity quotient influence on entrepreneurial interest
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Mateos, Maria-Victoria, Saad Z. Usmani, Sebastian Grosicki, Vladimir I. Vorobyev, Ivan Spicka, Vania T. M. Hungria, Sibirina Korenkova, et al. "Randomized, Open-Label, Non-Inferiority, Phase 3 Study of Subcutaneous (SC) Versus Intravenous (IV) Daratumumab (DARA) Administration in Patients (Pts) with Relapsed or Refractory Multiple Myeloma (RRMM): Body Weight Subgroup Analysis of Columba." Blood 134, Supplement_1 (November 13, 2019): 1906. http://dx.doi.org/10.1182/blood-2019-122501.
Full textAbstract:
Introduction: DARA, a human CD38 monoclonal antibody (mAb), is approved for intravenous (IV; 16 mg/kg) administration as a single agent or in combination with standard-of-care regimens for treatment of multiple myeloma. To reduce patient and provider burden and improve safety, a subcutaneous (SC) co-formulation of DARA (flat dose of 1,800 mg, ~70% bioavailability) with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) was developed. The phase 3, randomized, open-label COLUMBA study (NCT03277105) demonstrated the non-inferiority of DARA SC vs DARA IV in terms of co-primary endpoints (ORR and Ctrough) in pts with RRMM at a median of 7.5 months follow-up. Here, we present a body weight subgroup analysis of COLUMBA, based on data from the primary analysis. Methods: DARA SC (flat dose of 1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg) were given in 28-day cycles: QW Cycles 1-2, Q2W Cycles 3-6, and Q4W thereafter. DARA SC (15 mL) was given by manual push over 3-5 mins at alternating left/right abdominal sites. Eligible pts (≥18 yrs) with RRMM had ≥3 prior lines of therapy, including a PI and an IMiD, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum DARA Ctrough (pre-dose concentration on Cycle 3 Day 1 [C3D1]). A subgroup analysis was performed by body weight (≤65 kg, >65 to 85 kg, and >85 kg). Results: In the intent-to-treat (ITT) population, 522 pts were randomized to receive DARA SC (n = 263) or DARA IV (n = 259). Median baseline body weight was 73 kg. Flat dose DARA SC achieved adequate exposure for all body weight subgroups, as maximum Ctrough (C3D1 predose) exceeded the 236 μg/mL threshold previously established in DARA IV studies as necessary for 99% target saturation (Xu XS, et al. Clin Pharmacol Ther, 2017). Across each subgroup, there was considerable overlap in maximum Ctrough for both treatment groups (Figure); however, mean DARA concentrations were 60% higher for pts ≤65 kg and 12% lower for pts >85 kg treated with DARA SC vs IV. Nevertheless, the range of Ctrough across body weights for DARA SC was within the previously observed range (36 to 1764 µg/mL for C3D1 Ctrough) for the approved DARA IV 16 mg/kg. ORR in the ITT population was 41.1% vs 37.1% for DARA SC vs DARA IV. In the body weight subgroups, ORR was 43.6% vs 38.0%, 37.3% vs 39.0%, and 43.9% vs 32.8% for DARA SC vs IV in the ≤65 kg, >65 to 85 kg, and >85 kg groups, respectively. These data suggest that the slightly lower exposure observed at higher body weights was not clinically relevant. For both treatment groups, the incidence of grade 3/4 TEAEs, grade 5 TEAEs, serious TEAEs, and IRRs was similar across body weight subgroups. An increased incidence of TEAEs of any grade with decreasing body weight for DARA SC (≤65 kg, 94.6%; >65 to 85 kg, 87.3%; >85 kg, 78.5%) was observed; incidence of any grade TEAEs was similar across body weight subgroups for DARA IV (≤65 kg, 89.1%; >65 to 85 kg, 89.5%; >85 kg, 88.5%). At the preferred term level, an decreased incidence of grade 3/4 thrombocytopenia (≤65 kg, 16.1%; >65 to 85 kg, 14.7%; >85 kg, 9.2%) and grade 3/4 neutropenia (≤65 kg, 20.4%; >65 to 85 kg, 9.8%; >85 kg, 7.7%) with increasing body weight was observed for DARA SC. An increased incidence of grade 3/4 hypertension (≤65 kg, 4.3%; >65 to 85 kg, 5.7%; >85 kg, 9.8%) with increasing body weight was observed for DARA IV. However, the incidence of maximum Grade 3 and 4 TEAEs (DARA SC, 43.0%; DARA IV, 44.6%) and the incidence of Grade 5 TEAEs (6.5% for both) were similar between treatment groups in the lowest body weight subgroup. For subjects ≤65 kg, DARA SC had a lower incidence of serious TEAEs (DARA SC, 23.7%; DARA IV, 30.4%). Conclusions: In the primary analysis, efficacy and PK co-primary endpoints were met, demonstrating non-inferiority of DARA SC to DARA IV, with similar safety profiles and significant reduction in IRR rates with DARA SC. In this subgroup analysis, ORR in all body weight subgroups was consistent with ORR in the overall population. DARA SC achieved adequate exposure and was well tolerated across all body weight subgroups. The higher concentration of DARA SC in pts ≤65 kg did not have a clinically relevant effect on safety, suggesting no dose individualization is necessary on the basis of weight. Disclosures Mateos: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Usmani:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. Vorobyev:Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sanofi: Consultancy. Spicka:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Hungria:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Moreau:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kaiser:Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Iida:Abbvie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Gilead: Research Funding; Astellas: Research Funding; Teijin Pharma: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MSD: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Daichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Masterson:Janssen: Employment, Equity Ownership. Lantz:Janssen: Employment, Equity Ownership. O'Rourke:Janssen: Employment, Equity Ownership. Qin:Janssen: Employment, Equity Ownership. Parasrampuria:Janssen: Employment, Equity Ownership. Heuck:Janssen: Employment. Qi:Janssen: Employment. OffLabel Disclosure: This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.
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Steinmetz, H. Tilman, Moushmi Singh, Joseph Milce, Mohamad Haidar, Achim Rieth, and Andrea Lebioda. "Management of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Novel Therapies in Routine Clinical Practice in Germany." Blood 136, Supplement 1 (November 5, 2020): 32. http://dx.doi.org/10.1182/blood-2020-136491.
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Background: To better understand the clinical practice in Germany with respect to the rapidly evolving treatment landscape, we aim to describe the characteristics and treatment patterns of patients (pts) with relapsed/refractory multiple myeloma (RRMM) in Germany. Methods: In a national retrospective medical chart review including consecutive pts treated for RRMM in participating hospitals/centers and practices across Germany between Oct 2017 and Jun 2018, the following data were extracted from Oct 2019 to Feb 2020: pt demographics, disease characteristics, treatment history at MM diagnosis and at initiation of RRMM therapy, and distance to care. Physician's assessment of response to therapy and minimal residual disease (MRD) testing were also collected. Because this analysis was not powered to compare between regimens or lines of therapies, results are purely descriptive. Results: Physicians from 47 participating centers extracted 484 pt charts, that included 214 pts (44%) in 2nd line of therapy (2L), 160 (33%) in 3rd line (3L) and 110 (23%) in 4th line and beyond (4L+) (Figure 1). Half of the participating centers were office-based (52%) and 40% were hospitals. Results are summarized in Table 1 and regimens described by line of therapy in Figure 2: Among the 2L subgroup (N=214), median age was 72 years and the majority (73%) of pts had an ECOG status of 0-1 at 2L initiation. About one-third (31%) of pts had had a transplant. Carfilzomib (CFZ) or daratumumab (Dara)-based regimens were mainly used in 2L pts (40% and 41%, respectively). Among the 87 Dara pts, the triplet regimen Dara, lenalidomide (LEN) and dexamethasone (DRd) was used in more pts (58%) than the triplet with Dara, bortezomib (BTZ) and dexamethasone (DVd, 15%). Among the 85 CFZ pts, nearly half (47%) received the triplet regimen CFZ, LEN and dexamethasone (KRd) and 38% of CFZ pts received the doublet of CFZ and dexamethasone (Kd). Among the remaining 42 pts in 2L, other LEN use was described in 35 pts and BTZ in 7 pts. For 107 pts who completed 2L, median treatment duration was 8 months (9 months for CFZ pts; 8.5 months for Dara pts; 6 months for LEN pts). Where response was available (n=191/214), a complete response (CR) or very good partial response (VGPR) was achieved by 64% of pts, including 73% of Dara pts (n=53/73), 62% of CFZ pts (n=48/78), and 53% of LEN pts (n=18/34). 149 ptssteoprotective drugs at 2L initiation, mainly intravenous zoledronate (ZA, 44%) and subcuteaneous denosumab (Dmab, 42%). In the 3L subgroup (N=160), median age was 72 years. Over half (58%) of pts had an ECOG status of 0-1 at 3L initiation. Most 3L pts received Dara (51%, n=81) or CFZ (35%, n=57), and a further 9% (n=15) of 3L pts received other LEN combinations. In 3L, CFZ was more often used as a doublet (54% Kd vs. 28% KRd); Dara was mainly given in triplet regimens (23% DRd, 17% DVd vs. 12% Dara mono). For 118 pts who had completed 3L at time of data extraction, median treatment duration was 10 months (10 months for both CFZ and Dara pts, 7 months for LEN pts). Where response was available (n=139), CR/VGPR was achieved by 55% of pts in 3L, including 64% of Dara pts (n=46/72) and 41% of CFZ pts (n=20/49). Osteoprotective drugs (51% Dmab, 36% ZA) at 3L initiation were given in 69% (n=111) of pts. In the 4L+ subgroup (N=110), median age was 74 years. A high percentage (64%) of pts had an ECOG status ≥2 at 4L initiation. Over half (52%, n=57) received Dara, mostly as monotherapy (70% Dara; 9% DRd, 2% DVd), followed by CFZ in 26% (n=28) and pomalidomide (POM) in 16% (n=18) of pts in 4L+. For 97 pts who completed 4L at time of data extraction, median treatment duration was 8 months (9 months for both CFZ and Dara pts, 7 months for POM pts). Where response was available (n=106), 39% of pts achieved a CR/VGPR, including 46% of Dara pts (n=25/55) and 36% of CFZ pts (n=10/28). At 4L initiation, 66% (n=72) of pts were receiving osteoprotective drugs (51% Dmab, 40% ZA). Conclusion: This chart review indicates that pts with RRMM who underwent a MM therapy between Oct 2017 and Jun 2018 in routine practice across Germany, mostly received combination regimens with novel agents irrespective of the line of therapy. Lenalidomide is still often combined with novel agents. Patterns of treatment regimens differed by line of therapy and are adapted as disease progresses and ECOG status increases. Disclosures Steinmetz: Amgen; BMS, Celgene, Novartis; Janssen-Cilag; Omnicare, Vifor: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Alexion, Amgen, Bayer, BMS, Boehringer, Celgene, Janssen-Cilag, Novartis, Omnicare, Sanofi, Takeda: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; DGHO, ESMO, DGPM, BNHO, NIONo: Other: Memberships; Alexion, Accord Healthcare, Amgen; Ariad, Bluebird Bio, BMS, Boehringer, Celgene, Hexal-Sandoz, Novartis; Janssen-Cilag; Omnicare, Oncopeptides, Otsuka, Pfizer, Sanofi, Shire, TAD, Takeda, Vifor: Consultancy; Accord Healthcare, Amgen, Celgene, Novartis, Vifor: Research Funding. Singh:Amgen Ltd, UK: Current Employment. Milce:Amgen: Research Funding; Kantar Health, France: Current Employment. Haidar:Kantar Health, France: Current Employment; Amgen: Research Funding. Rieth:Amgen GmbH, Germany: Current Employment; Amgen: Current equity holder in private company. Lebioda:Amgen GmbH, Germany: Current Employment; Amgen: Current equity holder in private company.
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Connolly, Kevin, Aveek Bhattacharya, Katerina Lisenkova, and Peter G. McGregor. "Can a policy‐induced reduction in alcohol consumption improve health outcomes and stimulate the UK economy?: A potential ‘double dividend’." Drug and Alcohol Review 38, no. 5 (July 2019): 554–60. http://dx.doi.org/10.1111/dar.12962.
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Usmani, Saad Z., Maria-Victoria Mateos, Hareth Nahi, Sebastian Grosicki, Vladimir I. Vorobyev, Ivan Spicka, Vania T. M. Hungria, et al. "Randomized, Open-Label, Non-Inferiority, Phase 3 Study of Subcutaneous (SC) Versus Intravenous (IV) Daratumumab (DARA) Administration in Patients with Relapsed or Refractory Multiple Myeloma: Columba Update." Blood 134, Supplement_1 (November 13, 2019): 1865. http://dx.doi.org/10.1182/blood-2019-122765.
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INTRODUCTION: Daratumumab (DARA), a human IgGκ monoclonal antibody targeting CD38, is approved for intravenous (IV; 16 mg/kg) administration as a single agent or in combination with standard-of-care regimens for treatment of multiple myeloma (MM).To improve safety and reduce patient and healthcare provider burden, a subcutaneous (SC) formulation of DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.) was developed. The phase 3, randomized, open-label, non-inferiority COLUMBA study (NCT03277105) evaluated the efficacy, PK, and safety of DARA SC vs DARA IV in patients (pts) with RRMM. The results, showing the study met both co-primary endpoints (overall response rate [ORR] and Ctrough) at a median follow-up of 7.5 months, were previously presented. Here, we present updated data with longer follow-up. METHODS: DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg IV infusion) were given in 28-day cycles: QW Cycles 1-2, Q2W Cycles 3-6, and Q4W thereafter. DARA SC (15 mL) was given by manual push over 3-5 mins at alternating left/right abdominal sites. Eligible pts (≥18 yrs) with RRMM had ≥3 prior lines of therapy (LOT), including a PI and an IMiD, or were double refractory. Co-primary endpoints were overall response rate (ORR; analyzed by Farrington-Manning test, with non-inferiority defined as 60% retention of ORR) and maximum DARA Ctrough (pre-dose concentration on Cycle 3 Day 1; non-inferiority defined as the lower bound of 90% confidence interval [CI] for the ratio of the geometric means [GM] ≥80%). Secondary endpoints included rates of infusion-related reactions (IRRs), progression-free survival (PFS), very good partial response or better (≥VGPR), and complete response or better (≥CR). RESULTS: A total of 522 pts were randomized to receive DARA SC (n = 263) or DARA IV (n = 259). Median age was 67 yrs (20% ≥75 yrs). Median baseline body weight was 73 kg. Pts received a median of 4 LOT and 100% of pts were previously treated with both PI(s) and IMiD(s). 82.2% of pts were refractory to the last line of prior therapy, and 49.4% were refractory to both PI and IMiDs. 26.3% and 17.3% of pts had a high-risk cytogenetic abnormality at baseline in the DARA SC and DARA IV groups, respectively. After a median follow-up of 13.8 months, ORR was improved from 41.1% to 43.7% for DARA SC and 37.1% to 39.4% for DARA IV (Figure). ORR were comparable across all subgroups, including body weight. Rates of deep responses (≥VGPR, ≥CR) were similar between DARA SC and DARA IV, and deeper with longer follow-up (Figure). Median duration of treatment (~5.5 months) was similar for DARA SC and DARA IV. A significantly lower rate of IRRs was observed with DARA SC vs DARA IV. At the time of data cutoff, 118 pts (evenly distributed across both arms) continued treatment on study. CONCLUSIONS: With longer follow-up, safety and efficacy data continue to support that DARA SC and DARA IV have similar safety profiles with a statistically significant reduction in IRR rates. DARA SC has a reduced treatment burden due to a considerably shorter administration duration, and DARA SC pts reported higher treatment satisfaction. Collectively, the data demonstrate a favorable benefit/risk profile for the use of an 1800 mg flat dose of DARA SC. Disclosures Usmani: Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. Mateos:Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee; Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees. Vorobyev:Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy. Spicka:Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hungria:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bladé:Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. Moreau:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Celgene, Janssen: Research Funding; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Iida:Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Research Funding; Sanofi: Research Funding; MSD: Research Funding; Abbvie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Teijin Pharma: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Astellas: Research Funding. Masterson:Janssen: Employment, Equity Ownership. Lantz:Janssen: Employment, Equity Ownership. O'Rourke:Janssen: Employment, Equity Ownership. Heuck:Janssen: Employment. Qin:Janssen: Employment, Equity Ownership. Parasrampuria:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Bahlis:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. OffLabel Disclosure: This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.
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Kumar, Shaji K., Brian G. M. Durie, Zhuo Su, Joris Diels, Brian Hutton, Annette Lam, and Ito Tetsuro. "Adjusted Comparisons Suggest Daratumumab Is Associated with Prolonged Survival Compared with Standard of Care Therapies in Patients with Heavily Pre-Treated and Highly Refractory Multiple Myeloma." Blood 128, no. 22 (December 2, 2016): 4517. http://dx.doi.org/10.1182/blood.v128.22.4517.4517.
Full textAbstract:
Abstract Objective: To fully contextualize the benefit of novel agents such as daratumumab (DARA) monotherapy for the treatment of patients with heavily pre-treated and highly refractory multiple myeloma (MM), it is critical to understand the real-world outcomes of this patient population on current standard of care (SOC) therapies. The objective of this study was to perform adjusted comparisons to determine the comparative effectiveness of DARA monotherapy versus real-world SOC therapies. Methods: Data for patients treated with DARA 16 mg/kg monotherapy were available from clinical trials MMY2002 (n=106) and GEN501 (n=42), while patients treated with SOC therapies were derived from the International Myeloma Foundation (IMF) chart review of patients with MM who had ≥3 prior lines of therapy and were double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) (n=543) (Kumar et al., ASH 2016; submitted). The pooled DARA studies demonstrated a median overall survival (OS) of 20.1 months versus 13.0 months for SOC based on the IMF cohort (Usmani et al., Blood 2016; Kumar et al., ASH 2016; submitted). The relative treatment effect of DARA versus SOC was estimated using two adjusted comparison methodologies, propensity score matching (PSM) and multivariate Cox regression analyses. Both methodologies utilized individual patient data to compare OS. Modeled covariates for the PSM were age, gender, prior lines of therapy, albumin, and refractory status to bortezomib (BOR), carfilzomib (CAR), lenalidomide (LEN), and pomalidomide (POM). PSM was performed using caliper matching with a caliper width 25% of the standard deviation of the logit-transformed propensity score, using sampling without replacement. For the regression analysis, the covariates included in the multivariate proportional hazards regression model were age, gender, prior lines of therapy, albumin, beta-2 microglobulin, prior exposure to POM and CAR, and PI/IMiD refractory status. Clustering of observations at the treatment-line level within patients was controlled for using the robust sandwich estimate for the covariance matrix, making confidence intervals (CIs) more conservative. For both PSM and regression, statistical significance testing was performed using a two-tailed p-value of <0.05, and all comparisons between treatment groups were reported with hazard ratios (HRs) and 95% CIs. Results: Prior to PSM, imbalances between the DARA and SOC groups were significant for prior lines of therapy and proportions of patients refractory to POM, CAR, BOR, and LEN. After PSM, the DARA and SOC groups were well balanced for all covariates included in propensity score calculations. After PSM, comparisons found significant improvement in favor of DARA relative to SOC for OS (HR=0.44 [95% CI 0.31-0.63]) (Figure 1). Regression analyses revealed consistent results. After adjustment for differences in all covariates included in regression between the DARA and SOC groups, results showed significant improvement in favor of DARA compared with SOC for OS (HR=0.43 [95% CI 0.32-0.59]) (Figure 2). Conclusions: Findings from both PSM and regression analyses were consistent and suggest that DARA is associated with significant gains in OS compared with SOC therapies for patients with heavily pre-treated and highly refractory MM. References: 1. Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A et al. (2016) Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood 128 (1): 37-44. 2. Kumar SK, et al. (2016) Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. The 58th Annual Meeting of the American Society of Hematology: submitted. Disclosures Kumar: Celgene: Consultancy, Research Funding; Noxxon: Consultancy, Honoraria; Janssen: Research Funding; AbbVie: Research Funding; BMS: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria. Durie:Amgen: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Su:Janssen: Research Funding. Diels:Johnson & Johnson: Employment, Equity Ownership. Hutton:Essai Canada: Consultancy; Cornerstone Research Group: Consultancy; Janssen: Research Funding. Lam:Janssen: Employment. Tetsuro:Johnson & Johnson: Equity Ownership; Janssen: Employment.
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Grigg, Jodie, Monica J. Barratt, and Simon Lenton. "Double dropping down under: Correlates of simultaneous consumption of two ecstasy pills in a sample of Australian outdoor music festival attendees." Drug and Alcohol Review 37, no. 7 (July 11, 2018): 851–55. http://dx.doi.org/10.1111/dar.12843.
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