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1
Kreft, Ivan. "Note on the 14th International Symposium on Buckwheat at North-Eastern Hill University, Shillong, India from Sept. 3 to 6, 2019." Fagopyrum 37, no. 1 (May 25, 2020): 25–26. http://dx.doi.org/10.3986/fag0015.
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The Department of Botany, North-Eastern Hill University (NEHU), Shillong, India in collaboration with ICAR-Na- tional Bureau of Plant Genetic Resources (NBPGR), India, and DBT-Institute of Bioresources and Sustainable Development (IBSD), India organized the 14th International Symposium on Buckwheat at North-Eastern Hill University, Shillong from Sept. 3 to 6, 2019 at North Eastern Hill University, Shillong ...
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Kreft, Ivan. "Note on 40 years of organized international cooperation in buckwheat research / Zapis ob 40 letnici organiziranega mednarodnega sodelovanja pri raziskavah ajde." Folia biologica et geologica 61, no. 1 (June 3, 2020): 5–6. http://dx.doi.org/10.3986/fbg0061.
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The Department of Botany, North-Eastern Hill University (NEHU), Shillong, India in collaboration with ICAR - National Bureau of Plant Genetic Resources (NBPGR), India, and DBT - Institute of Bioresources and Sustainable Development (IBSD), India organized the 14th International Symposium on Buckwheat ...
3
Haidar, Ali, and Brijesh Verma. "Monthly rainfall forecasting using neural networks for sugarcane regions in Eastern Australia." Water Supply 17, no. 4 (June 20, 2016): 907–20. http://dx.doi.org/10.2166/ws.2016.099.
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Sugarcane is an important agricultural crop grown on the east coast of Australia. The timing and amount of rainfall is critical in determining both the yield of sugar and scheduling of harvesting operations. Rainfall forecasts issued through the Australian Bureau of Meteorology are based on general circulation models (GCMs) and have a poor skill levels. They are also limited in utility to end-users such as farmers as they cover very broad geographical areas and are only issued as probabilities above or below median. This paper presents an alternative approach for forecasting monthly rainfall with up to 12 month lead-time based on machine learning, in particular neural networks. Monthly rainfall forecasts have been developed for the eight locations in Eastern Australia at 3 and 12 month lead-time. The accuracy of the forecasts has been assessed relative to a skill scale with 0% representing climatology (the long term average) and 100% representing a perfect forecast (observation). On this scale, neural network forecasts are typically in the range 39.9–68% for all months using a single month optimization. This compares very favorably with forecasts using GCM from the Bureau that have skill levels only in the range −20% to 20%.
4
Aylan, Orhan, Aly Fahmy Mohamed El-Sayed, Firouzeh Farahtaj, Ali R. Janani, Olga Lugach, Olgha Tarkhan-Mouravi, Gaye Usluer, et al. "Report of the First Meeting of the Middle East and Eastern Europe Rabies Expert Bureau, Istanbul, Turkey (June 8-9, 2010)." Advances in Preventive Medicine 2011 (2011): 1–4. http://dx.doi.org/10.4061/2011/812515.
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Rabies is a threat in all parts of the world where animal reservoirs persists, including Eastern Europe and the Middle East. Rabies experts from seven Middle East and Eastern European countries (Croatia, Egypt, Georgia, Iran, Serbia, Turkey, and Ukraine) met for two days in Istanbul, Turkey (June 8-9, 2010), to exchange information on the epidemiological situation concerning human and animal rabies in their respective countries and to discuss strategies for rabies elimination and control. They decided to establish a regional network, the Middle East and Eastern Europe Rabies Expert Bureau (MEEREB), a regional network of experts, to increase collaboration in rabies prevention and control at the local, regional, and global levels.
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Hudson, Debra, Oscar Alves, Harry H. Hendon, Eun-Pa Lim, Guoqiang Liu, Jing-Jia Luo, Craig MacLachlan, et al. "ACCESS-S1 The new Bureau of Meteorology multi-week to seasonal prediction system." Journal of Southern Hemisphere Earth Systems Science 67, no. 3 (2017): 132. http://dx.doi.org/10.1071/es17009.
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ACCESS-S1 will be the next version of the Australian Bureau of Meteorology's seasonal prediction system, due to become operational in early 2018. The multiweek and seasonal performance of ACCESS-S1 has been evaluated based on a 23-year hindcast set and compared to the current operational system, POAMA. The system has considerable enhancements compared to POAMA, including higher vertical and horizontal resolution of the component models and state-ofthe-art physics parameterisation schemes. ACCESS-S1 is based on the UK Met Office GloSea5-GC2 seasonal prediction system, but has enhancements to the ensemble generation strategy to make it appropriate for multi-week forecasting, and a larger ensemble size.ACCESS-S1 has markedly reduced biases in the mean state of the climate, both globally and over Australia, compared to POAMA. ACCESS-S1 also better predicts the early stages of the development of the El Niño Southern Oscillation (through the predictability barrier) and the Indian Ocean Dipole, as well as multi-week variations of the Southern Annular Mode and the Madden-Julian Oscillation — all important drivers of Australian climate variability. There is an overall improvement in the skill of the forecasts of rainfall, maximum temperature (Tmax) and minimum temperature (Tmin) over Australia on multi-week timescales compared to POAMA. On seasonal timescales the differences between the two systems are generally less marked. ACCESS-S1 has improved seasonal forecasts over Australia for the austral spring season compared to POAMA, with particularly good forecast reliability for rainfall and Tmax. However, forecasts of seasonal mean Tmax are noticeably less skilful over eastern Australia for forecasts of late autumn and winter compared to POAMA.The study has identified scope for improvement of ACCESS-S in the future, particularly 1) reducing rainfall errors in the Indian Ocean and Maritime Continent regions, and 2) initialising the land surface with realistic soil moisture rather than climatology. The latter impacts negatively on the skill of the temperature forecasts over eastern Australia and is being addressed in the next version of the system, ACCESS-S2.
6
Bond, Nicholas A., and Karin A. Bumbaco. "Summertime Potential Evapotranspiration in Eastern Washington State." Journal of Applied Meteorology and Climatology 54, no. 5 (May 2015): 1090–101. http://dx.doi.org/10.1175/jamc-d-14-0228.1.
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AbstractThe demands for water in agricultural regions depend on the rate of evapotranspiration (ET). Daily records of potential ET (pET) are available from the late 1980s through the present for five stations in eastern Washington State (George, Harrah, LeGrow, Lind, and Odessa) through the Pacific Northwest Cooperative Agricultural Weather Network (AgriMet) under the auspices of the Bureau of Reclamation. These records reveal a secular increase in the summer (June–August) mean pET over the period 1987–2014. This increase can be attributed largely to an increase in solar irradiance of 20–30 W m−2 over the same period. The seasonal mean solar irradiance accounts for approximately 35%–50% of the variance in the interannual variations in seasonal mean pET at the individual stations and for approximately 60% of the variance from a five-station average perspective. The period of analysis includes a mean increase of temperature of about 0.3°C (10 yr)−1, and the variability in temperature relates more to the year-to-year fluctuations in pET than to the overall increase in pET. The time series of surface relative humidity and wind speed exhibit only minor trends. Daily and seasonal mean data for 500-hPa geopotential height and other variables are used to determine aspects of the regional atmosphere associated with periods of high pET. Anomalous ridging aloft and negative anomalies in 925-hPa relative humidity tend to occur over the study area during the summers with the greatest pET. The relationships that are emerging may provide a basis for empirical downscaling of pET from global climate model projections.
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Rosswurm, Steve. "Charles H. McCormick, Seeing Reds: Federal Surveillance of Radicals in the Pittsburgh Mill District, 1917–1921. Pittsburgh: University of Pittsburgh Press, 1997. ix + 244 pp. $37.50 cloth." International Labor and Working-Class History 57 (April 2000): 163–65. http://dx.doi.org/10.1017/s0147547900382801.
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Very well-researched and well-written, this book provides an excellent discussion of the activities of federal surveillance agencies in the Pittsburgh mill district (western Pennsylvania, northern West Virginia, and eastern Ohio). However, Seeing Reds is neither about surveillance agencies nor the Pittsburgh Left per se, but rather about their intersection: the “federal government's effort to define, understand, and suppress leftists” during the period of World War One. It begins with an excellent survey of the early history of federal surveillance agencies, including the Bureau of Investigation (BI), the Office of Naval Intelligence, the Military Intelligence Division, and the American Protective League. McCormick pays special attention to the BI, the original name of the Federal Bureau of Investigation. He looks closely at four men who, as special agents in the Pittsburgh Field Office, played a particularly important part in his story. Each had a background in either police and/or private investigative work or a college degree and/or legal training.
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Huggins, C. W., S. J. Johnson, J. M. Segreti, and J. G. Snyder. "Comparison of the Particle Size Distribution of Alpha Quartz in Respirable Coal Mine Dust Samples With Four Reference Standards." Proceedings, annual meeting, Electron Microscopy Society of America 43 (August 1985): 122–23. http://dx.doi.org/10.1017/s0424820100117613.
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For the past 3 years the Bureau of Mines, Avondale Research Center, has been doing extensive particle size measurements on respirable coal dust collected at surface and underground mines in the eastern United States. Respirable dust is the portion of airborne dust that penetrates the deepest portion of the lungs and is generally considered to be particles less than 10 μm in size. To monitor dust exposure, approximately 40,000 respirable dust samples are collected by inspectors annually. The quartz in these samples is determined by either infrared spectrophotometry or x-ray diffraction. Both methods require quartz standards. The response of both methods, however, as shown by Tuddenham, Huggins, and Klug is particle size dependent. Joint studies by the Bureau of Mines and Mine Safety and Health Administration show that inaccuracy in quantitative quartz values may be as much as 30% when the particle size of the quartz standard does not match that of the quartz in coal dust.
9
Hudson, Debra, Oscar Alves, Harry H. Hendon, Eun-Pa Lim, Guoqiang Liu, Jing-Jia Luo, Craig MacLachlan, et al. "Corrigendum to: ACCESS-S1: The new Bureau of Meteorology multi-week to seasonal prediction system." Journal of Southern Hemisphere Earth Systems Science 70, no. 1 (2020): 393. http://dx.doi.org/10.1071/es17009_co.
Full textAbstract:
ACCESS-S1 will be the next version of the Australian Bureau of Meteorology's seasonal prediction system, due to become operational in early 2018. The multiweek and seasonal performance of ACCESS-S1 has been evaluated based on a 23-year hindcast set and compared to the current operational system, POAMA. The system has considerable enhancements compared to POAMA, including higher vertical and horizontal resolution of the component models and state-ofthe-art physics parameterisation schemes. ACCESS-S1 is based on the UK Met Office GloSea5-GC2 seasonal prediction system, but has enhancements to the ensemble generation strategy to make it appropriate for multi-week forecasting, and a larger ensemble size.ACCESS-S1 has markedly reduced biases in the mean state of the climate, both globally and over Australia, compared to POAMA. ACCESS-S1 also better predicts the early stages of the development of the El Niño Southern Oscillation (through the predictability barrier) and the Indian Ocean Dipole, as well as multi-week variations of the Southern Annular Mode and the Madden-Julian Oscillation — all important drivers of Australian climate variability. There is an overall improvement in the skill of the forecasts of rainfall, maximum temperature (Tmax) and minimum temperature (Tmin) over Australia on multi-week timescales compared to POAMA. On seasonal timescales the differences between the two systems are generally less marked. ACCESS-S1 has improved seasonal forecasts over Australia for the austral spring season compared to POAMA, with particularly good forecast reliability for rainfall and Tmax. However, forecasts of seasonal mean Tmax are noticeably less skilful over eastern Australia for forecasts of late autumn and winter compared to POAMA.The study has identified scope for improvement of ACCESS-S in the future, particularly 1) reducing rainfall errors in the Indian Ocean and Maritime Continent regions, and 2) initialising the land surface with realistic soil moisture rather than climatology. The latter impacts negatively on the skill of the temperature forecasts over eastern Australia and is being addressed in the next version of the system, ACCESS-S2.
10
Azzizah, Yuni. "Socio-Economic Factors on Indonesia Education Disparity." International Education Studies 8, no. 12 (November 26, 2015): 218. http://dx.doi.org/10.5539/ies.v8n12p218.
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<p class="apa">Since 1998, regional governments in Indonesia have had greater autonomy due to the commencement of a reformation movement across Indonesia. Large portions of education management were delegated to the regional governments. Because of this, the education level varies strongly across Indonesia’ provinces. Referring to the data provided by the Indonesian Bureau of Statistics, it is found that Eastern Indonesia generally has a higher rate of uneducated than Western Indonesia. We review the current condition of Indonesian education in terms of regional disparity among eastern and western provinces and study the correlation between inequality in education and other related aspects, such as social and economic conditions. We find that inequality issues on socio-economic conditions are reflected in the education disparity between Eastern and Western Indonesia. By employing panel data with provinces as units of observations, we find that the difference in regional development among Indonesian provinces influences education issues. By evaluating the standard deviation of the statistic we were able to identify socio-economic factors that influence the regional education disparity.</p>
11
Dai, Limin, Guofan Shao, and Baoying Xiao. "Ecological classification for mountain forest sustainability in northeast China." Forestry Chronicle 79, no. 2 (April 1, 2003): 233–36. http://dx.doi.org/10.5558/tfc79233-2.
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This paper introduces the classification of Ecological Land Types (ELT) in eastern mountainous regions of northeast China and demonstrates ELT mapping for the Baihe Forestry Bureau on Changbai Mountain, lying along the border of China and North Korea. The development of ELTs will facilitate the adoption of ecological forest management and the restoration of native forest vegetation in northeast China. By overlaying forest inventory data with the ELT map, suggestions on ecosystem forest management are discussed in this paper. Key words: China's forestry, ecosystem management, ecological land types, geographic information systems, digital elevation models
12
Picot, V., A. Rasuli, A. Abella-Rider, M. Saadatian-Elahi, A. Aikimbayev, A. Barkia, S. Benmaiz, et al. "The Middle East and Eastern Europe rabies Expert Bureau (MEEREB) third meeting: Lyon-France (7–8 April, 2015)." Journal of Infection and Public Health 10, no. 6 (November 2017): 695–701. http://dx.doi.org/10.1016/j.jiph.2017.03.005.
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Siegel, David S., Gary Schiller, Kevin Song, Richy Agajanian, Keith Stockerl-Goldstein, Hakan Kaya, Michael Sebag, et al. "Investigating Efficacy, Safety, and Biomarkers in a Phase 2 Trial of Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Following Second-Line Lenalidomide-Based Therapy (Tx) in Relapsed or Refractory Multiple Myeloma (RRMM)." Blood 126, no. 23 (December 3, 2015): 1853. http://dx.doi.org/10.1182/blood.v126.23.1853.1853.
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Abstract Background: Preclinical studies indicate that lenalidomide (LEN) and POM are not cross-resistant (Ocio et al Leukemia, 2015) and that POM remains active in LEN-resistant myeloma cells (Lopez-Girona et al Leukemia, 2012). Likewise, POM + LoDEX showed comparable efficacy in patients (pts) refractory to LEN administered as last prior Tx vs the full population in subanalyses of the clinical trials MM-002 and MM-003 (San Miguel et al Lancet Oncol, 2013; Richardson et al Blood, 2014). To confirm these observations, we initiated a single-arm, phase 2 trial evaluating POM + LoDEX immediately following second-line LEN-based Tx in advanced RRMM (MM-014; NCT01946477). Methods: Eligible pts (aged ≥ 18 yrs) had received 2 prior lines of Tx, with ≥ 2 cycles of LEN-based Tx in the second line. Pts must have had documented progressive disease (PD) during or after their last antimyeloma Tx and Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. POM was administered 4 mg/day on days 1-21 of a 28-day cycle with LoDEX 40 mg/day (20 mg/day for pts aged > 75 yrs) on days 1, 8, 15, and 22 until PD or discontinuation for any reason. Pts received mandatory thromboprophylaxis. The primary end point was overall response rate by modified International Myeloma Working Group criteria (including minor response). Secondary end points included progression-free survival, overall survival, time to progression, safety, and duration of response. Exploratory end points were included to identify molecular, immune, and cellular biomarkers that might inform POM + LoDEX response, resistance, or mechanism of action. Results: As of March 20, 2015, 27 of the 85 planned pts were enrolled and received POM + LoDEX. Twelve pts remain on Tx, whereas 15 have discontinued, due to PD (n = 7) and withdrawal (n = 5), but not adverse events (n = 0). Males comprised 59% of pts; 85% were white and the median age was 69 yrs (range, 44-85 yrs), with 67% of pts aged ≥ 65 yrs. The median time since diagnosis was 3.9 yrs (range, 1.3-13.3 yrs), and 59% of pts received prior stem cell transplant. Most pts (81%) were refractory to the most recent prior LEN-containing Tx, and the median duration of the most recent prior LEN Tx was 8.3 mos (range, 0.3-56.3 mos). The 19% of pts who were not refractory to the most recent prior LEN-containing Tx remain on Tx. Pts predominantly had ECOG performance status 0 or 1 (30% and 63%, respectively) vs 2 (7%). Of the 19 pts with International Staging System assessment reported, most were stage I (n = 7) or II (n = 11) vs III (n = 1). Efficacy and safety data will be presented. Conclusions: The MM-014 study is assessing the efficacy and safety of POM + LoDEX in pts with RRMM who have received second-line LEN-based Tx. MM-014 is designed to confirm and expand the results from MM-002 and MM-003 with translational data. Clonality and biomarkers, including Aiolos, Ikaros, IRF-4, and c-Myc, will be evaluated to determine association with POM + LoDEX synergy, high-risk MM-associated genetic aberrations, clonal evolution, and minimal residual disease. Disclosures Siegel: Celgene Corporation: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Merck: Speakers Bureau; Novartis: Speakers Bureau. Schiller:Celgene Corporation: Research Funding. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stockerl-Goldstein:Celgene Corporation: Speakers Bureau; Onyx: Speakers Bureau. Kaya:Novartis: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Sebag:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Reu:Takeda/Millennium: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Mouro:Celgene Corporation: Employment, Equity Ownership. Sturniolo:Celgene Corporation: Employment. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Research Funding.
14
Zhao, Mei, Harry H. Hendon, Oscar Alves, Guoqiang Liu, and Guomin Wang. "Weakened Eastern Pacific El Niño Predictability in the Early Twenty-First Century." Journal of Climate 29, no. 18 (September 2, 2016): 6805–22. http://dx.doi.org/10.1175/jcli-d-15-0876.1.
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Abstract Predictive skill for El Niño in the equatorial eastern Pacific across a range of forecast models declined sharply in the early twenty-first century relative to what was achieved in the late twentieth century despite ongoing improvements of forecast systems. This decline coincided with a shift in Pacific climate to an enhanced east–west surface temperature gradient across the Pacific and a stronger Walker circulation at the end of the twentieth century. Using seasonal forecast sensitivity experiments with the Australian Bureau of Meteorology coupled model POAMA2.4, the authors show that this shift in background climate acted to weaken key ocean–atmosphere feedbacks that amplify eastern Pacific El Niño, thus resulting in weaker variability that is less predictable. These results indicate that extreme El Niños, such as those that occurred in 1982/83 and 1997/98, were conditioned by the background climate and so were favored to occur in the late twentieth century. However, anticipating future changes in El Niño variability and predictability is an outstanding challenge because causes and prediction of low-frequency variations of Pacific climate have not yet been demonstrated.
15
López, Raúl E., Ronald L. Holle, Andrew I. Watson, and Jon Skindlov. "Spatial and Temporal Distributions of Lightning over Arizona from a Power Utility Perspective." Journal of Applied Meteorology 36, no. 6 (June 1, 1997): 825–31. http://dx.doi.org/10.1175/1520-0450-36.6.825.
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Abstract This study was designed to determine whether a spatially significant and temporally persistent variation in cloud-to-ground lightning frequency exists across the Salt River Project (SRP) region of central Arizona. Cloud-to-ground lightning data for 8 years from the Bureau of Land Management detection network were compiled to develop maps of lightning strike density across Arizona and the SRP region. In space, lightning frequency varied significantly across both of these topographically diverse regions. There was nearly five times more lightning over the high-altitude eastern border of the SRP region than over the lower western desert portion. The spatial pattern was consistent through time, so that more substantial lightning protection is warranted over the eastern SRP region than over the west. However, lightning frequency is highly variable from month to month and year to year on both the state and SRP scales, so that the value of newly installed lightning protection cannot be judged on experiences from a few years.
16
Stilgenbauer, Stephan, Francesc Bosch, Véronique Leblond, Osman Ilhan, Jens Kisro, Béatrice Mahé, Eva Mikuskova, et al. "Obinutuzumab Alone or Combined with Chemotherapy in Previously Untreated (Fit or Unfit) or Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Patients: Final Results from the Phase IIIb GREEN Safety Study with a Focus on Efficacy." Blood 134, Supplement_1 (November 13, 2019): 3035. http://dx.doi.org/10.1182/blood-2019-123419.
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Introduction: Obinutuzumab (GA101; G) is a fully humanized, glycoengineered, type II anti-CD20 antibody that has demonstrated substantial activity in chronic lymphocytic leukemia (CLL). Results from the primary analysis of the phase IIIb, non-randomized, open-label, single-arm GREEN safety study (NCT01905943), have previously shown that G alone or in combination with chemotherapy has a manageable toxicity profile in first-line (1L; fit and unfit) and relapsed/refractory (R/R) patients (pts) with CLL (Stilgenbauer et al. Blood 2017; Leblond et al. Haematologica 2018). Here, we report the final analysis of the GREEN study. Methods: Enrolled pts were aged ≥18 years with documented CLL and Eastern Cooperative Oncology Group performance status 0-2. Pts received intravenous (IV) G 1000mg alone (fit or unfit pts, G-mono) on Day (D) 1, 8 and 15 of Cycle (C)1, and D1 of C2-6 (6 x 28-day cycles), with the C1D1 dose administered over 2 days, or with chemotherapy: investigator's choice of fludarabine and cyclophosphamide (G-FC) for fit pts (Cumulative Illness Rating Scale [CIRS] ≤6 and creatinine clearance [CrCl] ≥70mL/min) only; chlorambucil (G-Clb) for unfit pts (CIRS >6 and/or CrCl <70mL/min) only; or bendamustine (G-Benda) for any pt. All pts received IV corticosteroids 1h pre-dose on C1D1 and C1D2 to reduce the risk of infusion-related reactions. The primary endpoint was safety. Secondary efficacy measures included best overall response rate (BOR), complete response rate (CR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), time-to-next-treatment (TTNT) and minimal residual disease (MRD). Subgroup analyses were performed on suspected prognostic biomarkers in 1L CLL. No formal statistical hypothesis tests were performed. The database lock was January 31, 2019. Results: Of 972 enrolled pts, 630 received 1L CLL treatment (340 fit, 290 unfit; 1 unfit pt was enrolled but was never treated), and 341 had R/R CLL. In total, 63.5% were male. The mean (range) age was 65.4 (33-90) years. Median (range) observation time was 43.7 (0.3-59.2) months. Of the 630 pts receiving 1L treatment and 341 pts who were treated for R/R disease, 488 (77.5%) and 170 (49.9%), respectively, completed the study. At final analysis, no new safety signals were observed compared with the primary safety analysis. In total, 82.7% of pts receiving 1L treatment and 84.5% of pts who were treated for R/R disease experienced grade (Gr) ≥3 adverse events (AEs), and 58.1% and 62.5% experienced serious AEs. As expected, the most common Gr 3-5 events were neutropenia (50.5% 1L, 53.4% R/R) and thrombocytopenia (14.6% 1L, 19.1% R/R). The most common non-hematological AEs were infection (any Gr: 57.6% 1L, 61.3% R/R; Gr 3-5: 21.7% 1L, 30.8% R/R) and nausea (any Gr: 27.9% 1L, 27.6% R/R; Gr 3-5: 0.8% 1L, 1.2% R/R). BOR and CR were generally higher, and DoR, PFS and TTNT were longer for pts receiving 1L therapy compared with pts who were treated for R/R disease in all arms (Table 1). Median OS was not reached at the time of analysis in any arm. The median duration of MRD-negativity was longer for pts receiving 1L therapy compared with pts who were treated for R/R disease in all arms except for pts receiving G-mono (Table 1). In addition, the MRD negative status at final response assessment in blood and bone marrow was higher for pts receiving 1L therapy compared with pts who were treated for R/R disease in all arms with the exception of pts receiving G-Clb (Table 1). Table 2 shows the PFS event-free rate by genetic marker for 1L G-Benda and G-FC over 4 years, indicating that pts with mutated immunoglobulin heavy chain variable (IGHV), del(13q) and trisomy 12 derived the most benefit. Conclusions: In this final analysis of GREEN, no new safety signals were identified. Efficacy outcomes suggest a favorable benefit/risk profile in both 1L and R/R CLL, irrespective of chemotherapy regimen. PFS outcome for pts with 12q trisomy, del(13q) and IGHV mutated were favorable across treatment arms, while del(11q), del(17q), and unmutated IGHV showed a worse outcome. Multivariate analyses including treatment, clinical and laboratory parameters are currently being performed to identify pts who derive the most benefit. Disclosures Stilgenbauer: Pharmacyclics: Other: Travel support; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bosch:AstraZeneca: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Leblond:Astra Zeneca: 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; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Ilhan:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mikuskova:Novartis: Honoraria; Roche: Honoraria; Johnson & Johnson: Honoraria; Takeda: Honoraria; Abbvie: Honoraria; National Oncology Institute: Employment. Tausch:Roche: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau. Wójtowicz:Roche: Honoraria, Other: Sponsorship of 2019 EHA participation; Acerta Pharma/AstraZeneca: Honoraria; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Honoraria; Takeda: Honoraria; Amgen: Consultancy. Perretti:F. Hoffmann-La Roche Ltd: Employment. Van Hoef:F. Hoffman-La Roche: Employment. Foà:Celltrion: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: 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; Novartis: 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; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia, and in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen.
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Kane, Susan, William Raynolds, and Sam Carrier. "American Mission activities in Libya 2005–16: report." Libyan Studies 48 (September 14, 2017): 135–47. http://dx.doi.org/10.1017/lis.2017.3.
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AbstractThis essay outlines the capacity-building work of the American Archaeological Mission to Libya between the years 2005 and 2016. This work was made possible by grants from the US Embassy to Libya, the US State Department Ambassadors Fund for Cultural Preservation (AFCP) and the Bureau of Near Eastern Affairs in Washington, DC. The principles and objectives underlying our capacity-building programme were inspired by the 2003 UNESCO World Heritage Centre Mission Report by Giovanni Boccardi, in particular his recommendation that the Libyan Department of Antiquities obtain training in the best modern cultural heritage management practices via sustained partnerships with external professionals and organisations.
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Zhong, Aihong, Harry H. Hendon, and Oscar Alves. "Indian Ocean Variability and Its Association with ENSO in a Global Coupled Model." Journal of Climate 18, no. 17 (September 1, 2005): 3634–49. http://dx.doi.org/10.1175/jcli3493.1.
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Abstract The evolution of the Indian Ocean during El Niño–Southern Oscillation is investigated in a 100-yr integration of an Australian Bureau of Meteorology coupled seasonal forecast model. During El Niño, easterly anomalies are induced across the eastern equatorial Indian Ocean. These act to suppress the equatorial thermocline to the west and elevate it to the east and initially cool (warm) the sea surface temperature (SST) in the east (west). Subsequently, the entire Indian Ocean basin warms, mainly in response to the reduced latent heat flux and enhanced shortwave radiation that is associated with suppressed rainfall. This evolution can be partially explained by the excitation of an intrinsic coupled mode that involves a feedback between anomalous equatorial easterlies and zonal gradients in SST and rainfall. This positive feedback develops in the boreal summer and autumn seasons when the mean thermocline is shallow in the eastern equatorial Indian Ocean in response to trade southeasterlies. This positive feedback diminishes once the climatological surface winds become westerly at the onset of the Australian summer monsoon. ENSO is the leading mechanism that excites this coupled mode, but not all ENSO events are efficient at exciting it. During the typical El Niño (La Niña) event, easterly (westerly) anomalies are not induced until after boreal autumn, which is too late in the annual cycle to instigate strong dynamical coupling. Only those ENSO events that develop early (i.e., before boreal summer) instigate a strong coupled response in the Indian Ocean. The coupled mode can also be initiated in early boreal summer by an equatorward shift of the subtropical ridge in the southern Indian Ocean, which stems from uncoupled extratropical variability.
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Motrevich, Vladimir. "State Farm in Eastern Siberia in the Years of the Great Patriotic War (According to Consolidated Annual Reports)." Journal of Economic History and History of Economics 21, no. 1 (March 16, 2020): 117–43. http://dx.doi.org/10.17150/2308-2488.2020.21(1).117-143.
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The research used the materials of the consolidated annual reports of Soviet farms in the Krasnoyarsk Territory, Irkutsk and Chita Regions, Buryat-Mongol and Yakut Autonomous Soviet Socialist Republics and Tuva Autonomous Region to examine the state of agricultural production in the state farms of Eastern Siberia in 1941-1945. We analyzed the information on the size and structure of cultivated areas, agricultural yield and gross collection. The study also examined the data of the Central Statistical Bureau of the USSR on the state of farm animal production at the regional state farms, including the cattle's crop and its loss, its abundance, and performance rate. The influence of the war on the agricultural situation is studied. The study revealed that compared to agriculture extreme wartime conditions began to affect farm animal production somewhat later.
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Motrevich, Vladimir. "State Farm in Eastern Siberia in the Years of the Great Patriotic War (According to Consolidated Annual Reports)." Journal of Economic History and History of Economics 21, no. 1 (March 16, 2020): 117–43. http://dx.doi.org/10.17150/2308-2488.2020.21(1).117-143.
Full textAbstract:
The research used the materials of the consolidated annual reports of Soviet farms in the Krasnoyarsk Territory, Irkutsk and Chita Regions, Buryat-Mongol and Yakut Autonomous Soviet Socialist Republics and Tuva Autonomous Region to examine the state of agricultural production in the state farms of Eastern Siberia in 1941-1945. We analyzed the information on the size and structure of cultivated areas, agricultural yield and gross collection. The study also examined the data of the Central Statistical Bureau of the USSR on the state of farm animal production at the regional state farms, including the cattle's crop and its loss, its abundance, and performance rate. The influence of the war on the agricultural situation is studied. The study revealed that compared to agriculture extreme wartime conditions began to affect farm animal production somewhat later.
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Vesole, David H., Susanna Jacobus, S. Vincent Rajkumar, Rafat Abonour, Natalie Scott Callander, Philip R. Greipp, Rafael Fonseca, Michael S. Katz, and David Samuel diCapua Siegel. "Lenalidomide Plus Low-Dose Dexamethasone (Ld): Superior One and Two Year Survival Regardless of Age Compared to Lenalidomide Plus High-Dose Dexamethasone (LD)." Blood 116, no. 21 (November 19, 2010): 308. http://dx.doi.org/10.1182/blood.v116.21.308.308.
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Abstract Abstract 308 Introduction: The Eastern Cooperative Oncology Group (ECOG) has previously reported the superior 1 and 2 year survival of Ld versus LD as initial therapy in newly diagnosed symptomatic multiple myeloma (MM) (Rajkumar et al Lancet Oncol 2010; 11: 29–37). The 1 year and 2 year OS for Ld vs LD were 96% and 85% vs 88% and 78%, (p < 0.01), respectively. This despite higher ORR in LD vs Ld (79% vs 68%; p = 0.008). The difference in OS was predominantly due to early death in the LD group (5% vs 0.5%; p = 0.003). As a result of this analysis, Ld is now considered the standard of care. However, it should be noted that the majority of these deaths occurred in pts > 65. In this analysis, we evaluated the impact of age on dexamethasone dose intensity and OS. Methods: 445 pts were randomly assigned: 223 to LD and 222 to Ld. Pts were analyzed on an intent-to-treat basis for OS. The pts were analyzed by age in 2 groups: < 65 and > 65 (the age corresponding to transplant eligibility outside the US). The pts > 65 were then further subdivided into >70 and > 75 yrs. Results are expressed as OS probability at 1 and 2 years post randomization. In addition, to eliminate the early death ‘penalty’ in the LD group in the original analysis, a landmark analysis was performed at 4 months. Results: Overall Survival Probability: Intent-to Treat Analysis Overall Survival Probability: 4 month Landmark Analysis Conclusions: As previously reported, OS in the trial at 1 and 2 years was superior with Ld. OS was not superior with LD compared with Ld in any age group despite a higher response rate. This was true even when using a landmark analysis to eliminate the 5% early deaths seen in the first 4 months of treatment. We conclude the following: 1) LD is not definitively superior to Ld in any age group; 2) Given the higher toxicity in the absence of a clear survival benefit with LD, Ld remains the best choice for all ages. This analysis confirms the original opinion that low-dose dexamethasone is the standard of care for all newly diagnosed MM pts, regardless of age. Disclosures: Vesole: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centorcor-Ortho-Biotech: Speakers Bureau. Off Label Use: Lenalidomide for front-line therapy in multiple myeloma. Abonour:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Callander:Millennium Pharmaceuticals: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy; Intellikine: Consultancy. Siegel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees.
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Zinzani, Pier Luigi, Vincent Delwail, Shankara Paneesha, Simon Rule, Alejandro Martin Garcia-Sancho, Ana Marin-Niebla, Gilles Salles, et al. "Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Previously Treated with Ibrutinib (CITADEL-205)." Blood 136, Supplement 1 (November 5, 2020): 43–44. http://dx.doi.org/10.1182/blood-2020-134609.
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Background: Mantle cell lymphoma (MCL) accounts for approximately 5-7% of non-Hodgkin lymphomas (NHL). Bruton's tyrosine kinase (BTK) inhibitors, eg ibrutinib, are indicated for treatment of adults with MCL who have received ≥1 prior therapy. Primary and acquired resistance to ibrutinib is common and linked with poor outcomes, and remains an unmet medical need. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor, demonstrated clinical activity in patients (pts) with relapsed or refractory (R/R) NHL. We report preliminary results for parsaclisib monotherapy in a cohort of pts with R/R MCL who were previously treated with ibrutinib in the open-label, phase 2 study CITADEL-205 (NCT03235544). Methods: Pts must be ≥18 years of age with pathologically confirmed MCL, R/R disease to the most recent treatment, documented cyclin D1 overexpression or t(11;14) translocation, have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and received 1 to 3 prior systemic treatments (including ibrutinib). Prior treatment with PI3Ki was prohibited. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From October 2017 to January 17, 2020 (data cut-off), 47 pts were treated (WG, n = 12; DG, n = 35). Enrollment is ongoing. At cut-off, 70% of pts had discontinued treatment, most commonly due to progressive disease (62%). Median exposure (range) was 2.2 (0.1-18.0) months. Median age was 70 years and 79% of pts were men. Median time since initial diagnosis was 4.7 years. Most pts (85%) had ECOG PS ≤1 and 51% had high-risk MCL International Prognostic Index. The median number of prior systemic therapies was 3; 38% of pts had prior hematopoietic stem cell transplant, and 38% were refractory to most recent systemic therapy. At data cut-off, 46 pts were evaluable for efficacy, including 12 in WG and 34 in DG (Table). Median follow-up (range) for this population was 10.2 months (1.5-25.9) overall and 7.6 months (1.5-25.9) for DG. ORR (95% confidence interval [CI]) and CRR were 28.3% (16.0-43.5) and 2.2%, respectively in all evaluable pts, and 35.3% (19.7-53.5) and 2.9%, respectively in DG. Median time to complete or partial response was 7.6 weeks. Median DOR (95% CI) was 7.3 months (0.2-not estimable) among all responders and 3.7 months (0.2-7.3) for DG. Median PFS (95% CI) was 3.65 months (1.9-3.9) overall and 3.65 months (1.9-5.5) for DG. Among 47 safety-evaluable pts, most common treatment-emergent adverse events (TEAEs) occurring in >10% of pts were anemia (19.1%), diarrhea (19.1%), neutropenia (14.9%), asthenia and cough (12.8% each), decreased appetite, dyspnea, fatigue, pyrexia and rash (10.6% each). Most common grade ≥3 TEAEs reported in ≥5% of pts included anemia (12.8%), neutropenia (10.6%), thrombocytopenia and rash (6.4% each). TEAEs leading to dose interruption or reduction occurred in 31.9% and 2.1% of pts, respectively. TEAEs leading to treatment discontinuation occurred in 2 (4.3%) pts (diarrhea and colitis). Serious TEAEs reported in ≥2 pts were diarrhea, dyspnea, peripheral swelling and pneumonia (4.3% each). Two pts experienced fatal TEAEs (one pt had general physical health deterioration and respiratory tract infection, deemed not related to treatment; one pt had pneumonia, neutropenia, and septic shock, deemed related to treatment and disease progression). New or worsening grade ≥3 laboratory test values of clinical interest occurring in ≥5% of pts included decreased neutrophils (14.9%), platelets (10.6%), and hemoglobin (8.5%); there were no grade ≥3 increases in alanine/aspartate aminotransferase. Conclusion: Preliminary efficacy data indicate that parsaclisib monotherapy is clinically active in this difficult-to-treat patient population. Treatment with parsaclisib had an acceptable safety profile and was generally well tolerated. Updated study results will be presented. Disclosures Zinzani: EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, 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; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eusapharma: Consultancy, Speakers Bureau. Delwail:Amgen: Consultancy. Paneesha:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Rule:AstraZeneca: Consultancy; Celgene: Consultancy; Celltrion: Consultancy; Janssen Oncology: Consultancy, Research Funding, Speakers Bureau; Roche Pharma AG: Consultancy, Research Funding. Martin Garcia-Sancho:Roche, Celgene, Janssen, Servier, Gilead: Honoraria; Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy. Salles:Amgen: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Servier: Consultancy, Honoraria; Acerta Pharma: Consultancy; Kite Pharma: Consultancy; Merck: Consultancy, Research Funding; Novimmune: Consultancy; Pfizer: Consultancy; Sanofi: Other. Sancho:Sandoz: Consultancy; Celltrion: Consultancy; Roche: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria; Kern-Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Mehta:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gelgene/BMS: Research Funding; Affimed: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding; Juno Parmaceuticals/BMS: Research Funding; Innate Pharmaceuticals: Research Funding; Oncotartis: Research Funding; Roche-Genentech: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; fortyseven Inc/Gilead: Research Funding; Takeda: Research Funding.
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Popat, Rakesh, Sonja Zweegman, Jim Cavet, Kwee Yong, Lydia Lee, Jim Faulkner, Ekaterini Kotsopoulou, et al. "Phase 1 First-in-Human Study of AUTO2, the First Chimeric Antigen Receptor (CAR) T Cell Targeting APRIL for Patients with Relapsed/Refractory Multiple Myeloma (RRMM)." Blood 134, Supplement_1 (November 13, 2019): 3112. http://dx.doi.org/10.1182/blood-2019-126689.
Full textAbstract:
Introduction: Chimeric antigen receptor (CAR) T cell therapies directed against B cell maturation antigen (BCMA) have shown significant activity in patients with RRMM, however single antigen targeting with CAR-T cells can result in antigen negative relapse. Dual antigen targeting increases targetable tumor antigens and may reduce the risk of antigen negative disease escape. 'A proliferation-inducing ligand' (APRIL) is a natural high affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI). Like BCMA, TACI is also a tumor necrosis factor receptor and is involved in maturation of B-cells, including their maturation to plasma cells. Importantly, TACI is expressed on MM cells. In this study, we are evaluating the safety and efficacy of AUTO2, a CAR-T cell therapy designed to target BCMA and TACI. Methods: We designed a novel CAR construct using a truncated form of APRIL as the tumor-targeting domain which recognizes both BCMA and TACI on MM cells. AUTO2 is retrovirally transduced to express APRIL CAR and the RQR8 safety switch. The APRIL CAR construct is in a third-generation format with composite endodomains of CD28, OX40 and CD3 zeta. The cell product was manufactured on a semi-automated and closed process. Patients (≥ 18 years) with RRMM; Eastern Cooperative Oncology Group Performance Status <2, who have had at least 3 prior lines of therapy or have double refractory disease to proteasome inhibitors (PI) and immunomodulatory agents (IMiD), adequate hepatic and cardiac function and an absolute lymphocyte count ≥0.5 x 10e9/L are eligible. Patients with CNS disease, prior allogeneic stem cell transplant, are excluded. All patients receive lymphodepletion with 30 mg/m2/day fludarabine and 300 mg/m2/day cyclophosphamide for 3 days prior to AUTO2 infusion. Five dose levels are being explored (15 x 10e6; 75 x 10e6 ;225 x 10e6; 600 x10e6 x and 900x 10e6 transduced CAR-T cells). The primary endpoint of this phase 1 study is incidence of Grade 3 to 5 toxicity occurring within the DLT period (28 days post AUTO2 infusion), frequency of DLTs and the persistence of AUTO2. Key secondary endpoints include overall response rate, duration of response, and overall survival, as well as biomarker endpoints such as AUTO2 levels in blood. Results: As of the data cut-off date (July 03, 2019), 12 patients have been enrolled. Eleven patients have been dosed on study, 1 at 15 x10e6, 3 at 75x10e6, 3 at 225x10e6, 3 at 600x10e6 and 1 at 900x10e6 CAR-T cells. Two patients have been retreated. All patients were successfully manufactured and received target dose. Median age was 61 years (range 45-69 years), median 5 prior lines of treatment (range 3-6) ,73% had prior autologous transplant, 100% were refractory to a PI or IMiD, 80% were refractory to both and 45% were refractory to daratumumab. Eleven patients had a minimum of 4 week follow up and were evaluable for safety analysis. No AUTO2 related deaths were observed and no DLTs were observed. The most frequent ≥ Grade 3 adverse events (>30%) were anemia (82%), neutrophil count decreased (73%). Five patients (45%) experienced CRS, all were grade 1, no ≥ G2 CRS was noted. Tocilizumab was given to 3 patients (27%). No cases of neurotoxicity occurred. Seven patients were dosed, in the ≥ 225x10e6 dose cohorts, the ORR was 43% (28% PRs and 14% VGPRs). Interestingly the patient dosed at 15x10e6 CAR-T cells maintained stable disease (SD) for a year and was retreated at higher dose of 225x10e6 CAR-T cells and continues with SD without further treatment. This patient had the highest baseline levels of TACI and was previously primary refractory to treatment. Another patient initially treated at 75 x10e6 CAR -T cells was retreated with 225x 10e6 CAR-T cells and achieved a partial response. Updated data as well as cellular kinetics, product characteristics and additional biomarker analysis including BCMA and TACI will be presented. Conclusions: AUTO2 is a novel CAR-T therapy, with a manageable safety profile at doses up to 900x10e6 CAR-T cells. Disclosures Popat: Janssen: Honoraria, Other: travel support to meetings; GSK: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Other: travel, accommodations, expenses. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavet:Amgen: Other: congress support , Research Funding, Speakers Bureau; Oncopeptide: Other: congress support , Research Funding, Speakers Bureau; EUSA: Other: congress support , Research Funding, Speakers Bureau; GSK: Other: congress support, Research Funding, Speakers Bureau; Celgene: Other: congress support , Research Funding, Speakers Bureau; Janssen: Other: Congress support , Research Funding, Speakers Bureau; Takeda: Other: congress support , Research Funding, Speakers Bureau. Yong:Autolus: Consultancy; Sanofi: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Lee:Autolus Therapeutics: Equity Ownership, Research Funding. Faulkner:Autolus Therapeutics: Employment, Equity Ownership. Kotsopoulou:Autolus Therapeutics: Employment, Equity Ownership. Al-Hajj:Autolus Therapeutics: Employment, Equity Ownership. Thomas:Autolus: Employment, Equity Ownership. Cordoba:Autolus: Employment, Equity Ownership. Pule:Autolus: Employment, Equity Ownership, Patents & Royalties. Cerec:Autolus Therapeutics: Employment, Equity Ownership. Peddareddigari:Autolus Therapeutics: Employment, Equity Ownership. Khokhar:Autolus Therapeutics: Employment, Equity Ownership. Menne:Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant.
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Mehta, Amitkumar, Marek Trněný, Jan Walewski, Vincent Ribrag, Caroline Dartigeas, Jacob Haaber Christensen, Fabrizio Pane, et al. "Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated with a BTK Inhibitor (CITADEL-205)." Blood 136, Supplement 1 (November 5, 2020): 22–23. http://dx.doi.org/10.1182/blood-2020-134872.
Full textAbstract:
Background: Mantle cell lymphoma (MCL) accounts for approximately 5-7% of non-Hodgkin lymphomas (NHL). A number of therapies are used for second- and later-line treatment including Bruton's tyrosine kinase inhibitors (BTKi). However, treatment failure and intolerance are common and alternative therapies are needed. Parsaclisib is a potent, highly-selective, next-generation PI3Kδ inhibitor that demonstrated clinical activity in patients (pts) with relapsed or refractory (R/R) NHL. We report preliminary results for a cohort of BTK inhibitor-naïve pts with R/R MCL treated with parsaclisib monotherapy in the open-label, phase 2 study CITADEL-205 (NCT03235544). Methods: Pts must be ≥18 years of age with pathologically confirmed MCL, R/R to the most recent treatment, documented cyclin D1 overexpression or t(11;14) translocation, have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and received 1 to 3 prior systemic treatments. Prior treatment with BTKi and PI3Ki were prohibited. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From October 2017 to January 17, 2020 (data cut-off), 104 pts were treated (WG, n = 31; DG, n = 73). Enrollment was ongoing (target:100 pts). At cut-off, a total of 50 (48%) pts had discontinued treatment, including 31 (30%) pts for disease progression. The median exposure (range) was 4.0 months (0.1-19.1). The median age was 72 years and 80% of pts were men. The median time since initial diagnosis was 3.6 years. The majority of pts (92%) had ECOG PS ≤1, and 57% had high-risk MCL International Prognostic Index. The median number of previous systemic therapies was 1; 31% of pts had prior hematopoietic stem cell transplant, and 44% were refractory to their most recent systemic therapy. At the data cut-off, 92 pts were evaluable for efficacy including 31 in WG and 61 in DG (Table). The median follow-up duration (range) for this population was 11.8 months (1.9-24.0) overall and 9.1 (1.9-24.0) for DG. The ORR (95% confidence interval CI) and CRR were 66.3% (55.7-75.8) and 15.2%, respectively in all evaluable pts, and were 65.6% (52.3-77.3) and 11.5% for DG. The median time to response for pts with a complete or partial response was 7.9 weeks. The median DOR (95% CI) was 11.0 months (6.6-14.7) for all responders and 9.0 months (7.7-14.7) for DG. The median PFS (95% CI) was 11.1 (5.8-16.6) months overall, and 11.1 (5.6-16.6) months for DG. Among 104 safety-evaluable pts, most common treatment-emergent AEs (TEAEs) occurring in >10% of pts were diarrhea (25.0%), pyrexia (16.3%), constipation (11.5%), and neutropenia (10.6%). Most common grade ≥3 TEAEs reported in ≥5% of pts were neutropenia (8.7%) and diarrhea (7.7%). TEAEs leading to dose interruption or dose reduction occurred in 31.7% and 1.9% of pts, respectively. TEAEs leading to discontinuation occurred in 16.3% of pts including diarrhea (5.8%) and colitis (2.9%). Serious TEAEs reported in ≥2 pts included diarrhea (5.8%), colitis (2.9%), pyrexia (2.9%) and cytomegalovirus infection (1.9%). Four pts experienced fatal TEAEs. The fatal TEAEs in one pt (monocytic acute myeloid leukemia, leukocytosis, and acute kidney injury) were considered related to treatment. TEAEs of clinical interest included neutropenia (10.6%), rash (8.7%), colitis (4.8%), pneumonia (1.9%), PJP and pneumonitis (1% each). New or worsening grade ≥3 laboratory test values of clinical interest included decreased neutrophils (8.7%), platelets (7.7%), and hemoglobin (1.9%), and increases in alanine/aspartate aminotransferase (2.9%/1.9%). Conclusion: Parsaclisib demonstrated a high rate of rapid and durable response, and had an acceptable safely profile and was generally well tolerated. These preliminary results suggest that parsaclisib represents a potentially new drug class and treatment option for BTKi-naïve, R/R MCL. Updated study results will be presented. Disclosures Mehta: Takeda: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; Merck: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Research Funding; Roche-Genentech: Research Funding; Affimed: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Innate Pharmaceuticals: Research Funding; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding. Trněný:AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy; MorphoSys: Consultancy, Honoraria; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Amgen: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Walewski:Servier: Consultancy, Honoraria; GSK: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Ribrag:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Eisai: Honoraria; AZD: Honoraria, Other; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Institut Gustave Roussy: Current Employment; argenX: Current equity holder in publicly-traded company, Research Funding. Dartigeas:Janssen: Honoraria; Roche: Honoraria; Gilead: Other: non-financial support. Pane:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Janssen: Other: Travel Expenses; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Rodríguez:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zinzani:TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, 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; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Miyazaki, S., and R. J. Korsch. "COALBED METHANE RESOURCES IN THE PERMIAN OF EASTERN AUSTRALIA AND THEIR TECTONIC SETTING." APPEA Journal 33, no. 1 (1993): 161. http://dx.doi.org/10.1071/aj92013.
Full textAbstract:
The Bowen and Sydney Basins in eastern Australia contain vast coal resources which provide a source for coalbed methane. Through studies of the spatial and temporal distribution of the sedimentary packages, the structural geometry and tectonic setting of the sedimentary packages, and the maturation and burial history, the Australian Geological Survey Organisation (AGSO) is mapping the distribution and structural styles of the sources of methane, in particular, the Late Permian coal measures. AGSO's results from the Bowen Basin show at least two distinctly different structural styles of potential targets for coalbed methane drainage: on the Comet Ridge, the Permian coal measures are essentially subhorizontal and tectonically undisturbed, whereas in the western Taroom Trough, the coal measures are folded into a series of anticlines, each of which occurs above a thrust fault which in turn forms part of an imbricate thrust fan. Both of these styles occur at depths of less than 1000 m.Calculations by the Bureau of Resource Sciences (BRS) indicate that the inferred coalbed methane resources-in-place are 62 trillion cubic feet (1760 billion m3) for Australia, in which the Bowen and Sydney Basins are currently the only potential provinces of coalbed methane. The low permeability of the coal seams hinders attempts to utilise this vast amount of energy resources.Further exploration is necessary to delineate commercially feasible areas. This delineation is the only process that will be able to determine demonstrated coalbed methane resources.
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Herrera, Alex F., Carmelo Carlo-Stella, Graham P. Collins, Kami J. Maddocks, Nancy L. Bartlett, Kerry J. Savage, Paolo F. Caimi, et al. "Preliminary Results of a Phase 2 Study of Camidanlumab Tesirine (Cami), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Hodgkin Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 21–23. http://dx.doi.org/10.1182/blood-2020-137451.
Full textAbstract:
Introduction: Novel approaches to treating patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) have improved outcomes but some pts do not respond or, despite initial response, develop progressive disease and have limited treatment options. Camidanlumab tesirine (ADCT-301; Cami) is an antibody-drug conjugate composed of a human IgG1 anti-CD25 monoclonal antibody stochastically conjugated to a potent pyrrolobenzodiazepine (PBD) dimer warhead, which triggers cell death via formation of highly cytotoxic interstrand cross-links. Data from a Phase (Ph) 1 dose-escalation, dose-expansion trial demonstrated an overall response rate (ORR) in pts with cHL of 86.5% (48.6% complete response [CR] rate) at the 45 μg/kg dose. Cami had a generally acceptable safety profile at Ph 1 but there were 5/77 cases (6.5%) of Guillain-Barré syndrome (GBS)/polyradiculopathy (Preferred Terms: 4 GBS and 1 radiculopathy) (Collins et al, ICML June 18-22, 2019, Lugano, Switzerland, Abstract 055). Here, we present preliminary efficacy and safety results of a Ph 2 trial of single-agent Cami in pts with R/R cHL (NCT04052997). Methods: A single-arm, multi-center, open-label, Ph 2 trial is currently enrolling pts ≥16 yrs (US) and ≥18 yrs (outside US) with R/R cHL following ≥3 prior treatment lines (or ≥2 lines in pts ineligible for hematopoietic stem cell transplantation). Eligible pts had prior treatment with brentuximab vedotin and PD-1 blockade, measurable disease per 2014 Lugano Classification, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective is to evaluate efficacy of single-agent Cami by ORR as determined by central review. Secondary objectives include further characterization of additional efficacy endpoints and safety. Pts receive 30-min IV infusions of Cami on Day 1 of each 3-week cycle at a dose of 45 μg/kg for 2 cycles, followed by 30 μg/kg for subsequent cycles for up to 1 yr or until discontinuation due to disease progression, unacceptable toxicity, or other reasons. Pts deriving clinical benefit at 1 yr may be able to continue treatment on a case-by-case basis. Treatment-emergent adverse events (TEAEs) were defined as AEs occurring/worsening from time of first dose to either 30 days post last dose or to start of new anticancer therapy/procedure, whichever occurs first. This analysis was conducted after meeting a protocol-specified criterion for pausing enrollment (≥2 cases of GBS or other relevant severe neurologic toxicity). Results: As of June 15, 2020, 47 pts with R/R cHL were enrolled and are included in this analysis. Median age was 36 (range 23-74) yrs and pts had received a median of 7 (range 3-20) lines of prior therapy, including transplant (Table 1). Pts received a median of 5 (range 2-10; mean 4.9 [SD 1.86]) cycles of Cami. ORR was 80.9% (38/47 pts), with 18 (38.3%) and 20 (42.6%) pts attaining CR and partial response, respectively; 6 pts (12.8%) had stable disease (Figure 1). TEAEs were experienced by all 47 pts; the most common (≥20% of pts) were fatigue (22, 46.8%); nausea, pyrexia, and maculopapular rash (18, 38.3% each); anemia and headache (12, 25.5% each); pruritus (11, 23.4%); arthralgia, constipation, diarrhea, hypophosphatemia, and rash (10, 21.3% each). TEAEs thought to be PBD-associated included skin reactions and nail disorders (36, 76.6%), liver function test abnormalities (14, 29.8%), and edema or effusion (7, 14.9%). There were 3 (6.4%) pts with GBS/polyradiculopathy (Preferred Terms: grade 4 subacute inflammatory demyelinating polyneuropathy, grade 2 radiculopathy, and grade 2 peripheral motor and sensory neuropathy updated to GBS after data cut-off date). In total, 27 (57.4%) pts had grade ≥3 TEAEs; the most common (≥5% of pts) were hypophosphatemia (6, 12.8%) and gamma-glutamyltransferase increased (3, 6.4%). Overall, 3 (6.4%) pts had TEAEs leading to dose reduction/delay and 6 (12.8%) pts had TEAEs leading to treatment discontinuation. Conclusions: Current data show that therapy with Cami has encouraging anti-tumor activity in heavily pretreated pts with R/R cHL. Safety was consistent with that reported at Ph 1, with no new safety concerns identified and similar incidence of GBS/polyradiculopathy. Following a positive risk-benefit assessment, the enrollment pause was lifted, and pts continue to be enrolled. Updated efficacy and safety results will be presented at the meeting. Funding: Study funded by ADC Therapeutics SA. Disclosures Herrera: Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Research Funding; Immune Design: Research Funding. Carlo-Stella:Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim and Sanofi: Consultancy; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Collins:Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Amgen: Research Funding; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau. Maddocks:Morphosys: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics, AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Bartlett:Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; ADC Therapeutics: Consultancy; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding. Savage:BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Caimi:ADCT, Kite Therapeutics, Genentech, Amgen, Verastem, TG Therapeutics, Bayer: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zinzani:ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, 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; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cruz:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Wang:ADC Therapeutics America, inc: Current Employment, Current equity holder in publicly-traded company. Feingold:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wuerthner:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Ansell:Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding.
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Suchanek, Lucjan. "Комиссия Эмигрантологии Славян и Международный Конгресс Славистов в Белграде." Acta Polono-Ruthenica 2, no. XXIV (June 30, 2019): 7–13. http://dx.doi.org/10.31648/apr.4457.
Full textAbstract:
From 20 to 27 August 2018, the International Slavic Congress took place in Belgrade. The pro-gram of the Commission held meetings that are accredited (affiliated) at the International Committee of Slavists. The congress of researches on emigration provided an opportunity to discuss the current state of research and their prospects for further development. The author of the article discusses the specifics of emigration research, paying particular attention to the achievements of Polish stud-ies, and points out the most important tasks facing the Board and the Bureau of the Commission. An important stage in the activities of the commission is the decision to move its headquarters to Olsztyn, which strengthens the Institute of Eastern Slavic studies as one of the Leading centers of emigration research, not only in Poland, but also in European science.
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Caifei, Lv. "Empirical Analysis on the Effect of Agricultural Insurance on Production——Based on panel data of 31 provinces and cities in China from 2008 to 2018." E3S Web of Conferences 214 (2020): 01013. http://dx.doi.org/10.1051/e3sconf/202021401013.
Full textAbstract:
This paper uses panel data of Insurance Statistics Yearbook and the National Bureau of Statistics of China in 31 provinces and cities from 2008 to 2018. The random effects model is used to study the direction and intensity of agricultural production impacts from agricultural insurance and its compensation. The collinearity robustness and endogeneity tests are carried out as the empirical results. It shows that agricultural insurance has a significant promotion effect on the agricultural output, and its influence will increase with the growth of risks. From the regional sub-sample regression results, agricultural insurance in the central and eastern of China is more significant than the western. Therefore, China should continue to vigorously promote the reform and innovation of agricultural insurance and its system, expand the coverage of agricultural insurance, and accelerate its high-quality.
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Dalah, Chiwa Musa, and V. V. Singh. "A Survey and Assessment Report of Hiv/Aids Awareness of in North-Eastern Nigeria." International Journal of Advanced Research in Computer Science and Software Engineering 7, no. 11 (November 30, 2017): 105. http://dx.doi.org/10.23956/ijarcsse.v7i11.473.
Full textAbstract:
Prevention is better than Cure. The effect of Human Immunodeficiency Virus/Acquired Immune deficiency syndrome (HIV/AIDS) global epidemic continue to emerge decades after the first wave of infection. One key aspect of controlling the epidemic is by enlightening the general public on the epidemic. That is on how it can be contracted and controlled. Since the start of the epidemic many measures have been taken by government and non-governmental organizations to control the epidemic but still it continued to infect and kill many people. The measures taken includes manufacturing antiretroviral drugs and therapy, using of condoms and enlightment among others. Nigeria consist of thirty-six (36) states and the federal capital territory (FCT) Abuja, and these are grouped in to six geopolitical zones. North-Eastern Nigeria consist of six states (6) namely Adamawa, Bauchi, Borno, Gombe, Taraba and Yobe states with a total population of about twenty-five million (25m), most of the people live in the rural areas where level of education is low, level of poverty is high and culture and tradition may contribute to the spread of the epidemic. Using secondary data from Federal Ministry of Health, National Bureau of Statistics (NBS), and National Agency for the Control of Aids (NACA), State Agency for the Control of Aids (SACA) and other Non- governmental organizations, the study will find out are the people of North-Eastern Nigeria aware of HIV/AIDS? Statistical methods and techniques are used in analyzing the data.
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Ravandi, Farhad, Christopher Pocock, Dominik Selleslag, Pau Montesinos, Hamid Sayar, Maurizio Musso, Angela Figuera Alvarez, et al. "Gastrointestinal Events and Management Strategies for Patients with Acute Myeloid Leukemia (AML) in First Remission Receiving CC-486 in the Randomized, Placebo-Controlled, Phase III QUAZAR AML-001 Maintenance Trial." Blood 136, Supplement 1 (November 5, 2020): 22–23. http://dx.doi.org/10.1182/blood-2020-137669.
Full textAbstract:
INTRODUCTION: About 50% of older patients with AML attain remission with intensive induction chemotherapy (IC) but the majority will eventually relapse. Effective, well tolerated maintenance treatments are needed to reduce the risk of relapse and prolong survival for older patients with AML in remission, who are less likely than younger patients to be candidates for hematopoietic stem cell transplant (HSCT). CC-486 is an oral hypomethylating agent that allows for extended dosing schedules to sustain therapeutic activity. In the randomized, phase III QUAZAR AML-001 Maintenance Trial, CC-486 significantly prolonged overall survival (OS) and relapse-free survival (RFS) vs. placebo in patients aged ≥55 years with AML in first remission after IC ± consolidation. Gastrointestinal (GI) events were the most common treatment-emergent adverse events (TEAEs) reported in patients who received CC-486. Here we assess the rates of GI TEAEs and associated management strategies over time with CC-486 treatment in QUAZAR AML-001. METHODS: Eligible patients were aged ≥55 years and had AML with intermediate- or poor-risk cytogenetics and Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤3. Patients had achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) after IC ± consolidation and were not candidates for HSCT. Within 4 months of achieving CR/CRi, patients were randomized 1:1 to CC-486 300 mg or placebo, administered once-daily on days 1-14 of repeated 28-day treatment cycles. Safety was assessed among patients who received ≥1 dose of study drug, from the date of first dose through 28 days after the last dose. Prophylaxis and treatment of GI TEAEs were allowed but not mandatory. RESULTS: In all, 236 patients received CC-486 and were evaluated for safety. The median age at study entry was 68 years (range 55-86), 202 patients (85.6%) had intermediate-risk cytogenetics at diagnosis, 185 (78.4%) had achieved CR after induction, and 184 (78.0%) received ≥1 course of consolidation before randomization. Overall, nausea, vomiting, and diarrhea (any grade) were reported in 65%, 60%, and 50%, respectively, of patients treated with CC-486. Few patients experienced grade 3 TEAEs (nausea, 3%; vomiting, 3%; diarrhea, 5%) or serious events (0.4%, 0.8%, and 1.3%, respectively), and only 1 grade 4 event (diarrhea) was reported at any time on-study. Rates of GI TEAEs were highest during initial treatment and decreased thereafter. In cycles 1-2, 3-4, and 5-6, respectively, nausea was reported in 53%, 17%, and 15% of patients; vomiting in 49%, 15%, and 10% of patients; and diarrhea in 29%, 16%, and 11% of patients (Figure). The most commonly used concomitant GI medications were 5-HT3 antagonists, metoclopramide, lactulose, and loperamide; use of these agents was also highest during the first 2 treatment cycles and decreased over time (Figure). GI events required CC-486 treatment interruptions for 13% of patients, dose-reductions for 6% of patients, and treatment discontinuation for 5% of patients. DISCUSSION: Most GI-related TEAEs reported by patients treated with CC-486 were low-grade, and events decreased in frequency after initial treatment cycles, indicating these events were well managed. Use of GI medications decreased concurrently, suggesting progressive GI tolerance to CC-486 with continued therapy. Few patients discontinued CC-486 due to GI TEAEs. Prophylaxis and symptomatic intervention of GI events during early CC-486 therapy may facilitate treatment adherence to promote better outcomes. Disclosures Ravandi: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Selleslag:Alexion: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Sayar:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Safah:Amgen: Honoraria; Astellas: Speakers Bureau; Verastem: Honoraria; Janssen: Speakers Bureau. Hiwase:Novartis Australia: Research Funding. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dombret:Otsuka: Consultancy; Abbvie: Consultancy; Servier: Consultancy, Research Funding; Sunesis: Consultancy; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy.
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Van Bodegom-Vos, L., T. P. M. Vliet Vlieland, L. Carmona, N. Damjanov, A. Domjan, A. Goehmann, A. Iagnocco, et al. "THU0653-HPR BARRIERS FOR THE UPTAKE OF EULAR POSTGRADUATE EDUCATION FOR HEALTH PROFESSIONALS IN RHEUMATOLOGY IN EASTERN EUROPEAN COUNTRIES: RESULTS FROM 3 NATIONAL SURVEYS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 571. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4480.
Full textAbstract:
Background:Health professionals play an important role in the care for people with rheumatic and musculoskeletal diseases. In order to improve and maintain the quality of their work, appropriate professional education is needed. EULAR has developed several educational products and activities specifically targeted at Health Professionals in Rheumatology (HPR), but particularly in Eastern European countries, their uptake is limited. The overarching aim of a EULAR project (named HEE4ALL: Health professionals Education in Eastern European countries for All) is to develop and execute implementation strategies for EULAR educational activities in 3 eastern European countries.Objectives:The aim of the present analysis was to identify barriers and facilitators for the uptake of EULAR educational activities among HPR in Eastern European countries.Methods:First, a questionnaire was sent to representatives of national health professionals’ or patients’ organization in 17 Eastern European countries, in order to determine their eligibility to participate in the implementation project. Eligibility criteria were: Having a national HPR organization; Willing and able to compose a team with HPR, Patients, and Rheumatologists; and Interested to participate in the project. Selected countries (minimum 3) were requested to set up a national implementation team, and conduct a national, electronic survey among HPR on anticipated barriers and needs regarding educational activities. The survey included the following elements: a. characteristics of the responding HPRs; b. Familiarity with EULAR educational offerings; c. Anticipated barriers and facilitators (score 0=no barrier at all to10 very important barrier); d. Ability to pay for the HPR online course.Results:Representatives from 10/17 Eastern European countries responded to the first questionnaire, with 3 countries meeting the selection criteria: Hungary, Serbia and Turkey. Subsequently, 216 (H:106, S:42 and T:68) HPR completed the 3 national surveys. In all 3 countries, the majority of the respondents was female (93.1%), and nurse (70.8%) or physical therapist (19.0). Familiarity with EULAR educational offerings was poor, with the lowest proportions of HPR being familiar with postgraduate face-to-face courses (13.9%), educational visits (19.0%) and the EULAR online course for HPR (25.0%). The highest ranked barriers in all 3 countries included the costs of EULAR annual congress, the costs of the EULAR HPR online course and a lack of mastery of English language.The maximum amount of money HPR were able to pay for the EULAR online course was on average €66, €29 and €83 in Hungary, Serbia and Turkey, respectively.Conclusion:Based on a survey in 3 Eastern European countries, it appears that familiarity with EULAR educational offerings is suboptimal. However, when HPR are aware of the educational offerings, their costs and a lack of mastery of the English language seem to be the most important barriers for participation. Based on these results, the 3 national teams developed implementation plans during a 2-day meeting (October 2019). The implementation plans are now executed and a process and effect evaluation is planned by November, 2020.Acknowledgments:Supported by EULAR; Project HPR 042Disclosure of Interests:Leti van Bodegom-Vos: None declared, T.P.M. Vliet Vlieland: None declared, Loreto Carmona Grant/research support from: Novartis Farmaceutica, SA, Pfizer, S.L.U., Merck Sharp & Dohme España, S.A., Roche Farma, S.A, Sanofi Aventis, AbbVie Spain, S.L.U., and Laboratorios Gebro Pharma, SA (All trhough institution), Nemanja Damjanov Grant/research support from: from AbbVie, Pfizer, and Roche, Consultant of: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Speakers bureau: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Andrea Domjan: None declared, Alzbeta Goehmann: None declared, Annamaria Iagnocco Grant/research support from: Abbvie, MSD and Alfasigma, Consultant of: AbbVie, Abiogen, Alfasigma, Biogen, BMS, Celgene, Eli-Lilly, Janssen, MSD, Novartis, Sanofi and Sanofi Genzyme, Speakers bureau: AbbVie, Alfasigma, BMS, Eli-Lilly, Janssen, MSD, Novartis, Sanofi, Marija Kosanovic: None declared, Rikke Helene Moe: None declared, Wilfred Peter: None declared, Marija Segrt: None declared, Eda Tonga: None declared, Codruta Zabalan: None declared
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Gold, Thomas B. "New Shanghai: The Rocky Rebirth of China's Legendary City. By Pamela Yatsko. [New York: John Wiley, 2001. viii+298pp. Hard cover ISBN 0-471-84352-0; paperback ISBN 0-471-47915-2.]." China Quarterly 170 (June 2002): 477–502. http://dx.doi.org/10.1017/s0009443902230284.
Full textAbstract:
As an admitted Shanghai chauvinist, I look forward to reading books dealing with the city where I studied more than two decades ago, particularly ones such as this which promise a rather comprehensive overview of the Shanghai scene at the turn of the millennium. Pamela Yatsko served as Far Eastern Economic Review bureau chief there in the mid-to-late 1990s, and obviously knows the city and its people well. She shared, as I did, their frustration throughout the 1980s as they watched cities such as Hong Kong become world economic powers (spearheaded by Shanghainese refugees), and backwaters such as Shenzhen, which barely existed until the 1980s, attract global attention for their explosive growth. And she cannot avoid being struck by the rapidity with which Shanghai rebuilt itself once Beijing gave the green light after Deng Xiaoping's 1992 visit.
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Daver, Naval G., Pau Montesinos, Daniel J. DeAngelo, Eunice S. Wang, Nikolaos Papadantonakis, Eric Deconinck, Harry P. Erba, et al. "A Phase I Study of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia, Blastic Plasmacytoid Dendritic Cell Neoplasm, and Other CD123-Positive Hematologic Malignancies." Blood 134, Supplement_1 (November 13, 2019): 1334. http://dx.doi.org/10.1182/blood-2019-128275.
Full textAbstract:
Background: Overexpression of CD123, the alpha subunit of the IL-3 receptor, occurs in multiple hematological malignancies, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute lymphoblastic leukemia (ALL) and others, thus making this antigen an attractive target for the development of new therapeutics. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprising a novel anti-CD123 antibody coupled, via a peptide linker, to a unique DNA-alkylating cytotoxic payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class. Preclinically, IMGN632 has demonstrated potent activity against AML, BPDCN and ALL models, with a wide therapeutic index in animal models, as well as a 150-fold differential cytotoxicity in AML patient samples compared to normal hematopoietic progenitors (PMIDs: 29661755, 30361418). Remarkable sensitivity of BPDCN patient derived xenografts to IMGN632 has been demonstrated (Blood 2018 132:3956). These findings suggest a potential profile of robust efficacy and favorable tolerability in multiple hematologic malignancies. Study Design and Methods: This open-label Phase 1 study comprises a dose escalation phase designed to establish the maximum tolerated dose (MTD) for IMGN632 administered using two dosing schedules, as well as subsequent dose expansion cohorts to further explore the safety and preliminary anti-leukemia activity of IMGN632 in relapsed AML and BPDCN. Adult patients with CD123-positive, relapsed or refractory AML or BPDCN, may be eligible to enroll. Additional inclusion criteria include up to 3 prior lines of therapy (which may include transplant) and an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Patients with active central nervous system disease, history of veno-occlusive disease of the liver, or history of grade 3-4 capillary leak syndrome or non-cardiac grade 3-4 edema are ineligible. Two schedules have been evaluated during dose escalation: Schedule A, IMGN632 administered intravenously on Day 1 of a 21-day cycle (Q3W); and Schedule B, fractionated dosing (i.e. one-third total dose) of IMGN632 administered on Days 1, 4, and 8 of a 21-day cycle. IMGN632 was escalated from 0.015 to 0.45 mg/kg on Schedule A in both AML and BPDCN patients, and from 0.015 to 0.06 mg/kg on schedule B in patients with AML. Escalation on both schedules is complete. Currently, two expansion cohorts have been opened, with patients receiving IMGN632 at 0.045 mg/kg IV Q3W. In cohort 1, a total of 50 relapsed/refractory BPDCN patients are planned to assess the activity of IMGN632 in this population; prior SL-401 is allowed. In cohort 2, 20 relapsed AML patients (1 or 2 prior lines of therapy, and who have previously achieved a complete response) will be enrolled to aid in the design of future monotherapy and combination studies. Given the rarity of BPDCN, and the lack of therapeutic options for relapsed/refractory patients, enrollment of these patients continues with high priority. Clinical results from this study and the design of the phase 1b/2 combination study are reported in separate abstracts. Clinical trial information: NCT03386513. Disclosures Daver: Agios: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Abbvie: Consultancy, Research Funding; NOHLA: Research Funding; Jazz: Consultancy; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; Astellas: Consultancy; BMS: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Otsuka: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Abbvie: Consultancy, Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Sunesis: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Servier: Research Funding; NOHLA: Research Funding; Celgene: Consultancy; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Research Funding. Montesinos:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. DeAngelo:Abbvie: Research Funding; Glycomimetics: Research Funding; Blueprint: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Papadantonakis:Agios: Consultancy, Honoraria. Erba:Pfizer: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy. Pemmaraju:mustangbio: Consultancy, Research Funding; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Lane:AbbVie: Research Funding; Stemline Therapeutics: Research Funding; N-of-One: Consultancy. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Konopleva:Agios: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Astra Zeneca: Research Funding. Sloss:ImmunoGen: Employment. Culm-Merdek:ImmunoGen Inc: Employment. Wang:ImmunoGen Inc: Employment. Malcolm:ImmunoGen Inc: Employment. Zweidler-McKay:ImmunoGen: Employment. Kantarjian:Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding.
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Payne, Tony. "Robert Thomson, Green Gold: Bananas and Dependency in the Eastern Caribbean (London: Latin America Bureau, 1987, £12.95 hb, £3.95 pb). Pp. vii + 93." Journal of Latin American Studies 20, no. 2 (November 1988): 493–94. http://dx.doi.org/10.1017/s0022216x00003308.
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Litten, Frederick S. "The Noulens Affair." China Quarterly 138 (June 1994): 492–512. http://dx.doi.org/10.1017/s0305741000035852.
Full textAbstract:
The arrest in Shanghai of Hilaire Noulens and his “wife” (their real names were Yakov Rudnik and Tatyana Moiseenko, see below), members of the Communist International's (Comintern) apparat in East Asia, the seizure of a cache of documents concerning the Far Eastern Bureau (FEB) of the Comintern and the Chinese Communist Party (CCP), the subsequent trial of the Noulens by the Chinese authorities, and the interest taken in the case by numerous Communist-led organizations and fellow-travelling intellectuals was a cause célèbre in the early 1930s, in the foreign community in China as well as in Europe and North America. Despite having been compared to the notorious Sacco-Vanzetti case, and having been nearly as spectacular and important as the 1927 raid on the Soviet Embassy in Peking, the Noulens Affair as a whole has not been the subject of any reliable study.
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Phillips, Tycel J., Paolo Corradini, Ronit Gurion, Caterina Patti, Monica Tani, Abraham Avigdor, Wojciech Jurczak, et al. "Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Marginal Zone Lymphoma (CITADEL-204)." Blood 136, Supplement 1 (November 5, 2020): 27–28. http://dx.doi.org/10.1182/blood-2020-134451.
Full textAbstract:
Background: Marginal zone lymphoma (MZL) is a clinically heterogeneous, indolent, non-Hodgkin lymphoma (NHL) with 3 subtypes classified as extranodal, nodal, and splenic MZL. Parsaclisib, a potent, highly-selective, next-generation phosphatidylinositol 3 kinase (PI3K) δ inhibitor, has shown promising response rates in a phase 1/2 study in patients with previously treated B-cell malignancies. CITADEL-204 (NCT03144674) is a multicenter, open-label phase 2 study of parsaclisib in patients with relapsed or refractory (R/R) MZL. Here, we report preliminary results for patients who were not previously treated with a Bruton's tyrosine kinase inhibitor (BTKi-naïve). Methods: Eligible patients were ≥18 years of age with histologically confirmed MZL who received ≥1 prior line of systemic therapy, including anti-CD20 therapy, but were BTKi-naïve. Patients had documented disease progression or lack of response to the most recent regimen, had radiologically measurable lymphadenopathy or extranodal lymphoid malignancy (or histologically confirmed bone marrow infiltration in cases of splenic MZL), and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Patients were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were assessed by an independent review committee (IRC). Safety was evaluated in all treated patients, and efficacy was evaluated in all treated patients who had a follow-up of ≥9 weeks, had at least 1 post-baseline assessment, or discontinued study participation prematurely. Results: From December 2017 to January 17, 2020 (data cut-off), 99 patients (WG, n = 28; DG, n = 71) were treated. Median age was 71 years; 52.5% of the patients were male, 94.9% had an ECOG PS ≤1, and 31.3%, 33.3%, and 35.4% had nodal, extranodal, and splenic MZL, respectively. The median number of prior systemic therapies was 2. At cut-off, 40 (40.4%) patients had discontinued treatment, including 20 (20.2%) for disease progression. The median parsaclisib exposure (range) was 7.5 months (0.4−22.4). At the data cut-off, 94 patients were evaluable for response, including 66 in DG (Table). Median (range) follow-up for the efficacy evaluable population was 11.1 months (1.2−25.0) overall and 9.5 months (1.2−25.0) in DG. The ORR (95% confidence interval [CI]) was 54.3% (43.7−64.6) overall and 57.6% (44.8−69.7) in DG; the ORR (95% CI) was 48.3% (29.4−67.5), 50.0% (31.9−68.1), and 63.6% (45.1−79.6) for patients with nodal, extranodal, and splenic MZL, respectively (Table). The median time to response was 8 weeks. The median DOR (95% CI) was 9.3 months (6.2−not evaluable [NE]) among all responders and 9.4 months (6.0-NE) in DG. The median PFS (95% CI) was 13.8 months (8.8−NE) overall and 11.5 months (8.3-NE) in DG. Among the 99 treated patients, the most common treatment-emergent AEs (TEAEs) were diarrhea (36.4% of patients), cough (18.2%), and rash (14.1%). The most common TEAEs grade ≥3 were neutropenia and diarrhea (8.1%, each). The most common serious TEAEs were febrile neutropenia and pneumonia (5.1%, each). TEAEs leading to dose interruption or dose reduction occurred in 47.5% and 14.1% of patients, respectively. TEAEs leading to discontinuation occurred in 15.2% of patients; the most common events were diarrhea (5.1%) and colitis (3.0%). TEAEs leading to death occurred in 4 patients, with 2 events, febrile neutropenia (n = 1) and sepsis (n = 1), deemed treatment related. New or worsening grade ≥3 laboratory test values of clinical interest included increase in alanine/aspartate amino transferase (2.0%/1.0% of patients), and decrease in neutrophil count (13.1%), platelet count (3.0%), and hemoglobin (3.0%). Conclusion: BTKi-naïve patients with R/R MZL achieved rapid and durable responses with single-agent parsaclisib. Comparable efficacy was observed in patients diagnosed with nodal, extranodal, or splenic MZL. Treatment with parsaclisib was generally well tolerated without unexpected toxicities. Updated data will be presented. Disclosures Phillips: Incyte: Consultancy, Other: travel expenses; Seattle Genetics: Consultancy; BMS: Consultancy; Bayer: Consultancy, Research Funding; Pharmacyclics: Consultancy; Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Beigene: Consultancy; Karyopharm: Consultancy; Cardinal Health: Consultancy. Corradini:KiowaKirin: Consultancy, Honoraria; Incyte: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Servier: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Gurion:Medison: Consultancy; Gilead Sciences: Consultancy; Takeda Pharmaceuticals: Consultancy; JC Health CARE: Honoraria; Roche: Honoraria. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Jurczak:MorphoSys: Research Funding; European Medicines Agency,: Consultancy; Sandoz-Novartis: Consultancy; Takeda: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; MEI Pharma: Research Funding; Janssen China R&D: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Research Funding; Afimed: Research Funding; Celgene: Research Funding; Epizyme: Consultancy; Gilead Sciences: Research Funding; Nordic Nanovector: Research Funding; Servier: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; TG Therapeutics, Inc.: Research Funding; Acerta: Consultancy, Research Funding; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; AstraZeneca: Consultancy. Mehta:Affimed: Research Funding; Kite/Gilead: Research Funding; Roche-Genentech: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; Innate Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding; fortyseven Inc/Gilead: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Research Funding; Juno Parmaceuticals/BMS: Research Funding. Zinzani:Gilead: Consultancy, Honoraria, 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; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lossos:Seattle Genetics: Consultancy, Other; NCI: Research Funding; Stanford University: Patents & Royalties; Janssen Scientific: Consultancy, Other; Verastem: Consultancy, Honoraria; Janssen Biotech: Honoraria. Thieblemont:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Incyte: Honoraria; Bayer: Honoraria; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hospira: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. Rappold:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zhao:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Johnson:Incyte: Honoraria; Kite Pharma: Honoraria; Kymera: Honoraria; Boehringer Ingelheim: Consultancy; MorphoSys: Honoraria; Oncimmune: Consultancy; Takeda: Honoraria; Novartis: Honoraria; Epizyme: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Honoraria; Bristol-Myers: Honoraria; Genmab: Honoraria; Epizyme: Consultancy, Research Funding; Janssen: Consultancy; Oncimmune: Consultancy.
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Hillmen, Peter, Jennifer R. Brown, John C. Byrd, Barbara F. Eichhorst, Nicole Lamanna, Susan M. O'Brien, Lugui Qiu, et al. "Alpine: Phase 3 Trial of Zanubrutinib (BGB-3111) Vs Ibrutinib in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)." Blood 134, Supplement_1 (November 13, 2019): 4307. http://dx.doi.org/10.1182/blood-2019-124213.
Full textAbstract:
Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic (PK) and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may also be co-administered with strong or moderate CYP3A inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients (pts) with either non-Hodgkin lymphoma, Waldenström macroglobulinemia, or CLL/SLL suggests that zanubrutinib has been generally well tolerated amongst pts with B-cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data in pts with treatment-naïve (TN; n=22) or relapsed/refractory (R/R; n=56) CLL/SLL showed that zanubrutinib was highly active: 96.2% overall response rate (ORR), including 4.5% and 1.8% with complete response in TN and R/R CLL/SLL, respectively (Tam et al. Blood 2019). Study Design and Methods: This ongoing phase 3, randomized, global study (ALPINE; NCT03734016) is designed to compare the efficacy of zanubrutinib to ibrutinib based on ORR in pts with R/R CLL/SLL (Figure). This open-label study randomizes approximately 400 pts 1:1 to each arm, stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region (China vs other), and del(17p)/TP53 mutation status (present vs absent). The study population includes adult pts who have had prior treatment for their CLL/SLL and were either refractory to or relapsed from prior CLL/SLL treatment. Major inclusion criteria include R/R CLL/SLL requiring treatment per International Workshop on CLL (iwCLL) criteria, disease measurable by computed tomography/magnetic resonance imaging, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematologic function. Major exclusion criteria include prior treatment with a BTK inhibitor, current or past history of Richter transformation, clinically significant cardiovascular disease, or history of severe bleeding disorder. Zanubrutinib is dosed at 160 mg twice daily, and ibrutinib is dosed per label at 420 mg daily; treatment in both arms may continue until progression. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for pts with CLL and per 2014 Lugano Classification for pts with SLL. The study is powered to test the non-inferiority, and subsequently the superiority, of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, ORR as determined by investigator, safety, duration of response, overall survival, and pt-reported outcomes. Exploratory endpoints include the correlation between clinical outcomes and prognostic and predictive biomarkers. Recruitment began in November 2018 and is ongoing in 14 countries. Disclosures Hillmen: Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: 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, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Brown:AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Juno/Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Byrd:Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S. Eichhorst:BeiGene: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lamanna:Celgene: Consultancy; Oncternal: Research Funding; TG Therapeutics: Research Funding; Ming: Research Funding; Infinity/ Verastem: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Regeneron: Research Funding; Eisai: Consultancy; Celgene: Consultancy; Aptose Biosciences, Inc: Consultancy; TG Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Verastem: Consultancy; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; Vaniam Group LLC: Consultancy. Salmi:BeiGene: Employment. Hilger:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie company: Honoraria; Novartis: Honoraria; BeiGene: Honoraria; Roche: Honoraria. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US
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Voichenko, V. V., G. G. Roshchin, O. O. Dyadyk, I. V. Irkin, O. Yu Petrochak, Е. Ya Kostenko, V. V. Vyun, and M. D. Zubko. "Expediemcy of using a comprehensive approach in the identification of missing persons." Biomedical and Biosocial Anthropology, no. 37 (December 26, 2019): 10–14. http://dx.doi.org/10.31393/bba37-2019-02.
Full textAbstract:
The identification of missing persons in armed conflict and with mass casualties in emergencies has its own characteristics and requires an integrated approach to increase accuracy and objectivity. The aim of the study justification of the appropriateness of an integrated approach in identifying persons missing in an armed conflict with mass casualties. In the work, archival materials of forensic medical examinations of the commemorative institution “Dnipropetrovsk Regional Bureau of Forensic Medical Examination” were used regarding those who died during the armed conflict with mass casualties in eastern Ukraine during 2014-2019. Research methods: anthropometric, morphometric, photographic, radiological, forensic methods, computer simulation method, molecular genetic, statistic. The article sets out the domestic experience of increasing the objectivity and accuracy of identifying missing persons and determining the characteristics of bodily injuries and traumatic factors through an integrated approach using anthropometric, morphometric, photographic, radiological, molecular genetics and medical and criminalistics methods and in situations of armed conflict with mass casualties. However, the presence of only a modern morgue and the latest equipment in the laboratory department of the forensic medical examination bureau is not a guarantee of a successful examination to identify the deceased. As the experience of different countries in the case of mass natural and man-made disasters shows – the key element is the correct and consistent organization of research. The experience of conducting identification studies in Ukraine of missing persons in an armed conflict with mass casualties of people indicates the appropriateness of applying an integrated approach that improves the objectivity and accuracy of the study.
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Chrzanowski, Bogdan. "Concepts for reconstruction of the maritime economy of the polish underground state...in the years 1940–1944." Annales Universitatis Paedagogicae Cracoviensis. Studia Politologica 24, no. 324 (May 15, 2021): 142–51. http://dx.doi.org/10.24917/20813333.24.10.
Full textAbstract:
The regaining of the country’s independence, and then its revival after the war damages, including itseconomic infrastructure – these were the tasks set by the Polish government in exile, first in Paris and thenin London. The maritime economy was to play an important role here. The Polish government was fullyaware of the enormous economic and strategic benefits resulting from the fact that it had a coast, withthe port of Gdynia before the war. It was assumed that both in Gdynia and in the ports that were to belongto Poland after the war: Szczecin, Kołobrzeg, Gdańsk, Elbląg, Królewiec, the economic structure was to betransformed, and they were to become the supply points for Central and Eastern Europe. Work on thereconstruction of the post-war maritime economy was mainly carried out by the Ministry of Industry, Tradeand Shipping. In London, in 1942–1943, a number of government projects were set up to rebuild the entiremaritime infrastructure. All projects undertaken in exile were related to activities carried out by individualunderground divisions of the Polish Underground State domestically, i.e. the “Alfa” Naval Department of theHome Army Headquarters, the Maritime Department of the Military Bureau of Industry and Trade of the Headof the Military Bureau of the Home Army Headquarters and the Maritime Department of the Departmentof Industry Trade and Trade Delegation of the Government of the Republic of Poland in Poland. The abovementionedorganizational units also prepared plans for the reconstruction of the maritime economy, and theprojects developed in London were sent to the country. They collaborated here and a platform for mutualunderstanding was found.
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Park, Soon-Ung, and Jeong Hoon Cho. "Air Quality in East Asia during the heavy haze event period of 10 to 15 January 2013." International Journal of Energy and Environment 15 (March 24, 2021): 1–9. http://dx.doi.org/10.46300/91012.2021.15.1.
Full textAbstract:
A prolonged heavy haze event that has caused for the Environmental Protection Bureau (EPB) in Beijing to take emergency measures for the protection of the public health and the reduction of air pollution damages in China has been analyzed with the use of the Aerosol modeling System (AMS) to identify causes of this event. It is found that the heavy haze event is associated with high aerosols and water droplets concentrations. These high aerosol concentrations are mainly composed of anthropogenic aerosols, especially secondary inorganic aerosols formed by gas-to-particle conversion of gaseous pollutants in the eastern part of China whereas those in the northeastern parts of China are composed of the mixture of the anthropogenic aerosols and the Asian dust aerosol originated from the dust source regions of northern China and Mongolia. These high aerosol concentrations are found to be subsequently transported to the downwind regions of the Korean Peninsula and Japan causing a prolonged haze event there. It is also found that the Asian dust aerosol originated from northern China and Mongolia and the anthropogenic aerosols produced by chemical reactions of pollutants in the high emissions region of eastern China can cause significantly adverse environmental impacts in the whole Asian region by increased atmospheric aerosol loadings that may cause respiration diseases and visibility reduction and by excess deposition of aerosols causing adverse impacts on terrestrial and marine eco-systems.
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Furman, Richard R., William G. Wierda, Anna Schuh, Stephen Devereux, Jorge M. Chaves, Jennifer R. Brown, Peter Hillmen, et al. "Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: 42-Month Follow-up of a Phase 2 Study." Blood 134, Supplement_1 (November 13, 2019): 3039. http://dx.doi.org/10.1182/blood-2019-128706.
Full textAbstract:
Background: Targeted inhibition of Bruton tyrosine kinase (BTK) has improved clinical outcomes for patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a highly selective, covalent BTK inhibitor. A recently completed phase 3 trial showed acalabrutinib improved progression-free survival (PFS) vs idelalisib or bendamustine + rituximab in relapsed/refractory (R/R) CLL patients (ASCEND: Ghia et al. EHA 2019;273259:LB2606). This is an updated analysis with extended follow-up of a phase 1-2 multicenter study (NCT02029443) in patients with R/R CLL/small lymphocytic lymphoma (SLL), to demonstrate the durability of response and long-term tolerability of acalabrutinib. Methods: Patients with CLL or SLL were eligible if they were R/R after ≥1 prior treatment. Eligible patients were ≥18 years of age with an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Oral acalabrutinib 100 mg was administered twice daily. All patients were treated until progressive disease or unacceptable toxicity occurred. Study endpoints included overall response rate (ORR), PFS, duration of response (DOR) and safety, with post hoc analysis of event-free survival (EFS). Response rates were based on the International Workshop on Chronic Lymphocytic Leukemia 2008 criteria (Hallek et al., 2008) with modification for lymphocytosis (Cheson et al., 2012). Nine patients had longitudinal peripheral blood mononuclear cell samples from pre-treatment baseline, during treatment and at progression analyzed for whole exome sequencing, to assess acquired mechanisms of treatment resistance. Results: In total, 134 patients with R/R CLL/SLL received ≥ 1 dose of acalabrutinib. The median age was 66 years (range, 42-85 years). Baseline characteristics included ECOG PS ≤1 (97%), bulky lymph nodes ≥5 cm (39%), unmutated immunoglobulin heavy chain variable region (IGHV; 73%), chromosome 17p13.1 deletion (23%), chromosome 11q22.3 deletion (18%), and complex karyotype (≥3 abnormalities; 35%). The median number of prior therapies was 2 (range, 1-13). Patients received acalabrutinib for a median of 41 months (range, 0.2-58 months). Most adverse events (AEs) were mild to moderate, and most commonly were diarrhea (52%), headache (46%), and upper respiratory tract infection (36%). Grade ≥3 AEs occurred in 66% of patients; most commonly (≥5% of patients) neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%) and diarrhea (5%). AEs of interest included atrial fibrillation (7% all grades; 3% Grade ≥3) and major bleeding events (5% all grades; 3% Grade ≥3). Most patients (56%) remained on treatment. The most common reasons for discontinuing treatment were progressive disease (21%) and AEs (11%). AEs leading to discontinuation occurring in ≥1 patient included pneumonia (4 events), anemia, neutropenia, and thrombocytopenia (2 events each). The ORR (partial response with lymphocytosis or above) was 94% (95% confidence interval [CI]: 89-97%); with 4% of patients having complete response, 84% having partial response and 6% having partial response with lymphocytosis (Table). The median DOR, PFS and EFS were not reached; the estimated 42-month DOR was 61% (95% CI: 49-71%), PFS was 68% (95% CI: 59-76%) and EFS was 64% (95% CI: 54-71%). Responses were similar regardless of genomic features, including unmutated IGHV, chromosomal deletions and complex karyotype (Table). Upon relapse during acalabrutinib treatment, whole exome sequencing detected BTK mutations in 6 of 9 (67%) tested patients that were not detectable at baseline. Of the 6 patients with detectable BTK C481X mutations, 4 had expansion to high allele frequency of the BTK mutation at progression (up to 58%). In a longitudinal analysis of patients who had a sample after 6 months of treatment, the BTK mutation was not detectable. No PLCG2 gene mutations were detected using exome analysis in the 9 patients analyzed. Conclusions: These updated results confirm the earlier reports of acalabrutinib efficacy for the treatment of CLL and provide additional data on DOR and long-term tolerability. Reported AEs indicate a tolerable and consistent safety profile, with a low rate of major bleeding events. Genomic profiling in a small subset of patients indicated that acquired mutation of BTK was the most frequent mechanism of acalabrutinib resistance. Disclosures Furman: Genentech: Consultancy. Wierda:Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding. Schuh:Roche: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Devereux:Servier: Speakers Bureau; Roche: Consultancy, Other: Travel expenses, Speakers Bureau; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau. Brown:Pfizer: Consultancy; Sun: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy; Morphosys: Other: Data safety monitoring boards ; Sun Pharmaceuticals, Inc: Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Martin:Karyopharm: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy. Awan:Sunesis: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Innate Pharma: Research Funding; Gilead: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Stephens:Acerta: Research Funding; Gilead: Research Funding; Karyopharm: Research Funding. Ghia:Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy. Barrientos:Bayer: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Burke:AstraZeneca: Employment, Equity Ownership. Covey:Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership. Gulrajani:AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership. Hamdy:Acerta Pharma: Employment, Equity Ownership. Izumi:Acerta Pharma: Employment, Equity Ownership. Frigault:Acerta Pharma: Employment; AstraZeneca: Employment, Equity Ownership. Patel:Acerta Pharma: Employment, Equity Ownership. Rothbaum:Acerta Pharma: Employment, Equity Ownership. Wang:AstraZeneca: Equity Ownership; Acerta Pharma: Employment. O'Brien:Eisai: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; Verastem: Consultancy; Vaniam Group LLC: Consultancy; Astellas: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding. Byrd:Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau. OffLabel Disclosure: This is a Phase 1/2 investigational study of acalabrutinib in chronic lymphocytic leukemia
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Fowler, Nathan H., Judith Trotman, Rebecca Auer, Christopher R. Flowers, William F. Reed, Elena Ivanova, Jane Huang, and Pier Luigi Zinzani. "Randomized Phase 2 Zanubrutinib (BGB-3111) + Obinutuzumab Vs Obinutuzumab Monotherapy in Patients with Relapsed/Refractory Follicular Lymphoma (R/R FL)." Blood 134, Supplement_1 (November 13, 2019): 5252. http://dx.doi.org/10.1182/blood-2019-122628.
Full textAbstract:
Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. First generation BTK inhibitor ibrutinib has limited activity as monotherapy in R/R FL (Gopal et al. J Clin Oncol 2018). Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic (PK) and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may also be co-administered with strong or moderate CYP3A inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. In preclinical studies, zanubrutinib had minimal inhibitory effects against ITK and did not inhibit ITK-mediated anti-CD20-induced antibody-dependent cell-mediated cytotoxicity (Li et al. Cancer Res 2015). Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients (pts) with either non-Hodgkin lymphoma (NHL), Waldenström macroglobulinemia, or chronic lymphocytic leukemia suggests that zanubrutinib was generally well tolerated amongst pts with B cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data from a phase 1b dose-escalation study including 36 pts with R/R FL (median 2 [range, 1-9] prior lines of therapy) treated with the combination of zanubrutinib with anti-CD20 antibody obinutuzumab reported an overall response rate (ORR) of 72.2% including complete response in 14 pts (38.9%); median progression-free survival was 24.9 mo (Tam et al. ICML 2019). Study Design and Methods: This ongoing phase 2, global, randomized, open-label, active-controlled study (ROSEWOOD; NCT03332017) is examining zanubrutinib + obinutuzumab vs. obinutuzumab monotherapy in pts with R/R FL who have received ≥2 prior lines of therapy (Figure). Eligible pts must have histologically-confirmed grade 1-3a B-cell FL and measurable disease, and have received prior anti-CD20 antibody and alkylator-based combination therapy. Pts are randomized 2:1 to receive oral zanubrutinib 160 mg twice daily + obinutuzumab or obinutuzumab alone (both arms in 28-day cycles, at 1000 mg IV on days 1, 8, and 15 of cycle 1; day 1 of cycles 2-6; and then once every 8 weeks) until progressive disease (PD), toxicity or a maximum of 30 mo of obinutuzumab. Pts receiving zanubrutinib should remain on study treatment until PD. Randomization is stratified by prior therapies (2-3 vs >3) and rituximab-refractory status. Disease response is assessed per the 2014 Lugano Classification for NHL. The primary endpoint is ORR by independent review committee (IRC). Response rates will be compared between groups in an intent-to-treat analysis. Key secondary endpoints include ORR by investigator assessment, rate of complete response or complete metabolic response, time to and duration of response, progression-free survival (all IRC and investigator assessments), overall survival, and safety. At the investigator's discretion, pts in the obinutuzumab arm can cross over to the combination arm if they have PD at any time or less than partial response after 12 mo. Recruitment is ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Trotman:Celgene: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Janssen: Research Funding. Auer:Hartley Taylor: Honoraria; Janssen: Honoraria, Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees; Celgene: Other: personal fees. Flowers:TG Therapeutics: Research Funding; National Cancer Institute: Research Funding; Spectrum: Consultancy; V Foundation: Research Funding; BeiGene: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Denovo Biopharma: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Bayer: Consultancy; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Optimum Rx: Consultancy; Eastern Cooperative Oncology Group: Research Funding. Reed:BeiGene: Employment, Equity Ownership, Other: Travel & Accommodations. Ivanova:BeiGene: Employment. Huang:BeiGene: Employment, Equity Ownership. Zinzani:TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US
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Shallis, Rory M., Maximilian Stahl, Wei Wei, Pau Montesinos, Etienne Lengline, Judith Neukirchen, Vijaya R. Bhatt, et al. "Outcomes of Patients with Newly-Diagnosed Acute Myeloid Leukemia and Hyperleukocytosis Who Did Not Undergo Intensive Chemotherapy: Results from a Large International Database." Blood 132, Supplement 1 (November 29, 2018): 3999. http://dx.doi.org/10.1182/blood-2018-99-119755.
Full textAbstract:
Abstract Introduction: Hyperleukocytosis at time of acute myeloid leukemia (AML) diagnosis is associated with increased disease-related complications as well as early mortality. Many AML patients are not candidates for intensive chemotherapy (IC) because of disease-related or patient-specific factors. Limited data is available regarding the characteristics and outcomes of newly-diagnosed AML who present with hyperleukocytosis and do not receive IC. Methods: We retrospectively analyzed data from patients with newly-diagnosed AML and hyperleukocytosis (defined as white blood cell count [WBC] of 50 × 109/L or greater) who were reported not to have received IC at 12 major institutions in the United States, Spain, Germany and France from 1982 to the end of 2016. Collected variables included age, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), WBC, hemoglobin level, platelet count, renal and hepatic chemistry parameters, cytogenetic risk group, molecular abnormalities (if available), presence of tumor lysis syndrome (TLS), disseminated intravascular coagulation (DIC), clinical evidence of leukostasis, admission to an intensive care unit (ICU) at presentation, receipt of hydroxyurea, and administration of leukapheresis. Clinical evidence of leukostasis was defined as new onset hypoxia, chest pain, headache, focal neurological symptoms, priapism, intestinal ischemia and acute renal failure attributed to hyperleukocytosis by the primary provider of the patient. Kaplan-Meier analysis was used to estimate overall survival (OS) from time of presentation until death or end of follow-up. Patients with hyperleukocytosis who received IC are described in a separate abstract. Results: Of 1050 patients with AML and hyperleukocytosis reported to our dataset, 220 patients were reported not to have received IC and were included in this analysis. For those 220 patients, median age was 75 years, 57.7% were male, and most (62.8%) had an ECOG PS of 2 or greater. Median WBC, hemoglobin, and platelet count at presentation were 131.4 × 109/L (range [R], 50.4-620), 8.96 g/dL (R, 3.6-15.9), and 34 (R, 3-393), respectively; 61.5% presented with a WBC greater than 100 × 109/L. Cytogenetically-defined poor risk AML was diagnosed in 26.1% of patients. TLS, DIC or clinical leukostasis was present in 25.6%, 15.7%, and 32.5% of patients, respectively. Pulmonary, central nervous system, renal, cardiac, gastrointestinal, or retinal clinical evidence of leukostasis was present in 52.9%, 17.1%, 11.4%, 10%, 5.7% and 2.9%, respectively, of those with clinical leukostasis. The majority (72.9%) of patients received initial therapy with hydroxyurea with a median time from presentation to administration of 12 hours (R, 1-144). Only 15% of patients underwent leukapheresis. Commonly-used non-IC therapies included hypomethylating agents, clofarabine, low dose cytarabine, or best supportive care. The median OS of the entire cohort was only 22 (95%CI: 13-37) days. The 30-day mortality was 57.4%. The 60-day, 90-day, 180-day, and one-year OS probabilities were 37%, 31%, 20%, and 12%, respectively. Only 4.3% of patients proceeded to allogeneic stem cell transplant. Patients presenting with WBC >100 × 109/L (N=79) had a worse OS than those presenting with WBC <100 × 109/L (N=126), (median OS 0.4 [95%CI, 0.3-0.7] vs. 2 [95%CI, 1.2-3.5] months, respectively, p=0.02) and those with clinical evidence of leukostasis (N=50) had worse OS than those who did not (N=104), (median OS, 0.2 [95%CI, 0.1-0.8] vs 2.2 [95%CI, 1.3-3.5] months, respectively, p<0.0001) (Figure). Patients who underwent leukapheresis (N=31) did not have a significantly improved OS compared to those who did not undergo leukapheresis (N=175) with a median OS of 1.2 (95%CI, 0.2-12.4) vs. 0.7 (95%CI, 0.4-1.2) months, respectively (p=0.12) (Figure). The small number of patients undergoing leukapheresis limited assessment of impact of leukapheresis in multivariable analysis. Conclusions: We report the largest studied cohort of patients with newly-diagnosed AML presenting with hyperleukocytosis who did not receive IC. Outcomes were very poor with a median OS of 22 days and only 12% alive at one year. WBC >100K x 109/L and clinical leukostasis were associated with inferior survival, while leukapheresis did not seem to impact survival. Novel and effective therapies are urgently needed for this group of AML patients. Disclosures Montesinos: Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Bhatt:Incyte: Research Funding; CSL Behring: Consultancy; Pfizer: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Fathi:Agios: Honoraria, Research Funding; Astellas: Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Khan:Teva: Speakers Bureau. Roboz:AbbVie: Consultancy; Cellectis: Research Funding; Celltrion: Consultancy; Argenx: Consultancy; Aphivena Therapeutics: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Roche/Genentech: Consultancy; Roche/Genentech: Consultancy; Eisai: Consultancy; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Sandoz: Consultancy; Orsenix: Consultancy; AbbVie: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Celltrion: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Argenx: Consultancy. Cluzeau:Pfizer: Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Mukherjee:Takeda: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Projects in Knowledge: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; LEK Consulting: Consultancy, Honoraria; Bristol Myers Squib: Honoraria, Speakers Bureau; BioPharm Communications: Consultancy; Aplastic Anemia & MDS International Foundation in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria. Brunner:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Novartis: Research Funding. Ritchie:NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Podoltsev:Astex Pharmaceuticals: Research Funding; Celator: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Boehringer Ingelheim: Research Funding; CTI biopharma: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria. Gore:Celgene: Consultancy, Research Funding. Zeidan:Otsuka: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria.
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Ege, Carl. "Devils playground, Box Elder County." Geosites 1 (December 31, 2019): 1–7. http://dx.doi.org/10.31711/geosites.v1i1.79.
Full textAbstract:
Why take your kids to the neighborhood playground, when you can visit a playground that inspires their sense of geologic adventure? Devils Playground is not your ordinary community playground, but a wonderland of granitic rock weathered into fantastic forms and weird shapes. Occupying an assortment of Bureau of Land Management, state, and private land in the Bovine Mountains, Devils Playground is a relatively unknown geologic curiosity found in a remote corner of northwestern Utah. Devils Playground is situated in the physiographic region known as the Great Basin province that extends across western Utah, Nevada, and to the Sierra Nevada Mountains in eastern California. The area is composed mostly of granitic rocks of the Emigrant Pass intrusion. A combination of granitic rock, faulting, and weathering under a semiarid climate created favorable conditions for the creation of Devils Playground. Desert plants such as sagebrush,Utah juniper, pinyon pine, Mormon tea, and cheatgrass are common throughout the area.
45
Yeh, Wen-Hsin. "Dai Li and the Liu Geqing Affair: Heroism in the Chinese Secret Service During the War of Resistance." Journal of Asian Studies 48, no. 3 (August 1989): 545–62. http://dx.doi.org/10.2307/2058639.
Full textAbstract:
The nationalist military intelligence service has long been a controversial topic in the history of the Chinese Republic (1912–49). This organization, known as the Military Bureau of Statistics and Investigation (Junshi Weiyuanhui Tongji Diaocha Ju, or Juntong), first impinged on civilian society in the 1930s, when it carried out violent deeds against urban-based intellectuals critical of the Nationalist party's rule. Newspaper writers and editors subsequently compared Juntong to the infamous Eastern Depot and Embroidered Guards of the despotic Ming emperors, denouncing the “feudal” and “fascist” nature of Nationalist rule in political tracts and assemblies. During the Pacific War the image of Juntong's chief, General Dai Li (1897–1946), was blackened when he was compared to the Nazi Heinrich Himmler by the Western press. In the bitter and protracted civil struggles between the Chinese Communist party (CCP) and the Guomindang (GMD) after 1941, the Communists focused sharply on the atrocities committed by Juntong and portrayed Dai Li as a monstrous instrument of Chiang Kai-shek's dictatorship.
46
Anghie, Antony T. "Introduction to Symposium on the Many Lives and Legacies of Sykes-Picot." AJIL Unbound 110 (2016): 105–8. http://dx.doi.org/10.1017/s2398772300002890.
Full textAbstract:
Although their motivations varied, many senior British officials who were expert in imperial and Middle-Eastern matters condemned the Sykes-Picot treaty as a mistake almost as soon as it was signed. T.E. Lawrence wanted the British government to repudiate it and was assured by Gilbert Clayton, the head of the Arab Bureau in Cairo, in a letter he wrote to Lawrence in 1917, that “‘It is in fact dead and, if we wait quietly, this fact will soon be realized’.” Lord Curzon denounced the treaty as “not only obsolete ‘but absolutely impracticable,’” and further declared that only “gross ignorance” could account for the boundary lines in the treaty. Sir Mark Sykes was said to be ashamed of his involvement in the Treaty that was to bear his name. Despite these efforts, so soon after its birth, to announce the demise and irrelevance of Sykes-Picot, its complex, variegated, and evolving legacy has survived and is still very much with us.
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Ran, Liu. "An Empirical Study on the Effect of Agricultural Infrastructure Investment on Economic Growth." E3S Web of Conferences 275 (2021): 01004. http://dx.doi.org/10.1051/e3sconf/202127501004.
Full textAbstract:
In this paper, using the panel data of the National Bureau of Statistics database from 2010 to 2019, and using the random effect model, we studied the impact of agricultural infrastructure investment on economic growth. The empirical results show that the investment in agricultural infrastructure can significantly improve the national economy, among which the investment in new infrastructure promotes the economic growth to a certain extent. After comparing the eastern, central and western regions, it is found that the investment in agricultural infrastructure in the western region contributes more to the economic growth, and the statistical results are more significant. Based on the analysis of the role of agricultural infrastructure investment in promoting economic growth, this paper will further discuss the relevant suggestions of the “two new and one heavy” policy in the agricultural field, and promote the adjustment of agricultural industrial structure with the improvement of agricultural infrastructure, and promote the formation of a new development pattern of “double circulation”.
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Wang, Michael, Simon Rule, Pier Luigi Zinzani, Andre Goy, Olivier Casasnovas, Stephen D. Smith, Gandhi Damaj, et al. "Long-Term Follow-up of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 2876. http://dx.doi.org/10.1182/blood-2018-99-110327.
Full textAbstract:
Abstract Background: Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, remains incurable with standard therapies. The highly selective, potent Bruton tyrosine kinase (BTK) inhibitor acalabrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data showing a high rate of durable responses and a favorable safety profile (Lancet 2017;391:659-667). Here, we present long-term follow-up in these patients. Methods: Eligible patients were aged ≥18 years, had confirmed MCL, Eastern Cooperative Oncology Group performance status ≤2, and had relapsed and/or were refractory to 1-5 prior therapies. Exclusion criteria included prior BTK or BCL-2 inhibitor exposure and concomitant warfarin or equivalent vitamin K antagonists. Oral acalabrutinib 100 mg twice daily was administered until progressive disease or unacceptable toxicity. Response was assessed by investigators based on the Lugano classification (J Clin Oncol 2014;32:3059-3068).Analysis of minimal residual disease using next-generation sequencing (10-6) is ongoing for a subset of patients with available samples and will be presented upon completion. Results: A total of 124 patients were treated; 80% were men, and median age was 68 years (range, 42-90 years) with 65% aged ≥65 years. At baseline, 93% of patients had Eastern Cooperative Oncology Group performance status ≤1, 8% had bulky lymph nodes ≥10 cm, 72% had extranodal involvement, and 44%/17% had intermediate-/high-risk simplified MCL International Prognostic Index scores. The median number of prior therapies was 2 (range, 1-5); 24% were refractory to the most recent prior treatment. As of February 12, 2018, median time on study was 26.3 months (range, 0.3-35.1 months), and 40% of patients remain on treatment. Median relative dose intensity (ratio of actual to planned cumulative dose during drug exposure period) was 99% (range, 27%-100%). Investigator-assessed overall response rate was 81% (95% CI: 73%, 87%), with 43% (95% CI: 34%, 52%) achieving complete response (Table). Overall response rates were consistent across prespecified subgroups of tumor bulk, presence of refractory disease and number/type of prior treatment. Median duration of response was 25.7 months (95% CI: 17.5 months, not reached). Median progression-free survival (PFS) was 19.5 months (95% CI: 16.5 months, 27.7; Figure). Median overall survival (OS) was not reached; the estimated 24-month OS rate was 72% (95% CI: 64%, 80%). The most frequent adverse events (AEs; ≥20%) were primarily Grade 1/2 and included headache (38%), diarrhea (36%), fatigue (28%), cough (22%) and myalgia (21%). Grade 3/4 AEs (≥5%) included anemia (10%), neutropenia (10%) and pneumonia (6%). There were 13 patients (10%) with 16 cardiac events, including 4 Grade 3/4 events (3%) in 1 patient each (acute coronary syndrome, acute myocardial infarction, cardiorespiratory arrest, coronary artery disease). Four patients had hypertension events (3%); 1 event was Grade 3. The most common bleeding events were contusion (13%) and petechiae (9%); all bleeding events were Grade 1/2 except for 3 Grade 3 events (gastrointestinal hemorrhage, hematuria, hematoma). Grade 3/4 infections occurred in 15% of patients and none were Grade 5; there was one case of cytomegalovirus viremia and one case of pneumocystis jiroveci pneumonia (both Grade 2). Treatment discontinuation was primarily due to progressive disease (n=54; 44%) and AEs (n=10; 8%).Twelve AEs led to discontinuation in 10 patients; all of these AEs occurred in only 1 patient each.There were 43 deaths (35%), most commonly from progressive disease (n=29; 23%) or AEs (n=6; 5%). Deaths due to AEs included bilateral pulmonary embolism, critical aortic stenosis, myelodysplastic syndrome, pneumonia, suicide, and non-small cell lung cancer; none were considered to be related to acalabrutinib. Conclusion: Response to acalabrutinib remained consistent during long-term (>24-month) follow-up, including high response rates, median PFS of 19.5 months, and a median OS that has not yet been reached, confirming efficacy in patients with relapsed/refractory MCL. The AE profile was largely similar to earlier reporting, with limited additional safety events observed with an additional year of follow-up. Disclosures Wang: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding; Kite Pharma: Research Funding; Novartis: Research Funding. Rule:Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; Kite: Membership on an entity's Board of Directors or advisory committees. Zinzani:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: 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, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau. Casasnovas:MSD: Honoraria; Merck: Honoraria; Takeda: Honoraria; Roche: Honoraria; Gilead Sciences: Research Funding; Roche: Research Funding; Janssen: Consultancy; Gilead Sciences: Consultancy; MSD: Consultancy; merck: Consultancy; takeda: Consultancy; Roche: Consultancy; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Smith:Genentech: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck Sharpe Dohme and Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding. Morschhauser:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Panizo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Roche: Consultancy, Speakers Bureau. Davies:Janssen: Consultancy, Honoraria; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; ADC Therapeutics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding. Jacobsen:Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Merck: Consultancy. Kater:Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Acerta/AZ: Research Funding; Genentech: Honoraria, Research Funding. Robak:Gilead: Consultancy; Janssen: Consultancy, Honoraria; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria. Dua:Acerta Pharma: Employment. Frigault:AstraZeneca: Employment, Equity Ownership. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acerta Pharma, various patents for ACP-196. Nguyen:Acerta Pharma: Employment. Patel:Acerta Pharma: Employment, Equity Ownership. Yin:Acerta Pharma: Employment. Jurczak:European Medicines Agency: Consultancy; Astra Zeneca/Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Afimed: Research Funding; Bayer: Research Funding; Beigene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding.
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Speer, Milton, Lance Leslie, Joshua Hartigan, and Shev MacNamara. "Changes in Frequency and Location of East Coast Low Pressure Systems Affecting Southeast Australia." Climate 9, no. 3 (March 5, 2021): 44. http://dx.doi.org/10.3390/cli9030044.
Full textAbstract:
Low pressure systems off the southeast coast of Australia can generate intense rainfall and associated flooding, destructive winds, and coastal erosion, particularly during the cool season (April–September). Impacts depend on coastal proximity, strength and latitude. Therefore, it is important to investigate changes in frequency, duration, location, and intensity of these systems. First, an existing observation-based database of these low pressure systems, for 1970–2006, is extended to 2019, focusing on April–September and using archived Australian Bureau of Meteorology MSLP charts. Second, data consistency between 1970 and 2006 and 2007 and 2019 is confirmed. Third, permutation testing is performed on differences in means and variances between the two 25-year intervals 1970–1994 and 1995–2019. Additionally, trends in positions, durations and central pressures of the systems are investigated. p-values from permutation tests reveal statistically significant increases in mean low pressure system frequencies. Specifically, a greater frequency of both total days and initial development days only, occurred in the latter period. Statistically significant lower variance for both latitude and longitude in systems that developed in both subtropical easterly and mid-latitude westerly wind regimes indicate a shift south and east in the latter period. Furthermore, statistically significant differences in variance of development location of explosive low pressure systems that develop in a low level easterly wind regime indicate a shift further south and east. These changes are consistent with fewer systems projected to impact the east coast. Finally, important changes are suggested in the large scale atmospheric dynamics of the eastern Australian/Tasman Sea region.
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Keliyo, Edao Tesa, Meka Kedir Jibril, and Girma Tadesse Wodajo. "Prevalence of Antenatal Depression and Associated Factors among Pregnant Women Attending Antenatal Care at Health Institutions of Faafan Zone, Somali Region, Eastern Ethiopia." Depression Research and Treatment 2021 (August 27, 2021): 1–8. http://dx.doi.org/10.1155/2021/2523789.
Full textAbstract:
Background. Depression is a common global mental health tragedy which affects more than 30 million people of all ages. Antenatal depression is higher among low-income countries where maternal and psychosocial factors act as determinant factors for its occurrence. Aim. This study is aimed at assessing the prevalence of antenatal depression and its associated factors among pregnant women attending health institutions of Faafan zone of Somali regional state, Eastern Ethiopia. Method. An institutional-based cross-sectional study design was conducted among randomly selected 403 pregnant women from January to September 2015. EPDS with 13 cutoff points was used to screen antenatal depression. Bivariate and multivariate logistic regressions were used to identify associated factors. Result. The study showed that 24.3% of women had antenatal depression. Marital status, educational status, chronic medical illness, previous depression history, and social support were factors associated with antenatal depression. Conclusion. The study revealed that the prevalence of antenatal depression was 24.3%. Ethiopia Federal Ministry of Health and Somali Regional Health Bureau should work very hard to create awareness on the importance of pregnancy planning and social support during pregnancy.