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Demetrio, D., A. Magalhaes, M. Oliveira, R. Santos, and R. Chebel. "11 Invivo-derived embryo pregnancy rates at Maddox Dairy from 2008 to 2018." Reproduction, Fertility and Development 32, no. 2 (2020): 130. http://dx.doi.org/10.1071/rdv32n2ab11.
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Maddox Dairy, located in Riverdale, CA, USA, is a Holstein herd that milks 3500 cows with a 305-day mature-equivalent milk production of 12 800 kg, and they have been producing high genetic animals by embryo transfer (ET) since the early 1980s. Invivo-derived embryos from Holstein donors were transferred fresh (grade 1 or 2) or frozen (grade 1), at morula (4), early blastocyst (5), or blastocyst (6) stage, to virgin heifers (VH, natural oestrus, 13-15 months old) or lactating cows (LC, Presynch-Ovsynch, 86 days in milk, first or second lactation) 6 to 9 days after oestrus. Pregnancy diagnosis was done by transrectal ultrasonography at 32-46 days in VH and by the IDEXX PAG test at 30 days in LC. June, July, August, September, and October were called critical months (first service AI conception rate drops below 44%) and compared with the other months. The data from 32 503 ETs between January 2008 and December 2018 are summarised on Table 1. Pregnancy rates (PR) are lower for LC recipients than for VH. Embryo transfers performed 7 or 8 days after oestrus had higher PR in both types of recipients and embryos, but Day 6 and 9 oestrus are also used with fair results. The season does not seem to affect PR. There is not enough difference in the combination of stage and days from oestrus for invivo-derived embryos. These numbers do not belong to a planned experiment. Several management changes during the years were made, which make it very difficult to apply statistical methods to analyse the data correctly. They are used as a tool to make decisions in an attempt to improve future results. Table 1.Pregnancy rate (PR) of virgin heifers (top) and lactating cows (bottom)-fresh (SH) and frozen (OZ) invivo-derived embryo transfer1 Heat-months SH-ST4 SH-ST5 SH-ST6 SH-All OZ-ST4 OZ-ST5 OZ-ST6 OZ-All PR% n PR% n PR% n PR% n PR% n PR% n PR% n PR% n Heifers 6 d-CM 62 934 66 243 68 69 63 1246 56 473 58 219 62 42 57 734 6 d-OM 62 1623 67 489 69 211 64 2323 56 600 55 296 48 137 55 1033 6 d-T 62 2557 67 732 69 280 63 3569 56 1073 57 515 51 179 56 1767 7 d-CM 64 1506 68 495 67 221 65 2222 60 822 62 340 63 156 61 1318 7 d-OM 66 2723 68 1021 69 510 67 4254 57 1120 59 581 57 231 58 1932 7 d-T 66 4229 68 1516 69 731 67 6476 58 1942 60 921 60 387 59 3250 8 d-CM 65 1348 64 518 67 322 65 2188 59 595 64 258 63 108 61 961 8 d-OM 66 2166 68 886 70 510 67 3562 61 770 60 364 51 130 60 1264 8 d-T 66 3514 67 1404 69 832 66 5750 60 1365 62 622 56 238 60 2225 9 d-CM 60 109 56 43 70 20 60 172 60 5 33 6 50 4 47 15 9 d-OM 58 129 63 57 60 40 60 226 63 16 50 18 75 4 58 38 9 d-T 59 238 60 100 63 60 60 398 62 21 46 24 63 8 55 53 All-CM 64 3897 66 1299 67 632 65 5828 58 1895 61 823 63 310 60 3028 All-OM 65 6641 67 2453 69 1271 66 10 365 58 2506 58 1259 53 502 58 4267 All-T 65 10 538 67 3752 69 1903 66 16 193 58 4401 60 2082 57 812 59 7295 Lactating cows 6 d-CM 54 265 48 86 50 12 53 363 38 141 31 77 50 10 36 228 6 d-OM 49 463 52 203 45 56 50 723 46 101 48 54 59 27 48 182 6 d-T 51 728 51 289 46 68 51 1086 41 242 38 131 57 37 42 410 7 d-CM 54 755 59 274 56 103 55 1137 43 928 48 450 43 192 45 1570 7 d-OM 55 914 66 367 54 109 58 1393 46 1052 45 564 47 353 46 1969 7 d-T 55 1669 63 641 55 212 57 2530 45 1980 46 1014 46 545 45 3539 8 d-CM 63 252 68 82 76 33 65 368 48 219 56 80 42 33 50 332 8 d-OM 61 257 64 161 53 47 61 466 50 191 53 77 56 16 51 284 8 d-T 62 509 65 243 63 80 63 834 49 410 55 157 47 49 50 616 All-CM 56 1272 58 442 60 148 57 1868 44 1288 47 607 43 235 45 2130 All-OM 55 1634 62 731 51 212 56 2582 47 1344 46 695 48 396 47 2435 All-T 55 2906 60 1173 55 360 57 4450 45 2632 47 1302 46 631 46 4565 1ST=stage; CM=critical months (June, July, August, September, and October); OM=other months.
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VE, Edem, Abubakar AW, Etukakpan MN, and Elijah AI. "Microbial Assessment of Fura-Nunu Sold in Eiyenkorin, Kwara State, Nigeria." International Journal of Natural Sciences Research 10, no. 1 (May 23, 2022): 30–42. http://dx.doi.org/10.18488/63.v10i1.3000.
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Food-borne diseases are the global public health problems encountered as a result of consumption of contaminated foods. To this end, this study was designed to evaluate the microbial quality of fura-nunu sold in Eiyenkorin, Kwara State, Nigeria. Samples of fura-nunu were collected at different locations within Eiyenkorin and were transported to laboratory for analyses. Microbiological analyses were performed using standard methods. Data obtained from microbial counts were subjected to analysis of variance (ANOVA). Results of total heterotrophic bacteria count (THBC), total coliform count (TCC) and total fungal count (TFC) of fura-nunu indicated that THBC ranged from 1.6 ± 0.03 × 107 - 2.3 ± 0.01 × 107cfu/ml, TCC ranged from 2.5 ± 0.71 - 15.0 ± 1.41 cfu/100ml while TFC was between 4.0 ± 0.41 × 106 and 5.0 ± 5.58 ×107 cfu/g. There were significant differences (P<0.05) in THBC, TCC and TFC of fura-nunu samples. pH values ranged from 4.25 ± 0.31 – 5.30 ± 0.21. The identified bacteria with percentage occurrence (%) include; Lactobacillus spp. (14.81%), Staphylococcus aureus (12.96%), Escherichia coli (17.59%), Bacillus subtilis (6.48%), Pseudomonas aeruginosa (3.70%), Enterococcus spp. (8.33%), Micrococcus spp. (6.48%), Salmonella spp. (13.88%), Klebsiella spp. (4.62%) and Lactobacillus plantarium (11.11%). Fungi species and prevalence (%) were Aspergillus flavus (21.21%), Aspergillus niger (30.30%), Saccharomyces cerevisiae (16.66%), Penicillium spp. (12.12%) and Mucor spp. (19.69%). Results of handling and hygienic practices showed poor handling, storage and hygienic practices by fura-nunu vendors. Hence, there is need for proper education of the vendors on general food safety practices.
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Chen, Tao, Howard Reed, Fiorella Parra-Mujica, Elliott Aidan Johnson, Matthew Johnson, Martin O'Flaherty, Brendan Collins, and Chris Kypridemos. "Quantifying the mental health and economic impacts of prospective Universal Basic Income schemes among young people in the UK: a microsimulation modelling study." BMJ Open 13, no. 10 (October 2023): e075831. http://dx.doi.org/10.1136/bmjopen-2023-075831.
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ObjectiveUniversal Basic Income (UBI)—a largely unconditional, regular payment to all adults to support basic needs—has been proposed as a policy to increase the size and security of household incomes and promote mental health. We aimed to quantify its long-term impact on mental health among young people in England.MethodsWe produced a discrete-time dynamic stochastic microsimulation that models a close-to-reality open cohort of synthetic individuals (2010–2030) based on data from Office for National Statistics and Understanding Society. Three UBI scheme scenarios were simulated: Scheme 1—Starter (per week): £41 per child; £63 per adult over 18 and under 65; £190 per adult aged 65+; Scheme 2—Intermediate (per week): £63 per child; £145 per adult under 65; £190 per adult aged 65+; Scheme 3—Minimum Income Standard level (per week): £95 per child; £230 per adult under 65; £230 per adult aged 65+. We reported cases of anxiety and depression prevented or postponed and cost savings. Estimates are rounded to the second significant digit.ResultsScheme 1 could prevent or postpone 200 000 (95% uncertainty interval: 180 000 to 210 000) cases of anxiety and depression from 2010 to 2030. This would increase to 420 000(400 000 to 440 000) for Scheme 2 and 550 000(520 000 to 570 000) for Scheme 3. Assuming that 50% of the cases are diagnosed and treated, Scheme 1 could save £330 million (£280 million to £390 million) to National Health Service (NHS) and personal social services (PSS), over the same period, with Scheme 2 (£710 million (£640 million to £790 million)) or Scheme 3 (£930 million (£850 million to £1000 million)) producing more considerable savings. Overall, total cost savings (including NHS, PSS and patients’ related costs) would range from £1.5 billion (£1.2 billion to £1.8 billion) for Scheme 1 to £4.2 billion (£3.7 billion to £4.6 billion) for Scheme 3.ConclusionOur modelling suggests that UBI could substantially benefit young people’s mental health, producing substantial health-related cost savings.
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Lelamali, Kumtorn, Piyarek Papirachanat, and Thitiya Puavilai. "Predicting arterio-venous fistula failure by urea–method derived access blood flow in chronic hemodialysis patients." Journal of Vascular Access 21, no. 6 (May 11, 2020): 1011–16. http://dx.doi.org/10.1177/1129729820920115.
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Background: Dialysis access is an essential part of hemodialysis. Determining the access blood flow (Qa) can help predict arterio-venous fistula thrombosis. Qa determination by the urea method, which was previously described in the past is simple and is available in most of the dialysis units but was not be able to predict arterio-venous fistula thrombosis. Aim: To compare the efficacy of Qa determination by the urea method and by ultrasound dilution methods in predicting arterio-venous fistula failure. Methods: Qa was measured by urea method and by ultrasound dilution simultaneously, every 3 months for a period of 1 year, in stable chronic hemodialysis patients with arterio-venous fistula. Arterio-venous fistula failure determined by clinical parameters and confirmed by Doppler ultrasound before sending the patient for interventional angioplasty. Results: This study enrolled a total of 16 patients, with 63% being male, 75% with lower-arm arterio-venous fistula and around 43% with previously done angioplasty. 59-Qa measurements were done, and 6 patients underwent angioplasty (one patient for severe upper limb edema, one for access thrombosis, and four for access dysfunction). Qa determination by the urea method had non-significantly lower Qa, (745 mL/min (interquartile range: 509–1143) and 779 mL/min (interquartile range: 530–1160), (p = 0.58)) and high correlation (r = 0.83, p < 0.001) to Qa by ultrasound dilution. The cut-off criteria with its sensitivity and specificity in predicting the access failure were 440 mL/min, 66.67%, and 96.15% for Qa determination by the urea and 400 mL/min, 66.67% and 90.38% for Qa by ultrasound dilution, respectively, with no difference in the area under the receiver operating characteristic curve. Conclusion: Measurement of Qa determination by the urea method is well correlated with Qa by ultrasound dilution and can be used to predict vascular access failure.
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Rahman, Md Mahmudur, Md Enamul Kabir, Md Mominul Islam, Md Abu Bin Hasan Susan, and Muhammed Shah Miran. "Preparation and Characterization of Porous Carbon Material from Banana Pseudo-Stem." Dhaka University Journal of Science 72, no. 1 (March 25, 2024): 63–70. http://dx.doi.org/10.3329/dujs.v72i1.71190.
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In this work, pseudo-stem of a banana plant was used as a sustainable and affordable source to prepare porous carbon materials (PCM) on a large scale. After fine treatment, the material was annealed at 500, 600, and 700 °C using a tube furnace under nitrogen flow. The prepared materials were characterized by Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). FT-IR spectra show that the broad peak at the range of 1110-1160 cm-1 comes from the superimposed peaks of C-N for a single or more than one functional group which debunks the possibility of generating nitrogen-doped carbon. TEM and SEM analyses confirmed the porous structure of PCM with the pores connected to one, and a spongy structure was observed in the prepared carbon material. XRD analysis revealed that the carbon materials are crystalline. XPS investigation provided information regarding the dimension of which elements are present in the valence states and constituent elements, depicting the presence of a dominant graphitic C1speak at approximately 284 eV, along with a distinct O1s peak at around 532 eV. Additionally, a relatively weaker N1s peak (approximately 400 eV) was observed. Dhaka Univ. J. Sci. 72(1): 63-70, 2024 (January)
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СЕМЕНОВ, В. Г., А. А. ИШТУДОВ, Д. А. НИКИТИН, В. А. АЛЕКСЕЕВ, and А. С. ТИХОНОВ. "PROPHYLACTIC IMMUNODEFICIENCY OF DOGS COMPLEX BIOLOGICAL PREPARATION." VESTNIK RIAZANSKOGO GOSUDARSTVENNOGO AGROTEHNOLOGICHESKOGO UNIVERSITETA IM P A KOSTYCHEVA, no. 1(49) (March 30, 2021): 66–74. http://dx.doi.org/10.36508/rsatu.2021.49.1.010.
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Цель работы – изучение морфофизиологического профиля и неспецифических защитных сил организма служебных собак в условиях кинологического центра на фоне профилактики иммунодефицита биопрепаратами Dоg-Stim-N-B и Prevention-N-Е. Методология. Исследовательская работа проведена в условиях центра кинологической службы МВД и ветеринарной клиники «Айболит» г. Чебоксары на протяжении 2016-2020 гг. Для проведения научно-исследовательской работы подобрали три группы собак одной породы двухмесячного возраста по 5 особей в каждой (контрольная, 1-я и 2-я опытные). С целью профилактики иммунодефицита организма собакам опытных групп выполнили двукратное внутримышечное инъецирование биопрепаратов Prevention-N-Е (1-я опытная) и Dоg-Stim-N-B (2-я опытная) в дозе 0,1 мл на 1 кг живой массы. Результаты. Двукратная внутримышечная инъекция служебным собакам 1-й и 2-й опытных групп биопрепаратов Dоg-Stim-N-B и Prevention-N-Е на 61-63 и 68-69 сутки после рождения повышала концентрацию гемоглобина в крови по сравнению с контролем на 2,0-5,0 и 4,0-15,0 г/л, количество красных кровяных телец – на 1,09 и 1,10×1012/л, уровень общего белка – на 2,8-5,4 и 2,8-8,2 г/л, в том числе альбуминов – на 2,5-3,4 и 3,3-4,3 г/л, а γ-глобулинов – на 0,8-2,4 и 0,3-2,9 г/л. Кроме того, биопрепараты способствовали активизации клеточного и гуморального звеньев неспецифической устойчивости организма. Заключение. Разработанные биопрепараты Dоg-Stim-N-B и Prevention-N-Е стимулируют гемопоэз, развивают физиологическую эозинофилию, нейтрофилопению со сдвигом ядра вправо и лимфоцитоз, активизируют обмен белка, синтез альбуминов и γ-глобулинов, повышают активность клеточных и гуморальных факторов неспецифической резистентности организма. The purpose of the work – study of morphophysiological profle and non-specifc protective forces of the body of service dogs in the conditions of a canine center against the background of prevention of immunodefciency with biological preparation Dog-Stim-N-B and Prevention-N-E. Methodology. Research work was carried out in the conditions of the center of the canine service of the Ministry of Internal Afairs and the Aibolit veterinary clinic in Cheboksary during 2016-2020. For research work, 3 groups of dogs of one breed were formed at the age of 2 months, 5 heads in each group. In order to prevent immunodefciency of the body, dogs of the 1st experimental group were injected intramuscularly with the biopreparation Prevention-N-E at a dose of 0.1 ml/kg of live weight twice on the 61-63 and 68-69 day after birth, dogs of the 2nd experimental group at the same dose and at the same time injected with the biopreparation Dog-Stim-N-B. Results. Two-fold intramuscular injection to service dogs of the 1st and 2nd experimental groups of DogStim-N-B and Prevention-N-E biologics on the 61-63 and 68-69 day after birth increased blood hemoglobin concentration compared to 2 control.0-5.0 and 4.0-15.0 g/l, number of red blood cells - by 1.09 and 1,10 × 1012/l, the concentration of total protein - on 2.8-5.4 and 2.8-8.2 g/l, including the albumin fraction - on 2,5-3.4 and 3.3-4.3 g/l a γ-globulin - by 0.8-2.4 and 0.3-2.9 g/l. In addition, biologics contributed to an increase in plasma lysozyme activity and bactericidal activity of dog blood serum, which indicates an activation of the humoral link of the body's nonspecifc resistance. Conclusion. Biopreparation Dog-Stim-N-B and Prevention-N-E activate hematopoiesis, cause physiological eosinophilia, neutrophylopenia with neutrophilic nucleus shift to the right and lymphocytosis, stimulate protein exchange, synthesis of albumins and γ-globulins, increases cellular and humoral factors of non-specifc resistance
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Firănescu, Adela-Gabriela, and Maria Moța. "Pulmonary Tuberculosis Screening in Patients with Diabetes Mellitus." Romanian Journal of Diabetes Nutrition and Metabolic Diseases 26, no. 2 (June 1, 2019): 159–68. http://dx.doi.org/10.2478/rjdnmd-2019-0017.
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Abstract Background and aims: Diabetes mellitus (DM) is a risk factor for pulmonary tuberculosis (TB), increasing the risk of progression of latent tuberculosis infection (LTBI) to active TB threefold, threatening the TB control, especially in developing countries. The aim of this study was to assess active and latent TB infection frequency in patients with DM. Material and methods: There were enrolled in this study 503 adult DM patients. Active TB screening was performed through anamnestic data, clinical examination and chest X-ray and latent TB infection screening was evaluated using the tuberculin skin tests (TST). Results: A number of 63 (12.5%) patients had type 1 DM and 440 (87.5%) had type 2 DM. Personal history of TB was present in 21 (4.2%) subjects, 5 (8.1%) with type 1 DM and 16 (3.6%) with type 2 DM. The TST was positive in 258 (51.5%) patients and 54 (10.7%) presented cough for more than two weeks at the time of examination. The chest X-ray revealed suggestive lesions for active TB in 4 (1%) subjects and lesions of inactive TB in 90 (22.4%) subjects. Conclusions: TB screening must receive proper attention in patients with DM, being essential for diagnosis in those with nonspecific symptoms.
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Macchione, Nicola, Paolo Bernardini, Igor Piacentini, Barbara Mangiarotti, and Alberto Del Nero. "Flower Pollen Extract in Association with Vitamins (Deprox 500®) Versus Serenoa repens in Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Comparative Analysis of Two Different Treatments." Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 18, no. 2 (July 24, 2019): 151–61. http://dx.doi.org/10.2174/1871523018666181128164252.
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Objective: Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is reported in the literature ranging from 1 to 14.2%. The aim of the present study was to assess the impact on patient’s quality of life and symptoms of Flower pollen extract in association with vitamins (Deprox 500®) in comparison with Serenoa repens 320 mg (Permixon 320 mg® by Pierre Fabre) in patients with CP/CPPS. Methodology: All consecutive patients, with a diagnosis of CP/CPPS, referred to our center from January to August 2016, were screened to be enrolled in this single-center, randomized, controlled trial. The main outcome measure was the evaluation of IPSS/NIHCPSI (International Prostatic Symptom Score/NIH-Chronic Prostatitis Symptom Index) score variation and the assessment of the quality of life and symptoms at the end of the therapy. The second outcome measure was the evaluation of the comorbidity role in the CP/CPPS therapy. 63 patients were analyzed; patients were randomized into two groups: 29 patients were treated with Deprox 500® 2 tablets/day for 6 weeks and 34 patients with Serenoa repens 320 mg, 1 tablet/day for 6 weeks. Results: The mean score variation for IPSS was -12.7 ± 4.3 in the Deprox 500® group and -7.8 ± 4.7 in the Serenoa repens group (p=0.0005) while for NIH-CPSI was -17.3±3.1 in the Deprox 500® group and -13.6±4.8 in the Serenoa repens group (p=0.0016). By accounting only the symptoms part of NIH-CPSI questionnaire, the mean score variation reported was -11.5±2.5 in the Deprox 500® group and -9.02±4.0 in the Serenoa repens group (p=0.009321). Furthermore, analyzing the comorbidity subgroups, in patients with hypertension, the mean IPSS score variation was -14.3±3.2 in the Deprox 500® group and - 9.02±4.0 in the Serenoa repens group. Conclusion: In conclusion, in patients with CP/CPPS, Deprox 500® improves IPSS and NIH-CPSI scores up to 74.5% and 84.5% respectively. Furthermore, in patients with hypertension, the antioxidant effect of Deprox 500® reduces the mean IPSS score of 82.7%.
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Kunakhovitch, M. G., and A. M. Sokalskaya. "The reaction of mountain glaciers to climatic change under continental conditions." Annals of Glaciology 24 (1997): 415–20. http://dx.doi.org/10.3189/s0260305500012532.
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Data on the distribution of accumulation with elevation were used to calculate ablation, internal accumulation, annual mass balance and glacier runoff for the Tien Shan glaciers with a total area of about 15 500 km2. The altitudinal profile of normalized ablation is approximated by an exponential curve. Mass-balance components and glacier runoff are calculated for the whole possible range of glacier equilibrium-line positions in the major river and lake basins of the Tien Shan.For steady state it was found that the equilibrium line rises from 3600 m in western areas to 4400 m in the east, whilst the accumulation area ratio and glacier runoff increase eastward from 63% to 71%, and from 600 to 1200 mm, respectively. Losses of meltwater runoff for internal accumulation average 7% (5–11%).In abnormally warm years, mass balance may reach –2300 mm w. e. in the west and –855 mm in the east and in the internal Tien Shan (Khan Tengry massif). Glacier runoff volume in those years has been estimated at 40 km3 year–1, which is 2.5 times as large as for the steady state.
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Kunakhovitch, M. G., and A. M. Sokalskaya. "The reaction of mountain glaciers to climatic change under continental conditions." Annals of Glaciology 24 (1997): 415–20. http://dx.doi.org/10.1017/s0260305500012532.
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Data on the distribution of accumulation with elevation were used to calculate ablation, internal accumulation, annual mass balance and glacier runoff for the Tien Shan glaciers with a total area of about 15 500 km2. The altitudinal profile of normalized ablation is approximated by an exponential curve. Mass-balance components and glacier runoff are calculated for the whole possible range of glacier equilibrium-line positions in the major river and lake basins of the Tien Shan. For steady state it was found that the equilibrium line rises from 3600 m in western areas to 4400 m in the east, whilst the accumulation area ratio and glacier runoff increase eastward from 63% to 71%, and from 600 to 1200 mm, respectively. Losses of meltwater runoff for internal accumulation average 7% (5–11%). In abnormally warm years, mass balance may reach –2300 mm w. e. in the west and –855 mm in the east and in the internal Tien Shan (Khan Tengry massif). Glacier runoff volume in those years has been estimated at 40 km3 year–1, which is 2.5 times as large as for the steady state.
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Zuza, V., M. Shevchenko, R. Hutianskyi, and N. Kuzmenko. "Soil herbicides in sunflower crops in the Eastern Forest-Steppe of Ukraine." Interdepartmental Thematic Scientific Collection of Plant Protection and Quarantine, no. 68 (April 20, 2023): 98–113. http://dx.doi.org/10.36495/1606-9773.2022.68.98-113.
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Goal. To determine the influence of soil herbicides with different active substances on crop weediness and sunflower seed yield in the conditions of the Eastern Forest Steppe of Ukraine.
Methods. Field, measuring and weighting, and statistical.
Results. In 2019, with 13 mm of precipitation in the first period after applying soil herbicides, the effectiveness of herbicides in reducing the number and raw mass of weeds in sunflower crops was 60% and 45%, respectively, and in 2021 with 81 mm of precipitation, it was 89% and 95%. In 2021, there was phytotoxic suppression of culture plants by Kharnes, e.c. (acetochlor, 900 g/l), 2.5 l/ha. Despite this, Kharnes was the most effective in controlling the total number of weeds (91% and 96% for the first and second counts, respectively) and their raw mass (95%). Other preparations provided the following indicators: Proponit 720, EC (propisochlor, 720 g/l), 3.0 l/ ha (by quantity — 84% and 90%, by weight — 84%); Selefit, SC (promethrin, 500 g/l), 4.0 l/ha (by quantity — 79% and 81%, by weight — 70%); Prymekstra TZ Hold 500 SC (S-metolachlor, 312.5 g/l + terbuthylazine, 187.5 g/l), 4.5 l/ha (by quantity — 68% and 73%, by weight — 66%); Stomp 330, e.c. (pendimethalin, 330 g/l), 5.0 l/ha (by quantity — 51% and 63%, by weight — 60%); Komandyr, EC (clomazon, 480 g/l), 0.15 l/ha (26% and 52% by quantity, 37% by weight). Ambrosia artemisiifolia L. was resistant to the above soil herbicides. It was established that sunflower is a powerful competitor in agrophytocenosis. Its share in the total raw mass of agrophytocenosis, depending on the period of accounting, was from 65.8 to 82.0%, and in dry mass — from 61.8 to 80.2%. In addition, it was established that losses of the sunflower crop from weeds coincide with the specific share of weeds in the total mass of the agrophytocenosis. Soil herbicides provided the following increases in the yield of sunflower seeds (t/ha): Kharnes — 0.53; Proponit 720 — 0.46; Stomp 330 — 0.44; Prymekstra TZ Hold 500 SC and Selefit — 0.39; Komandyr — 0.17. It was found that sunflower was the most tolerant to Stomp 330, and the least — to Komandyr.
Conclusions. In terms of the level of weed death in sunflower crops and the increase in the yield of its seeds, Kharnes was the best among soil herbicides, and Komandyr was the worst.
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Kim, George P., Paul Cockrum, Andy Surinach, and Jim M. Koeller. "Real-world use of liposomal irinotecan-based regimens among patients (pts) with metastatic pancreatic adenocarcinoma (mPDAC) in the United States (U.S.)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16740-e16740. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16740.
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e16740 Background: The goals of randomized control trials (RCTs) are to make causal inferences and precise treatment comparisons, not to describe large heterogeneous pt populations. RWE allows population-based healthcare decision makers to assess and manage therapeutic and economic options for their pts, including those who would and would not have met inclusion/exclusion criteria of a given RCT and are instead managed under usual care, irrespective of clinical trial protocols. In the pivotal phase 3 trial, NAPOLI-1, 117 pts were treated with liposomal irinotecan + 5-fluorouracil/folinic acid, median age 63 years; 66% were treated first- (1L) or second line (2L), and 91% had performance score ECOG 0 or 1. Pts in the trial had overall survival (OS) of 6.2 months (mos), time to treatment failure (TTF) 2.3 mos, and 27% experienced grades 3-4 neutropenia. The present study describes the patient characteristics and outcomes of pts with mPDAC treated with liposomal irinotecan in the US. Methods: This retrospective observational study used data from Flatiron Health EHR-derived de-identified database from over 280 cancer clinics. Patient characteristics, OS, TTF, and rates of neutropenia during treatment (tx) were assessed in adult pts diagnosed with mPDAC who received liposomal irinotecan based tx between November 1, 2015 and October 31, 2019. Results: 600 pts with mPDAC treated with a liposomal irinotecan based regimen were identified. Of these, 56% were initially diagnosed with stage IV disease, 53% were male, 21% had undergone a previous Whipple procedure, and 61% initiated liposomal irinotecan in the 1L or 2L metastatic setting. Median age at tx initiation was 68 (IQR: 62 – 75) years. 92% of pts were treated in the community setting. Among pts with available ECOG (n = 440), 77.5% were score 0-1. Grade 3/4 neutropenia was observed in 11% (n = 66). Overall, median OS was 5.0 mos [95%CI: 4.2–5.6]. mOS among pts treated in 1L (n = 88), 2L (n = 280), and third line plus (3L+, n = 232) were 6.9 mos [5.3–9.2], 5.4 mos [4.6–6.4], and 4.0 mos [3.4–4.5], respectively. Overall, median TTF was 1.9 mos [1.6–2.1]. TTF by line was 3.5 mos [2.3–4.8] in 1L, 2.1 mos [1.7–2.8] in 2L, and 1.4 mos [1.2–1.6] in 3L. Conclusions: This real-world cohort of pts with mPDAC were older, had worse performance status, and had more prior lines compared to the pivotal trial for liposomal irinotecan. Median OS, TTF, and neutropenia were similar to those previously reported. As expected, pts receiving liposomal irinotecan in earlier lines had higher median OS and TTF.
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Patel, Vipul R., Sagar Shah, and David Arend. "Histopathologic Outcomes of Robotic Radical Prostatectomy." Scientific World JOURNAL 6 (2006): 2566–72. http://dx.doi.org/10.1100/tsw.2006.397.
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Robotically assisted laparoscopic radical prostatectomy is a minimally invasive alternative for the treatment of prostate cancer. We report the histopathologic and shortterm PSA outcomes of 500 robotic radical prostatectomies. Five hundred patients underwent robotic radical prostatectomy. The procedure was performed via a six trocar transperitoneal technique. Prostatectomy specimens were analyzed for TNM stage, Gleason’s grade, tumor location, volume, specimen weight, seminal vesicle involvement, and margin status. A positive margin was reported if cancer cells were found at the inked specimen margin. PSA data were collected every 3 months for the first year, then every 6 months for a year, then yearly. The average preoperative PSA was 6.9 (1–90) with Gleason’s score of 5 (2%), 6 (52%), 7 (40%), 8 (4%), and 9 (2%); postoperatively, histopathologic analysis showed Gleason's 6 (44%), 7 (42%), 8 (10%), and 9 (4%); 10, 5, 63, 15, 5, and 2% had pathologic stage T2a, T2b, T2c, T3a, T3b, and T4, respectively. Positive margin rate was 9.4% for the entire series. The positive margin rate per 100 cases was: 13% (1–100), 8% (101–200), 13% (201–300), 5% (301–400), and 8% (401–500). By stage, it was 2, 4, and 2.5% for T2a, T2b, T2c tumors; 23% (T3a), 46% (T3b), and 53% (T4a). For organ-confined disease (T2), the margin rate was 2.5% and it was 31% for nonorgan-confined disease. There were a total of 47 positive margins, 26 (56%) posterolateral, 4 (8.5%) apical, 4 (8.5%) bladder neck, 2 (4%) seminal vesicle, and 11 (23%) multifocal. Ninety-five percent of patients (n = 500) have undetectable PSA (<0.1) at average follow-up of 9.7 months. Recurrence has only been seen with nonorgan-confined tumors. Of those patients with a minimum follow-up of 1 year (average 15.7 months), 95% have undetectable PSA (<0.1). Our initial experience with robotic radical prostatectomy is promising. Histopathologic outcomes are acceptable with a low overall, positive margin rate. Shortterm biochemical recurrence-free survival has also been good. We believe that the precise dissection allowed by the advantages of laparoscopic robotic surgery will translate into excellent long-term oncologic outcomes. At this time, the lack of maturity of the PSA data prevent definitive comparison to the open approach.
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Kudo, A. M., M. E. Jackson, and J. W. Husler. "Phase chemistry of recent andesite, dacite, and rhyodacite of volcan Pico de Orizaba, Mexican Volcanic Belt: evidence for xenolitic contamination." Geofísica Internacional 24, no. 4 (October 1, 1985): 679–89. http://dx.doi.org/10.22201/igeof.00167169p.1985.24.4.1151.
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El volcan Pico de Orizaba, el mas alto del Cinturón Volcánico Mexicano, se desarrollo en tres diferentes etapas magmáticas iniciándose hace 1.5 Ma (Robin y Cantagrel, 1982). Las andesitas de dos piroxenos, dacitas y riodacitas de la tercera etapa (hace 13 000 años) han sido analizadas por fluorescencia de rayos-X y microsonda electrónica. Las muestras han sido recolectadas de flujos de lava, depositos de caídas y flujos piroclásticos, en localidades situadas sobre 4 500 m.s.n.m.Por lo menos ocurren dos tipos de andesita. Una andesita con presencia de olivino (60% Si02), con un volumen de 20 por ciento de plagioclasa y 15 por ciento de fenocristales de piroxeno, tiene una matriz vítrea con 61 por ciento en peso de SiO2, 17.7% Al2O3, 4.8% Na2O, y 2.5% K2O; sorprendentemente, este tipo de andesita contiene algunos granos corroídos de olivino que son ricos en Fo (Fo 87-89) con inclusiones de espinela crómica. La composicion del piroxeno es bimodal con distinto vacío composicional: los promedios de los ortopiroxenos son En79Fs19Wo2 y En57Fs40Wo3 y los promedios de los clinopiroxenos son En50Fs11Wo39 Y En44Fs18Wo38. Las composiciones del margen de plagioclasa tambien son bimodales (An70-78 y An46-63). La geotermometrfa reproduce temperaturas superiores a 1050°C para las parejas de piroxenos ricos en magnesio y alrededor de 960°C para las parejas ricas en fierro. La andesita libre de olivine tiene las composiciones del interior de la plagioclasa, las cuales son bimodales. Las dacitas y riodacitas (63 a 68% de SiO2, mayor que 16% de Al2O3) tienen de 20 a 40% de fenocristales de plagioclasa, de 3 a 20% de piroxeno, y de 0 a 15% de hornblenda. La matriz vítrea en estas rocas y la andesita libre de olivino son sirnilares y tienen 74 a 75% de SiO2, 11.8 a 12.6% de Al203, 2.5 a 4.0% de Na20 y 2.5 a 4.4% de K20 y caen cerca del mínimo en el sistema temario del granite. Las fases máficas son ricas en magnesio; se obtienen temperaturas sobre 980°C para los dos tipos de piroxeno. Las comsiciones de los dos tipos de piroxeno no parecen ser compatibles con el magma riolítico rico en sílice, el cual tiene una temperatura de saturaci6n abajo de 800°C.Por lo menos dos líquidos (una riolita rica en sílice y una andesita) han sido generados en la etapa mas reciente de la evolución de Orizaba. La andesita ha sido contaminada en parte por el olivino Y piroxeno ricos en magnesio, pero el ´líquido riolítico ha asimilado el material máfico de la corteza o del material de la chimenea, formándose así andesita, dacita y riodacita.doi: sin doi
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Guven, Serkan, Deniz Özmen, Yunus Çatma, Tuba Güllü Koca, Onur Kırkızlar, Ömer Şeker, Sercan Ünal, et al. "Real-Life Outcomes of Bosutinib in Patients with Chronic Myeloid Leukemia: A Multicenter Nationwide Study from Turkey." Blood 144, Supplement 1 (November 5, 2024): 6585. https://doi.org/10.1182/blood-2024-193433.
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Introduction: Although the prognosis of chronic myeloid leukemia (CML) changed dramatically with the introduction of imatinib (IM), some patients (pts) still need further BCR::ABL1 tyrosine kinase inhibitor (TKI) therapies due to resistance and/or intolerance to IM. 2nd-generation TKIs (2GTKIs) including bosutinib (BOS) can be utilized in those pts. In Turkey, IM is the only BCR::ABL1 TKI reimbursed in newly diagnosed pts, and BOS can be utilized in the 2nd and later lines of therapy. Real-life data of BOS in pts with CML failing previous lines of TKI therapy is still limited in the literature and the aim of this multicenter study is to evaluate the efficacy and safety of BOS therapy in pts with CML beyond first-line TKI therapy in the real-life setting. Methods: All information on demographics, previous treatments, TKI responses and toxicities, and follow-up data were gathered from the files of the pts retrospectively. Early molecular response (EMR) was defined as a BCR::ABL1IS transcript level <10% at 3 months. Major molecular response (MMR) and deep molecular response (DMR) were defined as BCR::ABL1IS transcript levels ≤0.1% and ≤0.01% (MR4.0) or deeper, respectively. between BCR::ABL1IS transcript levels between 0.1-1% were considered as complete cytogenetic response (CCyR). Results: Two hundred eighty-three pts from 40 centers were included. The median age was 58 years (range, 20-86 years), and 58% of the pts (n=167) were male. At diagnosis, 260 pts were in chronic phase (CML-CP) (91.3%), and 15 (5.3%) and 8 (2.8%) pts were in accelerated and blastic phases, respectively. Prior to BOS therapy, the median follow-up was 45.5 months (range, 0-288 months) and 5 pts (1.8%) received an allograft. The median number of prior TKIs was 2 (range, 0-4), and BOS was used as 1st-, 2nd-, 3rd-, and >3rd-lines of therapy in 2 (0.7%), 74 (26.1%), 98 (34.6%), and 109 (38.6%) pts, respectively. Of the CML-CP pts, 123 (47.3%) were switched to BOS due to resistance and 108 (40.4%) due to intolerance to prior TKI therapy and in 29 (11.2%), both due to intolerance and resistance. One hundred and eighty-three pts (64.6%) had at least one comorbidity, and the most common comorbidities were hypertension (39.9%), cardiovascular diseases (29%), and diabetes (23.3%). The initial daily dose was 500 mg in 194 pts (68.6%), 400 mg in 50 pts (17.7%), 300 mg in 28 pts (9.9%), 200 mg in 7 pts (2.5%), and 100 mg in 4 pts (1.4%). The mean BOS dose intensity was 449.47 mg/day (range, 100-500 mg/day). With a median duration of 17 months of BOS therapy (range, 3-178 months), 75.6% of 281 pts (n=214) experienced at least one AE, and the most common non-hematological adverse event (AE) was diarrhea, observed in 144 pts (43.8%). Of these, 130 (90.3%) and 14 (9.7%) pts experienced grade 1-2 and grade 3-4 diarrhea, respectively. The percentages of grade 3-4 anemia, neutropenia, and thrombocytopenia were 7.1% (20/282), 3.2% (9/282), and 3.2% (9/282), respectively. Dose reduction was required in 75 pts (26.5%) due to any AEs. In 58 pts (20.5%), BOS was interrupted and 92 pts (32.5%) discontinued BOS therapy permanently. Main reasons for permanent discontinuation were AEs (47.8%) and loss of response and/or progression (39.1%). The incidences of any AEs were comparable across treatment lines; 70.3% (52/74) in 2nd-line, 78.6% (77/98) in 3rd-line, and 77.1% (84/109) in >3rd-line (p=0.420). At time of BOS start, rates of any response less than CCyR, CCyR, MMR, and DMR were 53.7%, 11.7%, 15.9%, and 17.7%, respectively. Under BOS therapy, CCyR, MMR, and DMR rates were 4.6%, 23%, and 43.1%, respectively and 63 pts (22.3%) achieved a response level less than CCyR. The percentage of pts with optimal responses were significantly higher with BOS when compared to those achieved prior to BOS therapy (p<0.001). EMR rates were significantly higher in pts receiving 500 mg/day BOS than those with a daily dose <500 mg (34.2% vs. 64.8%, p=0.023). Conclusion: Our multicenter, nationwide study among pts with CML in the real world setting demonstrated that BOS is an effective 2GTKI in pts who failed at least one TKI therapy with a generally manageable toxicity profile.
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Zhao, Rui, and Shijun Chen. "Earthquake Magnitude-Frequency Relationship and Earthquake Magnitude Prediction in North China." Journal of Physics: Conference Series 2381, no. 1 (December 1, 2022): 012098. http://dx.doi.org/10.1088/1742-6596/2381/1/012098.
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Abstract The magnitude-frequency relationships of earthquakes of magnitude M L 2.0 or higher in North China, Shandong and neighboring areas since 1970 are calculated, and the long-term and annual-scale seismic intensities are analyzed. The maximum intercept magnitude and the annual-scale seismic intensity are M L 7.5 and M L 5.5, respectively, in North China within a long time frame. The three-year-scale time scan predicts that the maximum intercept magnitude and the seismic intensity in 2022 will be M L 5.3 and M L 4.8. In contrast, the maximum intercept magnitude and the annual seismic intensity in Shandong and neighboring areas are M L 6.2 and M L 4.5, and the three-year scale time scan predicts the corresponding values in 2022 will be M L 4.8 and M L 4.2, respectively. The predicted maximum earthquake magnitude in Shandong in 2022 has a high probability (63%) of not exceeding M L 4.8. Furthermore, the theoretical annual average occurrences and recurrence interval for each earthquake magnitude in Shandong and neighboring areas are calculated, with an average of 30 earthquakes per year for magnitude 3.0, 3.1 earthquakes per year for magnitude 4.0, once every 3.1 years for magnitude 5.0, 29 years for magnitude 6.0, 282 years for magnitude 7.0, and 2713 years for magnitude 8.0. The maximum intercept magnitude in North China has gradually weakened in the past 50 years, yet this tendency is not obvious in Shandong. It is noteworthy whether this indicates seismic activities in North China have gradually entered a quiet period.
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Rosario-Passapera, Richard, Ramaydalis Keddis, Ronald Wong, Richard A. Lutz, Valentin Starovoytov, and Costantino Vetriani. "Parvibaculum hydrocarboniclasticum sp. nov., a mesophilic, alkane-oxidizing alphaproteobacterium isolated from a deep-sea hydrothermal vent on the East Pacific Rise." International Journal of Systematic and Evolutionary Microbiology 62, Pt_12 (December 1, 2012): 2921–26. http://dx.doi.org/10.1099/ijs.0.039594-0.
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An aerobic, alkane-oxidizing bacterium, designated strain EPR92T, was isolated from hydrothermal fluids that had been collected from a deep-sea vent on the East Pacific Rise (at 9° 50′ N 104° 17′ W). The cells of the novel strain were Gram-staining-negative rods that measured approximately 1.4 µm in length and 0.4 µm in width. Strain EPR92T grew at 20–40 °C (optimum 35 °C), with1.0–5.0 % (w/v) NaCl (optimum 2.5 %), and at pH 4.0–8.5 (optimum pH 7.5). The generation time under optimal conditions was 63 min. Strain EPR92T grew aerobically in artificial seawater minimal medium with n-alkanes as sole carbon and energy sources, and also in artificial seawater medium supplemented with peptone and yeast extract. The predominant fatty acids were C18 : 1ω7c, C19 : 0 cyclo ω8c, 11-methyl C18 : 1ω7c and a putative C12 : 0 aldehyde. The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and four unidentified aminolipids. The major respiratory quinone was Q-10 and the genomic DNA G+C content was 60.7 mol%. Phylogenetic analyses of the 16S rRNA gene showed that strain EPR92T belongs in the class Alphaproteobacteria and the recognized species that were most closely related to the novel strain were identified as Parvibaculum indicum P-31T (98.7 % sequence similarity) and Parvibaculum lavamentivorans DS-1T (95.8 %). In DNA–DNA hybridizations, the level of DNA–DNA relatedness observed between strain EPR92T and P. indicum P-31T was 47.7 %, indicating that the two strains do not belong to the same species. Based on the phylogenetic, physiological, chemotaxonomic and genetic evidence, strain EPR92T represents a novel species within the genus Parvibaculum , for which the name Parvibaculum hydrocarboniclasticum sp. nov. is proposed. The type strain is EPR92T ( = DSM 23209 = JCM 16666T).
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Meijs, Anouk P., Esther F. Gijsbers, Paul D. Hengeveld, Christiaan Veenman, Annika M. van Roon, Angela H. A. M. van Hoek, Sabine C. de Greeff, Engeline van Duijkeren, and Cindy M. Dierikx. "Do vegetarians less frequently carry ESBL/pAmpC-producing Escherichia coli/Klebsiella pneumoniae compared with non-vegetarians?" Journal of Antimicrobial Chemotherapy 75, no. 3 (November 25, 2019): 550–58. http://dx.doi.org/10.1093/jac/dkz483.
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Abstract Background ESBL and plasmid-mediated AmpC (pAmpC)-producing Enterobacteriaceae are frequently found on meat products in Dutch retail, especially on poultry. Objectives We investigated whether vegetarians are at lower risk of carrying ESBL/pAmpC-producing Escherichia coli/Klebsiella pneumoniae (ESBL-E/K) compared with persons who consume meat. Methods Vegetarians, pescatarians (vegetarians who eat fish) and non-vegetarians (persons who eat meat at least three times per week) were asked to send in a faecal sample and a questionnaire. ESBL-E/K were cultured and MLSTs were determined. ESBL/pAmpC genes were analysed using PCR and sequencing. The risk of ESBL-E/K carriage in the three study groups was analysed using multivariable logistic regression. Results Prevalence of ESBL-E/K carriage was 8.0% in vegetarians (63/785; 95% CI 6.3–10.1), 6.9% in pescatarians (27/392; 95% CI 4.8–9.8) and 3.8% in non-vegetarians (14/365; 95% CI 2.3–6.3). Multivariable analysis showed an OR for ESBL-E/K carriage of 2.2 for vegetarians (95% CI 1.2–4.0) and 1.6 for pescatarians (95% CI 0.8–3.2) compared with non-vegetarians. The predominant MLST was E. coli ST131 and the most common ESBL genes were blaCTX-M-15, blaCTX-M-27, blaCTX-M-14 and blaCTX-M-1 in all diet groups. Independent risk factors for ESBL-E/K carriage were travel to Africa/Latin America/Asia (OR 4.6; 95% CI 2.8–7.7) in the past 6 months and rarely/never washing hands before food preparation (OR 2.5; 95% CI 1.2–5.0). Conclusions Vegetarians and pescatarians did not have a lower risk of ESBL-E/K carriage compared with non-vegetarians, indicating that eating meat is not an important risk factor for ESBL-E/K carriage.
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De Bem, T. H. C., R. Rochetti, P. R. L. Pires, F. F. Bressan, P. R. Adona, and C. L. V. Leal. "242 USE OF BRAIN-DERIVED NEUROTROPHIC FACTOR IN IN VITRO PREMATURATION OF BOVINE OOCYTES SUBJECTED TO PARTHENOGENETIC ACTIVATION." Reproduction, Fertility and Development 20, no. 1 (2008): 200. http://dx.doi.org/10.1071/rdv20n1ab242.
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Prematuration provides an additional time for oocyte capacitation and maturation in an attempt to improve in vitro embryo production (IVP) rates and allows media supplementation during this period for IVP. The aim of this study was to use brain-derived neurotropic factor (BDNF) in prematuration to improve maturation of bovine oocytes subjected to parthenogenetic activation and cultured with different media. Oocytes were subjected to prematuration in TCM-199 medium supplemented with 10 µm butyrolactone I, 2.0 mm pyruvate, and 10 µg mL–1 gentamicin for 24 h in the absence of BDNF (control) or in the presence of 10 ng mL–1 BDNF (BD). Oocytes were then in vitro-matured (IVM) in TCM-199 medium supplemented with 10% FCS, 0.5 µg mL–1 FSH, 5.0 µg mL–1 LH, 2.0 mm pyruvate, and 10 µg mL–1 gentamicin at 38.5�C under 5% CO2 in air. After 19 h oocytes were denuded using hyaluronidase and vortexing for 3 min for the 1st polar body (1PB) selection. Those which extruded the 1PB were maintained in IVM until 26 h, when parthenogenetic activation was performed (5 min in 5 µm ionomycin, followed by 3 h in 2 mm 6-DMAP). Activated oocytes were then transferred to in vitro culture (IVC) for embryo development evaluation. Embryos from both groups were cultured in SOF medium with 2.5% FCS, 0.05 g mL–1 BSA, 0.2 mm pyruvate, and 10 mg mL–1 gentamicin. Cleavage rates on the second day of in vitro culture (D2), embryo production at Days 7 and 8 (D7 and D8), and hatching rate at Day 8 were evaluated. Data regarding 1PB extrusion, cleavage, blastocyst development on D7 and D8, and blastocyst D8 hatching rates of three replicates were analyzed by chi-square test at 5% significance using the BIOESTATS 4.0 software. Control and BD, respectively, did not show differences (P > 0.05) regarding 1PB extrusion (n = 164, 63.81%, and n = 175, 66.79%) or cleavage (n = 117, 71.34%, and n = 138, 78.86%). However, for control and BD, respectively, blastocyst development on D7 (n = 63, 38.41%, and n = 89, 50.86%), D8 (n = 63, 38.41%, and n = 91, 52.00%), and hatching on D8 (n = 22, 34.92%, and n = 39, 43.82%) were all significantly higher for BD when compared with control (P < 0.05). In conclusion, BDNF during prematuration improved in vitro embryo development by increasing blastocyst and hatching rates of parthenogenetic embryos.
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Voshchenko, I., and M. Povod. "The influence of the size of the pig farm on the realization of the reproductive qualities of sows of danish breeding." Tehnologìâ virobnictva ì pererobki produktìv tvarinnictva, no. 1 (186) (May 24, 2024): 51–63. https://doi.org/10.33245/2310-9289-2024-186-1-51-63.
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The article studied the influence of the size of the pig farm on the realization of the genetic potential of Danish breeding pigs and the dependence of the intensity of sow use on farms of different capacity in the western part of the Jylland peninsula of the Kingdom of Denmark. It was established that with an increase in the average annual number of sows on a pig farm, their reproductive qualities improved. They were highest in sows at large enterprises, where their number exceeded 1500 heads. Sows on these pig farms had 1.6–3.5% better fertility, 3.2–5.5% better number of piglets at weaning, 0.5–3.8% better number of piglets born per farrowing unit and by 2.4–6.5% the number of weaned piglets per unit, 1.6–1.8% better preservation of piglets before weaning and 1.6–8.0% shorter duration of the suckling period. At the same time, the sows of this group, with almost identical average daily gains, had 0.5–8.1% lower absolute gains, 3.6–6.9% lower individual weight of piglets at weaning compared to groups of enterprises where the average annual number of sows was up to 1500 heads. Whereas no clear pattern has been established for piglet nest weight at this time. According to the complex indexes of reproductive efciency of sows, their growth was established with an increase in the average annual number of sows at the enterprise. These indices were also the highest in sows in the group of enterprises with an average number of more than 1,500 heads. They prevailed according to the comprehensive indicators of animals with a number of up to 500 sows by 3.9–4.2%, with their average annual number from 500 to 1000 by 2.7–3.7% and by 1.8–2.3% of their analogues with the number of animals from 1001 to 1500 heads. It was proved that with the growth of the size of the pig farm, the annual percentage of frst farrowing sows in the herd decreased by 1.6-4.0%, the proportion of sows that farrowed relatively inseminated increased by 0.2–3.1%, the average annual number of farrowings per sow increased by 1.0–3.1%, and the number of piglets weaned per year increased by 2.5–7.6%. At the same time, there is no clear trend has been established for the number of unproductive days per sow per year, the interval from weaning to insemination, and the proportion of dead sows. It was determined that the size of the farm probably had a 16.5 % effect on the sow's fertility, a 17.1 % effect on the number of piglets at weaning, and a 14.0 % effect on the weight of 1 piglet at weaning. The factor of the duration of the suckling period had a signifcant effect of 10.12 % on the weight of one piglet at weaning and 6.91 % on the weight of the piglet nest during this period, and did not affect the safety of piglets to weaning, while multiplicity and its interaction with the duration of lactation had no signifcant effect on these traits. Key words: sow, Danish breeding, genetic potential, farm size, reproductive productivity, intensity of use, genotype effect.
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Lee, Sunyoung S., Hop Sanderson Tran Cao, Ching-Wei David Tzeng, Zeyad Metwalli, Eugene Jon Koay, Ethan B. Ludmir, Yun Shin Chun, Stephen G. Chun, and Milind M. Javle. "Clinical outcomes analysis of TP53-mutated advanced and metastatic biliary tract cancers." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 4106. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.4106.
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4106 Background: Advanced biliary tract cancers (BTC) are lethal cancers with limited treatment options and short survival. Median progression-free survival (mPFS) in the ABC-02 trial was 8.0 months with gemcitabine-cisplatin (GC) and 5.0 m with gemcitabine alone in the front-line setting. The ABC-06 trial showed mPFS of 4.0 m with second-line FOLFOX. TP53 mutation is known to be associated with poor prognosis in other cancers, but its impact on survival in advanced or metastatic BTC has not been detailed. Methods: Mutational profiles were obtained from a retrospective database collected via an institutional DNA/RNA sequencing panel, FoundationOne, or Guardant360. Out of 149 patients with TP53 mutations in BTC, 90 had advanced or metastatic BTC treated at a single institution between 2015 and 2021. These patients were not candidates for surgery, radiation, or liver-directed therapy. Results: Intrahepatic, hilar, distal, and gallbladder cancer diagnoses were confirmed in 66, 11, 10, and 3 patients. Median age was 63, with a male:female ratio of 1:1. Poorly, moderately, and well-differentiated adenocarcinomas were found in 62, 20, and 1 (not available in 7 patients). The most common TP53 mutations were R175H (n = 5) and R248Q (n = 4). Common co-mutated genes included KRAS (n = 15), ARID1A (n = 15), FGFR2 fusion (n = 14), IDH1 (n = 13), BAP1 (n = 10), CDKN2A (n = 9), and HER2 amplification (n = 8). Microsatellite unstable (MSI-H) tumors were found in 3 patients. The median tumor mutational burden was 2.5/Mb. Patients received front-line GC (n = 54), GC-nab-paclitaxel (GAP, n = 14), FOLFIRINOX (n = 3), and GC with targeted or trial therapy (n = 11, e.g. trastuzumab). mPFS with front-line therapy was 5.0 m (n = 90); it was 4.7 m with GC and 5.1 m with GAP. Patients who had co-mutated IDH1 or FGFR2 fusion had longer mPFS (9.5 and 6.9 m, respectively) than those who did not (n = 63, 3.7 m, p < 0.05) from front-line chemotherapy. mPFS after second-line FOLFOX (n = 17) and FOLFIRI (n = 10) was 2.1 and 1.9 m, respectively, and mPFS after third-line FOLFOX/FOLFIRI was 1.8 m (n = 8). The median overall survival (OS) of patients with co-mutated FGFR2, IDH1, or neither was 34.5, 22.0, and 13.1 m, respectively (p < 0.05). TP53-mutated BTC with mutations other than FGFR2/IDH1 did not show statistically significant difference in PFS or OS. Conclusions: Patients with TP53-mutated advanced BTC have shorter PFS than those without TP53 mutation in front and further-line settings. The presence of co-mutated FGFR2 or IDH1 is associated with improved PFS with chemotherapy (not FGFR/IDH1 inhibitors) and longer OS. Other co-mutations do not appear to have a survival benefit. It is crucial for clinicians to take into account the worse prognosis with TP53 mutation before starting front-line therapy in patients with advanced BTC and consider early clinical trial options.
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Filon, Dvora, Marion Phylipsen, Piero C. Giordano, Deborah G. Rund, and Cornelis L. Harteveld. "Four Novel Deletions in Globin Genes Revealed by Multiplex Ligation Dependent Probe Amplification Assay (MLPA) Technology." Blood 108, no. 11 (November 16, 2006): 1593. http://dx.doi.org/10.1182/blood.v108.11.1593.1593.
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Abstract For nearly 2 decades, the Hadassah Hospital hematology laboratory has been performing DNA-based diagnosis of thalassemia patients and carriers of alpha and beta thalassemia trait. Despite exhaustive analysis using conventional methods, no mutation or deletion could be identified for several families. Recently, MLPA technology was successfully applied to the diagnosis of deletions of alpha and beta globin genes (Harteveld, 2005). This method uses 2 sets (of 35 and 50 probes) covering 700 kb of alpha-globin and 500 Kb of beta-globin, respectively. In the current study, we applied this technology to the analysis of four additional families. Three are Ashkenazi Jews with suspected thalassemia trait. The fourth is a Persian Jewish patient with HbH disease who was only found to have -α 3.7, with an unknown deletion of two alpha genes on the other chromosome. Hematological data are presented in Table 1. MPLA analysis revealed that three of the propositi (2 of the Ashkenazim and the Persian patient) carried large deletions of the alpha globin locus and the third Ashkenazi family carried a large deletion of the beta globin locus, all of which are previously undescribed. Family C was found to have a deletion encompassing a region upstream of the alpha globin cluster but the alpha-like genes are all present. Family K has a large deletion removing the entire alpha globin cluster. The Persian patient has a large deletion of 2 alpha globin genes. Lastly, Family M, of Ashkenazi origin, carries a large deletion of the beta globin cluster whose 5′ end has not yet been mapped. Notably, this family has no elevation of HbA2 or HbF to indicate that they carry beta-thalassemia trait. We conclude that, while large deletions of the alpha or beta globin cluster are not common, they can present a serious problem in diagnosis, potentially leading to erroneous genetic counseling. Identification of such deletions can allow accurate genetic counseling and prenatal diagnosis in appropriate families. MPLA technology is invaluable in characterizing these types of deletions which escape detection using more conventional techniques. Hematological data of Patients and Families Name, Ethnicity (sex, age) RBC Hb MCV MCH RDW Hb EP Family C, Ashkenazi Family C Mother (34y) 4.0 11.4 87 28.5 14.3 Family C Father (38y) 6.08 13.5 71 22.2 15.7 Family C Child I (F, 8y) 5.51 11.1 63 20.1 14.8 Family C Child II (M, 6y) 5.91 11.9 65 20.1 15.9 Family C Child III (F, 2.5y) 4.11 11.5 84.6 27.7 16.1 Family K, Ashkenazi Family K Propositus (M, 31y) 6.63 14.1 69.4 21.3 14.9 Family MF, Persian Family MF Propositus (M, 37y) 5.51 9.7 56.7 17.5 23.7 HbH 6% Family M (beta thal), Ashkezani Family M Mother (38y) 5.46 10.7 63.9 19.6 14.8 HbA2 2.8% Family M Father (51y) 5.07 13.3 80.3 26.2 13.2 HbA2 2.2% Family M Child I (F, 17y) 4.85 14.2 86.7 29.3 12 HbA2 2.6% Family M Child II (F, 13y) 5.43 10.6 62.3 19.5 14.8 HbA2 2.5% Family M Child III (F, 11y) 4.43 12.2 83.4 27.4 12.7 HbA2 2.4% Family M Child IV (F, 4y) 6.32 11.2 56.7 17.7 16.5 HbA2 2.5%
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Talarmin, A., F. Van Wambeke, P. Catala, C. Courties, and P. Lebaron. "Specific rates of leucine incorporation by marine bacterioplantkon in the open Mediterranean Sea in summer using cell sorting." Biogeosciences Discussions 7, no. 4 (August 30, 2010): 6545–88. http://dx.doi.org/10.5194/bgd-7-6545-2010.
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Abstract. Cell-specific leucine incorporation rates were determined in early summer across the open stratified Mediterranean Sea along vertical profiles from 0 to 200 m. During the period of our study, the bulk leucine incorporation rate was on average 5.0 ± 4.0 (n=31) pmol leu l−1 h−1. After 3H-radiolabeled leucine incorporation and SyBR Green I staining, populations were sorted using flow cytometry. Heterotrophic prokaryotes (Hprok) were divided in several clusters according to the cytometric properties of side scatter and green fluorescence of the cells: the low nucleic acid content cells (LNA) and the high nucleic acid content cells (HNA), with high size and low size (HNA-hs and HNA-ls, respectively). LNA cells represented 45 to 63% of the Hprok abundance between surface and 200 m, and significantly contributed to the bulk activity, from 17 to 55% all along the transect. The HNA/LNA ratio of cell-specific activities was on average 2.1 ± 0.7 (n=31). Among Hprok populations from surface samples (0 down to the deep chlorophyll depth, DCM), HNA-hs was mostly responsible for the leucine incorporation activity. Its cell-specific activity was up to 13.3 and 6.9-fold higher than that of HNA-ls and LNA, respectively, and it varied within a wide range of values (0.9–54.3×10−21 mol leu cell−1 h−1). At the opposite, ratios between the specific activities of the 3 populations tended to get closer to each other, below the DCM, implying a potentially higher homogeneity in activity of Hprok in the vicinity of nutriclines. Prochlorococcus cells were easily sorted near the DCM and displayed cell-specific activities equally high, sometimes higher than the HNA-hs group (2.5–55×10−21 mol leu cell−1 h−1). We then showed that all the sorted populations were key-players in leucine incorporation into proteins. The mixotrophic feature of certain photosynthetic prokaryotes and the non-negligible activity of LNA cells all over Mediterranean were reinforced.
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Hines, K. L., A. Braillon, and R. A. Fisher. "PAF increases hepatic vascular resistance and glycogenolysis in vivo." American Journal of Physiology-Gastrointestinal and Liver Physiology 260, no. 3 (March 1, 1991): G471—G480. http://dx.doi.org/10.1152/ajpgi.1991.260.3.g471.
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Administration of platelet-activating factor (PAF) to portal venous circulation of anesthetized fed rats produced decreases in mean arterial pressure and increases in hepatic portal pressure and blood glucose concentration. These responses to PAF were dose dependent with ED50 values of 0.02-0.05 micrograms/kg and specific as lyso- and enantio-PAF did not reproduce effects of PAF. Specific PAF receptor antagonist SRI 63-675 (75 micrograms/kg) inhibited significantly these PAF (0.1 micrograms/kg)-induced responses in rats. Administration of prazosin (500 micrograms/kg) and propranolol (400 micrograms/kg) to rats abolished phenylephrine (50 micrograms/kg)-induced increases in mean arterial pressure, hepatic portal pressure, and blood glucose concentration but did not prevent PAF (1 microgram/kg)-induced alterations in these parameters. Glycogen phosphorylase alpha levels were increased significantly in livers of rats after administration of PAF (1 microgram/kg) or phenylephrine (50 micrograms/kg). Administration of prazosin and propranolol to rats inhibited phenylephrine- but not PAF-induced activation of hepatic glycogen phosphorylase. Hepatic adenosine 3',5'-cyclic monophosphate (cAMP) concentration was increased slightly by PAF, but these increases were eliminated by adrenergic blockade, suggesting that activation of hepatic glycogen phosphorylase by PAF is not dependent on increases in cAMP. Increases in hepatic portal pressure and blood glucose concentration in response to PAF (0.1 micrograms/kg) were not attenuated in adrenalectomized rats. Moreover, PAF (0.1 micrograms/kg) stimulated increases in hepatic portal pressure after administration of the ganglionic blocking agent chlorisondamine (2.5 mg/kg) to adrenalectomized rats. Administration of PAF (0.05 micrograms/kg) to rats instrumented with pulse Doppler flow probes produced decreases in hepatic arterial and portal vein blood flow and increases in hepatic arterial and portal vascular resistance. These observations provide direct evidence that PAF regulates hepatic hemodynamics and glycogenolysis in vivo. It is suggested that PAF plays an important role in regulating hepatic blood flow and supplying extrahepatic tissues with energy substrates by sympathetic-independent mechanism(s) after its release in acute pathophysiological situations.
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Cabrera, Rafael A., Dolores Cabrera, Emily Bruder, and Gene Gourley. "283 Growth Performance, Carcass Characteristics and Economic Parameters Comparison Between Medicated and Antibiotics Free Programs in Wean-To-Finish Pigs." Journal of Animal Science 101, Supplement_2 (October 28, 2023): 177–78. http://dx.doi.org/10.1093/jas/skad341.196.
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Abstract The objective of this trial is to contrast the growth performance, carcass characteristics and economic parameters of pigs either raised with no antibiotics, antibiotics or supplemented with natural compounds from weaning to market. Barrows and gilts (1,260 Camborough 42 female x Waldo boars) were randomly assigned to 6 treatments (10 replicates, 21 pigs/pen): Negative Control (NC) with no antibiotics; Positive Control (PC) with antibiotics (600 g/ton of CTC, 35 g/ton of Denegard and 400 g/ton of CTC in phase 1, 2 and 3, respectively); TRT 3 had no medication and was supplemented 500 g/ton in the nursery and 250 g/ton of Oregano Essential Oil in G-F (Ecodiar, Nutrinae LLC, Palo Alto, CA); TRT4 had no medication and was supplemented with 250 g/ton of Oregano and 250 g/ton of Quillaja saponaria (Nuquil, Nutrinae LLC, Palo Alto, CA) in the nursery plus 125 g/ton of Oregano and 125 g/ton of Quillaja saponaria in the G-F period; TRT5 was as TRT3 plus Oregano liquid via water first 14 days in the nursery; and TRT6 was as TRT4 plus Oregano liquid via water first 14 days in the nursery. The PC treatment had no medication in phase 4 nursery diet and the entire grow-finish (G-F) period. Pigs were vaccinated at day 5 and day 21 pre-weaning with 1 mL of PCV and Mycoplasma, at day 62 post-weaning via water with Enterisol Ileitis and Salmonella vaccines and finally at day 63 post-weaning with 2 cc of an autogenous vaccine. Pigs were fed a 50% crumble diet in phase 1 and 2 nursery diets (5 and 12 lb./pig, respectively) and a meal diet in phase 3 and 4 (9.09 kg/pig for each phase). A meal diet was fed for the entire G-F period. Data were analyzed with PROC MIXED of SAS and P < 0.05 was used to identify significant differences among the LS Means. Results showed that PC treatment pigs were significantly heavier (P < 0.01) than any other treatments and they also had significantly (P < 0.01) improved FCR when compared with NC, TRT4 and TRT 6 at the end of the nursery period (0 to 42 days). The PC treatment had significantly (P < 0.05) lower feed cost/pig and feed cost/gain when compared with TRT4 and TRT6 during the G-F period (42 to 174 days). PC treatment had improved (P< 0.01) FCR and lower (P< 0.05) feed cost/pig and feed cost/gain when compared with TRT4 and TRT6 from wean-to-finish (0 to 174 days). TRT 5 had overall similar growth, economic and carcass performance as PC treatment from wean-to-finish. Carcass characteristics and carcass gain did not differ among the treatments. In conclusion, it is possible to raise ABF pigs from wean-to-finish when supplementing natural compounds in the feed in nursery and G-F diets and in the water during the nursery period.
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Naranjo, A., A. Molina, C. Rodriguez-Lozano, N. Martín, F. Santana, S. Fuentes, R. Navarro, et al. "AB1220 VERTEBRAL FRACTURE CHARACTERISTICS IN AN FLS UNIT ACCORDING TO THE IDENTIFICATION METHOD; EMERGENCY LIST, OUTPATIENT CLINIC OR VFA." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 1837.1–1837. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1169.
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BackgroundThe risk o subsequent fracture is very high after a vertebral fracture (VF)ObjectivesTo analyze the characteristics of patients with VF seen in a Fracture Liaison Service (FLS).MethodsOur FLS cares for patients from the emergency list (URG), referred by hospital or primary care doctors (HPC) with VF <12 months, and captured by DXA-VFA (Densitometry - VF Assessment) in patients with non-VF. The database included the FRAX items plus previous treatment and DXA results. Traumatic VFs or VFs with a known age > 1 year, infiltrative or neoplastic diseases, and patients with contraindications for treatment were excluded. The number and grade of VF (Genant’s scale) were analyzed.Results570 patients have been included (Table 1). The most frequent route of identification was HPCfollowed by the emergency registry and detection by DXA-VFA. The patients identified by VFA did not report a previous VF, as did 25 of the HPC cases, referred by a report of fracture by the radiologistst or by detection in the consultation by the rheumatologist.Figure 1 shows the identification of patients over the years.Figure 1.We observed a higher percentage of grade 3 fractures in those identified in the emergency registry. Those identified by HPC had a higher average number of fractures and a higher percentage of osteoporosis by DXA. In this group there was a greater frequency of previous fracture, as well as rheumatoid arthritis and glucocorticoid use. Patients referred through HPC had a higher adherence to treatment compared with the other groups.The 69 patients detected by DXA-VFA consisted of 30 humerus fractures, 1 pelvic, and 38 forearm, mostly women with a single fracture and lower percentage of osteoporosis by DXA.The adherence to treatment has changed over the years. In 2021 and 2022 it was 93%, compared to 79% in 2012-2020.Table 1.- Distribution according to identification group. Results represent n (%) and mean (SD) unless expressly indicated.All patients N=570Emergency registry N=198Outpatient N=303VFA N=69pAge73.6 (9.7)75.5 (9.4)72.6 (9.9)72.4 (8.8)0.003Women480 (84.2)156 (78.7)261 (86.1)63 (91.3)0.020Time from fracture to visit (weeks) Mean17 (11)13 (8)20 (12)13 (8)0.02 Median (IQR)13 (8-20)12 (8-16)13 (8-28)12 (8-16) <12 weeks214 (37)83 (42)101 (33)30 (43)0.08Vertebral fracturesNumber of VF mean2.0 (1.6)1.76 (1.4)2.35 (1.8)1.22 (0.5)0.000 median (IQR)1 (1-2)1 (1-2)2 (1-3)1 (1-1) Only fractures grade 124 (4.2)3 (1.5)20 (6.6)*0.007 ≥ 2 VF**259 (45.7)78 (39.3)169 (56.1)12 (17.4)0.000 At least one grade 3 fracture***274 (48.8)124 (63.9)141 (47.3)9 (12.0)0.000Risk factors for fracture Previous fracture155 (27.2)51 (25.8)89 (29.3)15 (20.0)0.362 Parental hip fracture51 (8.9)20 (10.1)25 (8.2)6 (8.0)0.775 Active smoking67 (11.7)21 (10.6)34 (11.2)12 (16.0)0.294 Glucocorticoids51 (8.9)9 (4.5)40 (13.2)2 (2.7)0.001 Rheumatoid arthritis22 (3.8)5 (2.5)17 (5.6)00.045 Secondary osteoporosis86 (15.0)37 (18.6)36 (11.8)13 (17.3)0.075 Alcohol21 (3.6)9 (4.5)10 (3.3)2 (2.7)0.712 BMI27.5 (5.0)28.5 (4.7)26.2 (5.3)28.7 (5.1)0.000 FRAX major12.7 (8.6)13.3 (9.6)13.0 (11.0)10.8 (7.9)0.156 FRAX hip5.6 (6.6)6.0 (7.9)5.9 (4.0)4.3 (6.6)0.231DXA # Normal46 (8.6)18 (10.0)18 (6.3)10 (13.3)0.000 Osteopenia175 (32.8)69 (38.5)75 (26.3)31 (41.3) Osteoporosis312 (58.5)92 (51.3)192 (67.3)28 (37.3) T-score lumbar-2.29 (2.0)-2.0 (1.7)-2.5 (2.3)-1.4 (1.5)0.000 T-score femoral hip-1.91 (1.0)-1.8 (1.2)-2.0 (1.0)-1.5 (0.9)0.003Treatment& Previous treatment124 (21.8)35 (17.6)80 (28.0)9 (12.0)0.012 Start within 6 months of the visit474 (83.1)161 (81.3)265 (87.4)48 (69.5)0.001* Only grade 2 and 3 fractures were considered. ** Available in 567 patients. ***Available in 561 patients.#Available in 533 patients.&Bisphosphonate, denosumab, SERM or teriparatide.ConclusionAll the ways to identify VF are important. The training campaign carried out in the healthcare area, including radiologists, has allowed us to improve the standard. The results will be helpful in the implementation and consolidation of the model based on FLS.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Celsa, Ciro, Naoshi Nishida, Shadi Chamseddine, Ashwini Arvind, Michael Li, Hidenori Toyoda, Susanna Varkey Ulahannan, et al. "Outcomes of durvalumab (D) with or without tremelimumab (T) in routine clinical practice according to HIMALAYA trial eligibility: Preliminary results of the international DT-real study." Journal of Clinical Oncology 43, no. 4_suppl (February 2025): 552. https://doi.org/10.1200/jco.2025.43.4_suppl.552.
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552 Background: HIMALAYA showed that D+T and D are effective options for unresectable hepatocellular carcinoma (uHCC). However, data on outcomes according to the adherence to HIMALAYA inclusion criteria in routine clinical practice are lacking. Methods: In the context of a prospectively maintained database including 1293 patients (pts) with uHCC treated with immunotherapy, we analysed pts treated with D+T or D across 8 centres in USA, Asia and Europe. Pts who met >1 key exclusion criterion of HIMALAYA (prior systemic therapy, Child-Pugh class B-C, Vp4 thrombosis) were defined HIMALAYA-OUT and compared with HIMALAYA-IN pts for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) by RECIST 1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0. Results: Up to February 2024, 108 pts (mean age 66 years, male sex 81%) started D+T (n=69, 64%) or D (n=39, 36%). 62 pts (57%) were treated in 1° line and 46 (43%) in >2° line. Child-Pugh class was A in 67 pts (62%). Vp4 was present in 17 pts (16%). 31 pts (29%) were HIMALAYA-IN and 19/31 (61%) received D+T. After a median follow-up of 4.3 months (m, 95%CI 3.3-4.9), median OS (mOS) was 11.5 m and 12-m OS rate was 42%. mOS was not reached in HIMALAYA-IN pts (12-m OS rate 62%) and 8.9 m (95%CI 6.0-12.1) in HIMALAYA-OUT pts. Survival hazard ratio (HR) for HIMALAYA IN vs OUT was 0.28 (95%CI 0.09-0.93, p=0.037). Median PFS was 2.6 m (95% CI 2.2-5.2) overall, 4.6 m (95%CI 2.1-8.5) in HIMALAYA-IN and 2.6 m (95%CI 1.9-5.2) in HIMALAYA-OUT pts (HR 0.70, 95%CI 0.38-1.30, p=0.266). ORR and DCR (evaluable in 53 pts, 49%) were 15.1% (95%CI 6.5-29.7%) and 43.4% (95%CI 27.5-65.1) (Table). Any grade TRAEs occurred in 31.5% (95% 21.8-44.0%), grade 3-4 TRAEs in 8.3% (95%CI 3.8-15.8%), TRAEs requiring systemic corticosteroids in 8.3% (95%CI 3.8-15.8%) and discontinuation due to toxicity in 3.7% (95%CI 1.0-9.5%). Conclusions: Preliminary observational data from DT-Real study suggest a reproducible efficacy and safety of D+T and D in pts with uHCC fitting the inclusion criteria of HIMALAYA in routine clinical practice. HIMALAYA IN (n=31) HIMALAYA IN HIMALAYA OUT (n=77) HIMALAYA OUT D+T (n=19) D (n=12) D+T (n=50) D (n=27) mOS (m, 95%CI) NR NR NR 8.9 (6.0-12.2) 11.2 (6.6-13.2) 4.9 (2.6-12.2) 12-m OS (%) 61.8 63 88.9 37.2 37.4 44.4 mPFS (m, 95%CI) 4.6 (2.1-8.4) 8.5 (2.1-8.5) 2.4 (1.6-2.5) 2.6 (1.9-5.2) 2.4 (1.8-6.7) 2.6 (1.8-5.2) ORR (%,95%CI) (N=53) 23.1 (4.8-67.4) 25.0 (5.1-73.1) 0 12.5 (4.1-29.2) 13.8 (3.8-35.3) 9.1 (0.2-50.6) DCR (%, 95%CI) 46.2 (16.9-100) 50.0 (18.3-100) 0 42.5 (24.8-68.1) 41.4 (21.4-72.2) 45.4 (14.8-100) Any grade TRAEs (%,95%CI) 32.3 (15.5-59.3) 31.6 (11.6-68.7) 33.3 (9.1-85.4) 31.2 (20.0-46.4) 28.0 (15.3-47.0) 37.1 (17.8-68.1) Grade 3-4 TRAEs (%, 95%CI) 9.7 (2.0-28.3) 15.8 (3.3-46.1) 0 7.8 (2.9-17.0) 4.0 (0.5-14.4) 14.8 (4.0-38.0)
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Family, Leila, Su-Jau Yang, Zandra Klippel, Yanli Li, John H. Page, Roberto Rodriguez, and Chun Chao. "Risk of Febrile Neutropenia (FN) in Select Myelosuppressive Chemotherapy Regimens." Blood 126, no. 23 (December 3, 2015): 3257. http://dx.doi.org/10.1182/blood.v126.23.3257.3257.
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Abstract Introduction Febrile neutropenia (FN) is a serious adverse effect of myelosuppressive chemotherapy, which often results in hospitalization and chemotherapy dose modification. FN risk depends on patient characteristics and chemotherapy regimen risk. Understanding the FN risk associated with individual chemotherapy regimens can help guide the use of prophylactic granulocyte colony-stimulating factor (G-CSF) and patient monitoring. To this end, the NCCN has classified regimens into high (≥20%), intermediate (10%-20%), or low (<10%) FN risk based primarily on clinical trial data. However, even for the same regimen, the FN risk is often higher in clinical practice than in clinical trials. In this study, we assessed the FN risk associated with several regimens for which FN risk has not been determined or has shown substantial variability outside of a clinical trial setting, using data from Kaiser Permanente Southern California (KPSC), a large, community-based practice. Methods Included were patients diagnosed with incident non-Hodgkin's lymphoma (NHL), breast cancer (BC), or multiple myeloma (MM) between 2008 and 2013 at KPSC who initiated the following chemotherapy regimens: bendamustine ± rituximab for NHL; docetaxel, carboplatin, and trastuzumab (TCH) or docetaxel and cyclophosphamide (TC) for BC; or Q4W lenalidomide 25 mg/dexamethasone for MM. Bendamustine ± rituximab, TCH, and lenalidomide are not classified by NCCN; TC is classified as intermediate FN risk but has shown considerable variability of FN incidence when used in clinical practice. Data on cancer diagnosis, chemotherapy use, G-CSF use, neutrophil count, and infections were obtained from KPSC's electronic medical records to estimate the incidence proportions of FN and grade 3 and 4 neutropenia. FN was defined as (1) hospitalization with absolute neutrophil count (ANC) <1000/µL or (2) hospitalization with primary or secondary diagnosis codes of neutropenia (ICD-9 288.0x) and fever (ICD-9 780.6), diagnosis code for bacterial/fungal infection, or antibiotic use. Grade 3 neutropenia was defined as ANC ≥500/µL to <1000/µL; grade 4 neutropenia as ANC <500/µL. Patients who received prophylactic G-CSF within 5 days of chemotherapy initiation were excluded from analysis. Results Overall, 40 (12%) NHL patients; 149 (24%) and 340 (28%) BC patients who received TCH and TC, respectively; and 0 (0%) MM patients were excluded due to prophylactic G-CSF. Over the first 6 cycles of bendamustine (median 338.4 mg/m2) ± rituximab for NHL patients (n = 307), 7.2% experienced FN, 4.2% grade 3 neutropenia, and 17.6% grade 4 neutropenia. Over the first 6 cycles of TCH for BC patients (n = 462), 24.2% experienced FN, 10.6% grade 3 neutropenia, and 44.6% grade 4 neutropenia. Over the first 6 cycles of TC for BC patients (n = 859), 20.5% experienced FN, 9.5% grade 3 neutropenia, and 37.5% grade 4 neutropenia. Over the first 4 cycles of lenalidomide/dexamethasone for MM patients (n = 186), 3.8% experienced FN, 5.9% grade 3 neutropenia, and 18.3% grade 4 neutropenia (Table 1). Conclusions Using NCCN criteria, bendamustine ± rituximab for NHL and lenalidomide/dexamethasone for MM would be classified as low-FN-risk regimens (<10%). By contrast, BC regimens TCH and TC would be classified as high-FN-risk regimens (>20%) based on our data. These results could help inform prophylactic G-CSF use for the selected regimens in clinical practice. Table 1. Number and Incidence Proportion of Neutropenic Outcomes Overall and by Cycle Cancer: Regimen Cycle Patients n FN Events n (%) Grade 3 Neutropenia Events n (%) Grade 4 Neutropenia Events n (%) NHL: Bendamustine ± rituximab Overall 307 22 (7.2) 13 (4.2) 54 (17.6) 1 307 12 (3.9) 5 (1.6) 28 (9.1) 2 225 3 (1.3) 4 (1.8) 21 (9.3) 3 173 2 (1.2) 4 (2.3) 15 (8.7) 4 130 2 (1.5) 4 (3.1) 10 (7.7) 5 92 4 (4.4) 4 (4.4) 8 (8.7) 6 69 2 (2.9) 2 (2.9) 0 (0) BC: TCH Overall 462 112 (24.2) 49 (10.6) 206 (44.6) 1 462 70 (15.2) 39 (8.4) 138 (29.9) 2 326 13 (4.0) 15 (4.6) 42 (12.9) 3 282 17 (6.0) 9 (3.2) 39 (13.8) 4 247 6 (2.4) 8 (3.2) 31 (12.6) 5 199 4 (2.0) 6 (3.0) 25 (12.6) 6 169 8 (4.7) 3 (1.8) 12 (7.1) BC: TC Overall 859 176 (20.5) 82 (9.5) 322 (37.5) 1 859 126 (14.7) 51 (5.9) 266 (30.9) 2 649 21 (3.2) 42 (6.5) 82 (12.6) 3 571 19 (3.3) 23 (4.0) 62 (10.9) 4 511 14 (2.7) 22 (4.3) 45 (8.8) 5 94 1 (1.1) 3 (3.2) 9 (9.6) 6 84 2 (2.4) 1 (1.2) 2 (2.4) MM: Lenalidomide / dexamethasone Overall 186 7 (3.8) 11 (5.9) 34 (18.3) 1 186 2 (1.1) 8 (4.3) 17 (9.1) 2 101 3 (3.0) 5 (5.0) 14 (13.9) 3 63 2 (3.2) 2 (3.2) 8 (12.7) 4 37 0 (0) 0 (0) 4 (10.8) Disclosures Family: Amgen Inc.: Research Funding. Klippel:Amgen Inc.: Employment, Equity Ownership. Li:Amgen Inc.: Employment, Equity Ownership. Page:Amgen Inc.: Employment, Equity Ownership.
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Wong, Carlos K. H., Julie Chen, Samuel K. S. Fung, Maggie M. Y. Mok, Yuk Lun Cheng, Irene Kong, Wai Kei Lo, Sing Leung Lui, Tak Mao Chan, and Cindy L. K. Lam. "Direct and indirect costs of end-stage renal disease patients in the first and second years after initiation of nocturnal home haemodialysis, hospital haemodialysis and peritoneal dialysis." Nephrology Dialysis Transplantation 34, no. 9 (January 21, 2019): 1565–76. http://dx.doi.org/10.1093/ndt/gfy395.
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AbstractPurposeTo estimate the direct and indirect costs of end-stage renal disease (ESRD) patients in the first and second years of initiating peritoneal dialysis (PD), hospital-based haemodialysis (HD) and nocturnal home HD.MethodsA cost analysis was performed to estimate the annual costs of PD, hospital-based HD and nocturnal home HD for ESRD patients from both the health service provider’s and societal perspectives. Empirical data on healthcare resource use, patients’ out-of-pocket costs, time spent on transportation and dialysis by ESRD patients and time spent by caregivers were analysed. All costs were expressed in Hong Kong year 2017 dollars.ResultsAnalysis was based on 402 ESRD patients on maintenance dialysis (PD: 189; hospital-based HD: 170; and nocturnal home HD: 43). From the perspective of the healthcare provider, hospital-based HD had the highest total annual direct medical costs in the initial year (mean ± SD) (hospital-based HD = $400 057 ± 62 822; PD = $118 467 ± 15 559; nocturnal home HD = $223 358 ± 18 055; P < 0.001) and second year (hospital-based HD = $360 924 ± 63 014; PD = $80 796 ± 15 820; nocturnal home HD = $87 028 ± 9059; P < 0.001). From the societal perspective, hospital-based HD had the highest total annual costs in the initial year (hospital-based HD = $452 151 ± 73 327; PD = $189 191 ± 61 735; nocturnal home HD = $242 038 ± 28 281; P < 0.001) and second year (hospital-based HD = $413 017 ± 73 501; PD = $151 520 ± 60 353; nocturnal home HD = $105 708 ± 23 853; P < 0.001).ConclusionsThis study quantified the economic burden of ESRD patients, and assessed the annual healthcare and societal costs in the initial and second years of PD, hospital-based HD and nocturnal home HD in Hong Kong. From both perspectives, PD is cost-saving relative to hospital-based HD and nocturnal home HD, except that nocturnal home HD has the lowest cost in the second year of treatment from the societal perspective. Results from this cost analysis facilitate economic evaluation in Hong Kong for health services and management targeted at ESRD patients.
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Pekhova, Ya G., M. Yu Martynov, I. A. Belayeva, A. S. Ryabov, A. A. Vershinin, and A. N. Boiko. "Effects of rehabilitation on functional independence in daily life, exercise tolerance and quality of life in patients with relapsing-remitting multiple sclerosis." Neurology, Neuropsychiatry, Psychosomatics 16, no. 2 (April 19, 2024): 19–25. http://dx.doi.org/10.14412/2074-2711-2024-2-19-25.
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Objective: to evaluate the efficacy of a comprehensive rehabilitation program on functional independence in daily life, exercise tolerance and quality of life (QoL) in patients with relapsing-remitting multiple sclerosis (RRMS) in remission.Material and methods. 38 patients with RRMS were analyzed (33 women and 5 men; age – 41.6±7.7 years; EDSS – 4.0 [3.5; 5.0] points, duration of MS – 8.0 [3.0; 21.0] years). The patients received comprehensive rehabilitation in a hospital for 2.5 weeks. The examination was carried out before and after the rehabilitation program. Independence in daily activities was assessed using the Functional Independence Scale, the Get Up and Go Test and the Berg Balance Scale. Exercise tolerance was determined using a cardiopulmonary exercise test (CPET) on a cycle ergometer. The following parameters were measured: oxygen consumption during exercise (VO2 peak oxygen uptake), percentage from the predicted VO2 peak (% pred VO2 peak) and maximal workload in metabolic units (MET). Walking speed was measured according to the Davis protocol in the SMART-D laboratory (Italy). QoL was determined using the SF-36 questionnaire, which assesses physical functioning (PF), general health (GH), vital activity (VT) and social functioning (SF). Cognitive functioning was assessed using the Montreal Cognitive Scale (MoCA) and depression using the Beck Depression Inventory (BDI). Results. After completion of the rehabilitation course, there was a significant increase in VO2 peak (from 18.8±3.8 to 20.4±4.3 ml/kg/min), % pred VO2 peak (from 59±13 to 63±14%), maximal workload (from 5.4±1.2 to 5.8±1.2 MET), maximal heart rate (from 140±14 to 147±13) and walking speed (from 0.84±0.29 to 0.97±0.28 m/s). At the same time, despite an improvement the patients did not reach the age- and gender adjusted reference values for exercise tolerance. QoL indicators also increased, reaching or exceeding the populational values obtained for the Russian population: PF – from 45 to 52.2; GH – from 51 to 52; VT – from 45 to 50; SF – from 62.5 to 75. The number of points on the BDI also decreased significantly (from 9 to 6), and the increase on the MoCA scale had tendency to significant difference (p=0.064). Conclusion. A comprehensive rehabilitation program in patients with RRMS in remission helps to increase exercise tolerance and improve functional independence and QoL.
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Willemze, Roelof, Stefan Suciu, Franco Mandelli, T. M. de Witte, Boris Labar, Jean-Pierre Marie, Giovanna Meloni, et al. "High Dose (HD-AraC) vs Standard Dose Cytosine Arabinoside (SD-AraC) during Induction in Acute Myelogenous Leukemia (AML): Impact on Stem Cell Mobilization after Consolidation and on Autologous Transplantation (Second Report of the EORTC-Leukemia Group (LG) - GIMEMA AML-12 Trial." Blood 108, no. 11 (November 16, 2006): 609. http://dx.doi.org/10.1182/blood.v108.11.609.609.
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Abstract The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) with the same drugs. Patients (pts) in complete remission (CR) received consolidation (Co) consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after Co in pts without a donor: auto-SCT followed or not by low dose IL-2. From 9 1999 till 7 2006, 1675 AML pts (APL excluded), age <61 years, from 67 centers (23 EORTC-LG and 44 GIMEMA) entered. Currently 1571 pts have been randomized for induction and 429 pts post-Co. During the induction toxicity was similar in the 2 arms except for conjunctivitis: 6% (HD-AraC) vs 0% (SD-AraC). HD-AraC given in the induction had no impact on the organ toxicity during Co but platelet recovery (> 50x109/l) was longer (median 4.0 vs 3.3 weeks; P=0.01). Among 886 pts randomized until 7 2005 by EORTC centers and 6 large GIMEMA centers, median follow-up of 2.5 years, 815 were evaluable for response. Out of 643 pts who reached CR, 57 went off study (toxicity, early progression). Among the remaining 586 who received Co, 37 could not be evaluated (early death/relapse, too early) and 549 were still CR after Co: 297 pts had no donor/no sibling, 197 had a donor and 55 were not typed. In these 3 groups the present estimates of the SCT rates are: 63% (auto-SCT), 71% (allo-SCT) and 69% (auto-SCT), resp. The 2.5-yr DFS rates (SE%) were 45% (3%), 61% (4%), and 67% (7%), resp. In pts < 50 yrs, 216 pts had no donor/no sibling, 135 had a donor and 14 have not been typed. For the first 2 groups, the 2.5 yr DFS rates (SE%) were 50% (4%) vs 68% (4.5%), hazard ratio=0.64, 95% CI (0.44, 0.93), P=0.02. In pts without a donor/a sibling successful mobilization of blood stem cells (b-SC) after Co was in HD-Ara-C vs SD-Ara-C arm 53 vs 69%, of failure/postponement 37 vs 24%, and other 9.5 vs 7%. The rate of auto-SCT was similar (65 vs 64%), but harvest of BM cells was more often required in the HD-AraC group (15 vs 4.5%). Pts with an insufficient/delayed b-SC harvest had a longer (P<0.001) platelet recovery (> 50x109/l) after Co than those with a successful harvest: median = 6.7 vs 3.3 wks. Among 393 pts with information on cytogenetics, 14% had good risk, 50% normal, 23% other and 13% poor risk (-5/5q-, -7/7q-, complex). The 2.5-year EFS (no CR, time to relapse or death in CR) rates (SE%) were 68% (7%), 42% (4%), 32% (5%) and 14% (5%), resp. So far: toxicity of HD-Ara-C was acceptable; in those who received HD-AraC in induction platelet recovery after Co was longer and the rate of successful b-SC collection was lower; SCT rates are high and similar in the 2 randomized arms; pts <50 yrs with a donor do have a longer DFS; pts with poor risk cytogenetics continue to have a poor prognosis.
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Lee, Donna, Lakshmi Mahali, and Vafa Tabatabaie. "Successful Multimodal Treatment of a TSH-Secreting Pituitary Adenoma (TSH-oma)." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A611—A612. http://dx.doi.org/10.1210/jendso/bvab048.1247.
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Abstract Background: TSH-omas are rare tumors accounting for 0.5-2% of all pituitary adenomas. Due to their indolent nature, most TSH-omas are diagnosed at the stage of invasive macroadenomas. Over the past several decades, the management of TSH-omas has evolved substantially. While surgery remains first-line therapy, somatostatin analogs have emerged as important therapeutic agents as a result of their effectiveness in normalizing thyroid hormone levels in ~95% of patients with severe hyperthyroidism and reducing TSH-oma size in ~50% of patients. Clinical Case: A 52-year-old woman with a history of multinodular goiter was incidentally found to have a 2.2 x 1.8 x 2.1 cm pituitary macroadenoma with suprasellar extension, mass effect on the optic chiasm, and left cavernous sinus involvement when she presented with chest pain, palpitations, headache, and left-sided numbness and weakness. Laboratory results showed high FT4/T4/T3 with inappropriately high TSH, elevated α-subunit, and low cortisol with low-normal ACTH highly suggestive of TSH-oma with concurrent secondary adrenal insufficiency. An ophthalmology exam revealed a left superior temporal defect. The patient was treated with atenolol, prednisone, and octreotide two weeks before surgery with symptomatic improvement and near-normalization of FT4. Following an uncomplicated transsphenoidal resection, FT4 normalized within one week. At her one-month follow-up, both TSH and FT4 were normal, and her secondary adrenal insufficiency had resolved. Her visual field defect also recovered. Laboratory Results: TSH 5.35 (normal range 0.40-4.60 μU/mL), FT4 3.0 (0.8-1.7 ng/dL), T4 18.1 (5.0-12.0 μg/dL), T3 235 (80-200 ng/dL), ACTH 10 (6-50 pg/mL), cortisol 4.5 (5.0-25.0 μg/dL), α-subunit 8.0 (0.1-1.5 ng/mL); after 2 weeks on SQ octreotide 50mg q12h: TSH 1.93 (0.30-4.20 μU/mL), FT4 1.7 (0.6-1.5 ng/dL); 1 month post-op: TSH 1.53 (0.30-4.20 μU/mL), FT4 0.8 (0.6-1.5 ng/dL), ACTH 12 (7.2-63 pg/mL), cortisol 6.9 (4.0-20.0 μg/dL) Conclusion: Since the first reported case of TSH-oma in 1960, the diagnostic and therapeutic management of these rare pituitary adenomas have evolved due to the emergence of ultrasensitive TSH assays, advanced imaging and surgical techniques, and somatostatin analogs. However, to this day, most TSH-omas are still diagnosed at the stage of invasive macroadenomas, when successful surgical resection becomes more difficult. Hence, up to two-thirds of patients may require adjuvant therapy with medication or radiation. As evidenced in our patient, who achieved a near-euthyroid state within just two weeks of starting low dose octreotide, somatostatin analogs are highly effective in controlling hyperthyroidism and have solidified their place in the therapeutic management of TSH-omas. This case highlights the success of a multimodal approach to the treatment of TSH-omas.
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Landsman-Blumberg, Pamela, Madhav Namjoshi, Erin Thomson, and William Johnson. "Real-world aromatase inhibitor use and failure in women with metastatic ER+/HER2- breast cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 593. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.593.
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593 Background: Aromatase Inhibitors (AIs) have replaced tamoxifen as first-line therapy for postmenopausal women with metastatic, ER+ breast cancer (BC). However, little information is available on the real-world use of AIs. The objectives of this retrospective claims study were to compare demographic, clinical and treatment characteristics of postmenopausal women with metastatic ER+/HER2- BC treated with AIs and experiencing 0, 1, 2 or ≥ 3 AI failures (AIF). Methods: Women ≥ 55 years old, newly diagnosed with metastatic BC (index) were identified in the 2006-2010 Thomson Reuters MarketScan databases and followed until chemotherapy or 03/31/2011. ER+/HER2- disease was defined as any endocrine therapy (ET: tamoxifen, fulvestrant) or AI (anastrozole, letrozole, or exemestane) use and no trastuzumab or lapatinib use in the 6-month pre-or variable post-index periods. Those with any post-index AI use were retained for study. AIF post-index was defined as a switch to an alternative AI, ET or chemotherapy, or AI discontinuation with no further BC treatment. Patients were stratified by number of post-index AIF: 0, 1, 2 or ≥ 3. Results: Among 4,274 patients identified, 61% had ≥ 1 AIF (1: 80%, 2: 15%, ≥3: 5%). There was no difference in pre-index AI use across AIF cohorts: 0, 1, 2, and ≥3 (54%, 52%, 48%, 56%; p=0.073). AIFs increased with Medicare-eligibility (51%, 56%, 60%, 61%) and bone metastases at index (48%, 53%, 62%, 63%). Among those with ≥1 AIF, median follow-up (FU) increased with each failure but there was no notable pattern to reason for FU end. Median FU of the 0 AIF cohort (408 days) fell between those of the 1 and 2 AIF cohorts, 335 and 517 days. Anastrozole was the most common first line treatment for all cohorts except ≥ 3 AIFs where letrozole was most common. Pre-index and first line fulvestrant use both increased with the number of post-index AIFs: 0.3%, 1.9%, 2.0%, 5.0% and 0.7%, 2.5%, 4.0%, 14.9% respectively. There was no association between number of AIFs and chemotherapy use (36%, 29%, 38%). Conclusions: Over 60% of women with ER+/HER2- metastatic BC treated with AIs failed at least 1 and 20% of those failed ≥ 2. Surprisingly, increased rates of prior fulvestrant treatment appear associated with increasing numbers of AIF.
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De Almeida, Tiago Paggi, David Perruchoud, Jérémy Alexandre, Pascale Vermare, Josep Sola, Jay Shah, Luisa Marques, and Cyril Pellaton. "COMPARATIVE EVALUATION OF THE AKTIIA CUFFLESS MONITOR AND STANDARD 24-H AMBULATORY BLOOD PRESSURE MONITOR." Journal of Hypertension 42, Suppl 1 (May 2024): e74. http://dx.doi.org/10.1097/01.hjh.0001019984.85980.45.
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Objective: Cuffless blood pressure (BP) monitors provide an innovative approach for BP assessment, transcending the episodic nature of traditional cuff-based, oscillometric modalities like ambulatory BP monitors (ABPM). However, the performance of these cuffless devices compared to their cuff-based counterparts remains debated. In this study, BP readings from a continuous cuffless BP monitor were compared against those from a standard 24-hour ABPM. Design and method: The study enrolled 63 subjects (NCT04548986, 53.1±7.2 years, 21.2% female, arm circumference 29.0±2.5 cm) participating in a 12-week cardiac rehabilitation (CR) program (Réseau Hospitalier Neuchâtelois, Switzerland). Comparisons encompassed 24-h, daytime (9am– 9pm), and night-time (11pm–7am) systolic and diastolic BP (SBP, DBP) using a 7-day average BP measurement from a cuffless monitor (Aktiia SA, Switzerland) overlapping with a 1-day average from the ABPM (Dyasis 3, Novacor, France), both recorded at the start and end of the CR program. Two sessions were analyzed: session 1 compared the first day's ABPM data with the first week's Aktiia data; session 2 compared the last day's ABPM data with the last week's Aktiia data. Only sessions with at least 20 daytime and 7 night-time valid measurements from both monitoring modalities were included in this analysis. Results: From the initial cohort, 51 subjects fulfilled the requirements of data availability of this analysis (Figure 1, 44 in session 1, 35 in session 2). No significant differences were found between Aktiia and ABPM monitors in 24-h and daytime SBP readings (24-hour: mean ± SD [95% CI] 2.6±12.3 [-0.2, 5.4] mmHg, correlation r=0.57, P=0.06; daytime: 1.2±12.4 [-1.6, 4.0] mmHg, r=0.60, P=0.38). However, night-time SBP readings showed more pronounced differences (12.5±14.4 [9.3, 15.8] mmHg, r=0.39, P<0.001). DBP readings were significantly different but within clinical acceptance for 24-h and daytime (24-hour: -2.9±7.9 [-4.7, -1.1] mmHg, r=0.63, P=0.002; daytime: -3.1±8.2 [-5.0, -1.3] mmHg, r=0.64, P=0.001), with notable night-time differences (4.1±8.5 [2.2, 6.0] mmHg, r=0.57, P<0.001). Conclusions: The findings reveal the Aktiia monitor's promising performance in continuous, long-term BP monitoring, especially during daytime, while noting important differences at night. Further research is underway to investigate nocturnal measurements.
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André, Thierry, Dominique Berton, Giuseppe Curigliano, Renaud Sabatier, Anna V. Tinker, Ana Oaknin, Susan Ellard, et al. "Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors." JAMA Network Open 6, no. 11 (November 2, 2023): e2341165. http://dx.doi.org/10.1001/jamanetworkopen.2023.41165.
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ImportanceMismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti–programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor.ObjectiveTo assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors.Design, Setting, And ParticipantsThe GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017. Participants had advanced or recurrent dMMR and microsatellite instability–high (MSI-H) or polymerase epsilon (POLE)–altered solid tumors. The data cut for this interim analysis was from November 1, 2021, with median follow-up of 27.7 months.InterventionsPatients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal.Main Outcomes and MeasuresThe primary objective was to evaluate objective response rate and duration of response in patients with dMMR solid tumors by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.ResultsThe efficacy population included 327 patients (median [range] age, 63 [24-85] years; 235 [71.9%] female; 7 [2.1%] Asian, 6 [1.8%] Black, and 206 [63.0%] White patients), with 141 patients (43.1%) with dMMR endometrial cancer, 105 patients (32.1%) with dMMR colorectal cancer, and 81 patients (24.8%) with other dMMR tumor types. All patients had at least 1 previous line of therapy. Objective response rate assessed per blinded independent central review for dMMR solid tumors was 44.0% (95% CI, 38.6% to 49.6%). Median duration of response was not reached (range, ≥1.18 to ≥47.21 months); 72.2% of responders (104 of 144) had a response lasting 12 or more months. Median progression-free survival was 6.9 months (95% CI, 4.2 to 13.6 months); probability of progression-free survival at 24 months was 40.6% (95% CI, 35.0% to 46.1%). Median overall survival was not reached (95% CI, 31.6 months to not reached). The most frequent immune-related adverse events were hypothyroidism (25 [6.9%]), alanine aminotransferase increase (21 [5.8%]), and arthralgia (17 [4.7%]). No new safety concerns were identified.Conclusions And RelevanceIn this nonrandomized controlled trial, dostarlimab was a well-tolerated treatment option with rapid, robust, and durable antitumor activity in patients with diverse dMMR solid tumors. These findings suggest that dostarlimab provides meaningful long-term benefit in a population with high unmet need.Trial RegistrationClinicalTrials.gov Identifier: NCT02715284
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Yoon, Shinkyo, Dok Hyun Yoon, Shin Kim, Kyoungmin Lee, Eun Hee Kang, Sang-wook Lee, Chan-Jeoung Park, Chan-Sik Park, Jooryung Huh, and Cheolwon Suh. "Proposal of New Prognostic Index for Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era." Blood 124, no. 21 (December 6, 2014): 1668. http://dx.doi.org/10.1182/blood.v124.21.1668.1668.
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Abstract Background The International Prognostic Index (IPI) has been useful prognostic tool to predict prognosis of aggressive non-Hodgkin lymphoma in the last 20 years. Since the advent of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy for diffuse large B-cell lymphoma (DLBCL), its utility has been challenged and other prognostic index including revised IPI and National Comprehensive Cancer Network (NCCN)-IPI were proposed, which are not popularly used yet. We aimed to develop new prognostic model for DLBCL in rituximab era. Method Between March 2004 and June 2012, patients with DLBCL treated with R-CHOP were identified in the database of the Asan Medical Center (AMC) Lymphoma Registry. Primary end point was to devise a new prognostic index for DLBCL. Secondary end point was to validate the NCCN-IPI in our cohort. We tested new prognostic index model in the training set of AMC cohort consisted of randomly selected 80% of the sample (503 patients). The remaining 20% (118 patients) was used as an internal validations set. Results The AMC cohort consisted of 621 patients. Median follow-up duration was 43.3 months (6.2-122.5 months). Baseline characteristics of AMC cohort are presented in table 1. Median age was 57 years (range, 16-85 years). Median ϐ-2 microglobulin (ϐ-2 MG) was 2.10 mg/L (range, 1.0-66.0 mg/L). The univariate analysis of baseline characteristics revealed that age (≦60 vs. >60 years), LDH (within normal vs. increased), ECOG performance (0 or 1 vs. ≧2), advanced stage (Ann Arbor stage I/II vs. III/IV), extra-nodal involvement (≦1 vs. >1), B symptoms (no vs. yes), and ϐ-2 MG (≦2.5 vs. >2.5) could predict overall survival (OS), whereas bulky disease and gender did not (p value 0.140, 0.621, respectively). In the multivariate analysis, age, LDH, ECOG performance status, and ϐ-2 MG were significantly associated with OS (p value 0.001, <0.001, 0.004, and 0.019, respectively), while stage, extra-nodal involvement, and B symptom did not (p value 0.057, 0.233, and 0.577, respectively). We developed a new prognostic model with these 4 significant factors in the multivariate analysis. One point is assigned for each of the risk factors without refined categorization. Four risk groups were composed as followings: low (0 point), low-intermediate (1 point), high-intermediate (2-3 points), and high (4 points). The new prognostic model showed better discriminative power compared with classic IPI (Figure 1A). Five-year OS of low- and high-risk subgroup in new scoring model and classic IPI model in AMC cohort were 95% and 32% versus 89% and 45%, respectively. Our model was validated in an internal validation set (Figure 1B). NCCN-IPI also could stratify four risk groups (Figure 1 A and B). Conclusion We propose a new prognostic index model for DLBCL in rituximab era with age, LDH, ECOG performance and ϐ-2 MG, which has good discriminative power and convenient to apply. It warrants further validation using an independent cohort. Table 1. Baseline Characteristics Characteristics Total N=621 % Training set N=503 % Validation set N=118 % Age, years Median, range ≦ 60 years > 60 years 57.0 377 244 16-85 60.7 39.3 57.0 300 203 16-84 59.6 40.4 57.0 77 41 17-85 65.3 34.7 Sex Male Female 343 278 55.2 44.8 273 230 54.3 45.7 70 48 59.3 40.7 ECOG PS 0 or 1 ≧ 2 569 52 91.6 8.4 462 41 91.8 8.2 107 11 90.7 9.3 Serum lactate dehydrogenase levels Normal Elevated 334 287 53.8 46.2 279 224 55.5 44.4 55 63 46.6 53.4 Ann Arbor stage I and II III and IV 293 328 47.2 52.8 236 267 46.9 53.1 57 61 48.3 51.7 Number of extranodal sites <2 ≧ 2 403 218 64.9 35.1 329 174 65.4 34.6 74 44 62.7 37.3 B symptoms No Yes 549 72 88.4 11.6 447 56 88.9 11.1 102 16 86.4 13.6 International prognostic index Low/ low-intermediate High-intermediate/high 404 217 65.1 34.9 327 176 65.0 35.0 77 41 65.3 34.7 ¥Â -2 microglobulin, mg/L Median, range ≦ 2.5 mg/L > 2.5 mg/L 2.1 422 199 1.0-66.0 68.0 32.0 2.1 339 164 1.0-29.6 67.4 32.6 2.1 83 35 1.0-66.0 70.3 28.7 Table 2. Multivariate Analysis for Factors Associated with Overall Survival Factors HR 95% CI P value Score Age, years ≦ 60 years > 60 years 1.000 2.051 1.362-3.090 0.001 1 Serum lactate dehydrogenase levels Normal Elevated 1.000 3.165 1.951-5.135 <0.001 1 ECOG PS 0 or 1 ≧ 2 1.000 2.073 1.261-3.407 0.004 1 ϐ -2 microglobulin, mg/L ≦ 2.5 mg/L > 2.5 mg/L 1.000 1.691 1.0391-2.622 0.019 1 Figure 1. IPI versus NCCN IPI versus new prognostic index model in Asan Medical Center training set (A) and internal validation set (B) Figure 1. IPI versus NCCN IPI versus new prognostic index model in Asan Medical Center training set (A) and internal validation set (B) Disclosures No relevant conflicts of interest to declare.
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Gaujoux-Viala, C., C. Traverson, E. Filhol, C. Daien, S. Laurent-Chabalier, B. Combe, C. Lukas, J. Morel, and C. Hua. "POS1239 POSITIVE IMPACT OF THE FIRST LOCKDOWN IN PATIENTS WITH CHRONIC INFLAMMATORY RHEUMATISM." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 902.2–903. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3203.
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Background:Since the beginning of 2020, the COVID-19 pandemic has caused a considerable amount of fear, worry and concern in the general population and among certain groups such as the elderly, healthcare providers and people with pre-existing conditions in particular. Our patients suffering from chronic inflammatory rheumatism (CIR), a group of autoimmune pathologies treated by immunosuppressant medication, are particularly concerned. Actions taken – particularly quarantine and its effects on the normal activities, habits or livelihoods of many people – also have a significant impact. There is little information on the impact of the lockdown in patients with CIR with data measured prospectively, in a standardized way, before and during the first lockdown period.Objectives:The objective of this ancillary study was to evaluate the psychological impact of the first lockdown period (anxiety, depression, sleep disorders, catastrophizing...) as well as the evolution of disease activity in patients suffering from CIR.Methods:At two French university hospitals, adult patients with rheumatoid arthritis (RA) according to the ACR-EULAR 2010 criteria, spondyloarthritis (SpA) fulfilling the ASAS 2009 criteria and psoriatic arthritis (PsA) according to the Caspar 2006 criteria were consecutively included in the Catastrophism in Chronic Inflammatory Rheumatism (CRIC) study from September 2019. Sociodemographic data, information on the disease and its treatments were collected as well as questionnaires on disease activity (DAS28, CDAI, BASDAI), function (HAQ), quality of life (SF12, EQ5D), anxiety and depression (HADS, GAD7), insomnia (ISI) and catastrophizing scores (PCS). These data were collected prospectively at baseline, 3, 6 and 12 months.In this ancillary study, data from patients with an assessment before and during lockdown were analyzed. Statistical analyses were descriptive with a paired Student’s T-test.Results:In all, 140 patients (49 RA, 69 SpA and 22 PsA) were evaluated before and during lockdown. The median age was 53.5 [44-63] years and 60.7% were women; 74 patients (53.2%) were professionally active and 102 (72.9%) were living as couples. The majority of patients (92.9 %) had a disease lasting more than 2 years. Concerning treatments, 63 (45%) were treated by bDMARD monotherapy, 40 (28.5%) by bDMARD+ csDMARD, 17 (12.1%) by csDMARD monotherapy and 2 patients by tsDMARD; 90.7% were not taking any corticosteroids and 8.6% were taking ≤5 mg/d; 30% were on NSAIDs.When comparing before and during lockdown, pain, tender joint count, swollen joint count, disease activity (CDAI, BASDAI) and function (HAQ, SF12 physical component) were similar. However, there was a significant improvement in psychological status, anxiety (HADS, GAD7), the mental component of SF12, catastrophizing and overall quality of life (EQ5D) (see Table 1 below).Conclusion:There are very few prospective, standardized data on the impact of lockdown in patients with CIR with an assessment before and during the first lockdown period. In patients with CIR, the first lockdown period had no impact on the activity of the disease and was well experienced psychologically with less anxiety and an improvement in quality of life.Table 1.Outcome (N)140 CIR: 49 RA, 69 SpA, 22 PsABefore lockdownMean (SD)During lockdownMean (SD)Mean change(SD)PPain VAS (138)39.4 (25.3)39.4 (25.0)-0.28 (27.1)NSTJC (57)4.0 (6.8)4.7 (4.4)0.7 (5.9)NSSJC (56)1.0 (2.6)1.6 (1.7)0.5 (2.4)NSCDAI (36)11.7 (1.4)12.3 (7.5)1.2 (8.7)NSBASDAI (84)4.7 (1.9)4.9 (2.0)0.14 (1.4)NSHAQ (135)0.72 (0.57)0.72 (0.53)0.03 (0.33)NSSF12 mental(136)32.7 (8.7)36.2 (8.4)3.46 (8.01)<0.0001GAD-7 (anxiety) (135)7.7 (5.5)5.0 (5.3)-1.73 (0.40)<0.0001HADS anxiety(137)8.5 (3.9)7.8 (3.9)-0.64 (2.91)0.0113EQ5D(139)0.55 (0.31)0.61 (0.29)0.06 (0.24)0.0078PCS (catastrophizing) (137)18.9 (13.3)15.9 (11.1)-3.10 (9.60)0.0003Disclosure of Interests:None declared
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Clé, Diego V., Elias H. Atta, Danielle S. P. Dias, Carlos B. L. Lima, Mariana M. Bonduel, Gabriela B. Sciuccati, Larissa A. Medeiros, et al. "Repeat Course of Rabbit Antithymocyte Globulin As Salvage Following Initial Therapy with Rabbit Antithymocyte Globulin in Acquired Aplastic Anemia." Blood 124, no. 21 (December 6, 2014): 2944. http://dx.doi.org/10.1182/blood.v124.21.2944.2944.
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Abstract In patients with severe acquired aplastic anemia (AA) not eligible for hematopoietic stem cell transplant (HSCT), immunosuppression with horse antithymocyte globulin (h-ATG) and cyclosporine (CsA) is standard and is associated with a high response rate of about 60-70% at 6 months (Scheinberg et al. N Engl J Med 365: 430, 2011). Patients who are unresponsive to initial h-ATG can be rescued with rabbit ATG (r-ATG) in a third of cases (Scheinberg et al. Br J Haematol 133: 622, 2006). Since 2007, h-ATG is no longer available in most Latin American, Asian and European countries, with rabbit ATG (r-ATG) the only ATG formulation available in these markets. However, the outcome with r-ATG as first therapy in SAA is significantly inferior to that of h-ATG with worst response rate and overall survival (Scheinberg et al. N Engl J Med 365: 430, 2011). The salvage rate for patients who failed initial r-ATG is low with alemtuzumab and horse ATG [Scheinberg et al. Blood 119: 345, 2012; Am J Hematol 89: 467, 2014]. However, the salvage rate of a repeat course of r-ATG after initial r-ATG is unknown. Thus, we conducted a retrospective analysis in marrow failure referral Brazilian and Argentinian centers to address this question. The primary endpoint was hematologic response at 3 and 6 months, which was defined as transfusional independence and no longer meeting criteria for severe AA. Secondary endpoints included relapse, clonal evolution, and overall survival. Since 2005, 37 patients (32 refractory and 5 relapsed; 57% males, median age, 17 years; range 3-63 years) were re-treated with r-ATG (Thymoglobuline¨, Genzyme, Cambridge, MA, USA) with median dose of 3.5 mg/kg/d (range 1.67-5.0) for 5 days and oral cyclosporine adjusted to maintain blood levels between 150 and 400 ng/mL for 6 months. Corticosteroids, usually methylprednisolone, were given for at least 2 weeks to prevent serum sickness and trimethoprim–sulfamethoxazole was administered as Pneumocystis jiroveci prophylaxis. Only patients that completed the 5 day r-ATG course were included in the analysis. Second treatment was administered at a median of 283 days from first r-ATG/CsA (range 118-2379 days). After a median follow-up of 726 days (range 7-2320 days), the overall response rates at 3 and 6 months for initial r-ATG refractory patients was 5/32 (16%) and 7/32 (22%), respectively, and for those who relapsed 60% (3/5) (Table). Among all responders, 2 (20%) relapsed at 170 and 897 days after second treatment. In total, clonal evolutions were observed in 6 patients; 5 in non-responders (4 to monosomy 7; 1 trisomy 8 and 21), and 1 in a responder (myelodysplastic syndrome with normal karyotype). Three non-responders underwent matched-unrelated donor allogeneic HSCT. Twelve patients died, all who were non-responders to repeat r-ATG. Overall survival at 4.1 years (censored at the time of HSCT) was 58% (95% CI, 36-75%) (Figure). Our findings indicate that only a minority of r-ATG refractory AA patients may be successfully rescued with a second course of the same immunosuppression. Similar low salvage rates have been reported with alemtuzumab and h-ATG for those refractory to initial r-ATG. In the aggregate, these data show that: 1) other therapies should be considered for those refractory to initial r-ATG such as alternative donor HSCT, thrombopoietin agonists, or other experimental therapies; 2) the high success rate of initial h-ATG therapies cannot be recapitulated when r-ATG is administered first given the low salvage rate with alemtuzumab, h-ATG and now (current data) with r-ATG; 3) for patients that relapse after first r-ATG treatment, second course r-ATG may be a reasonable option. Table: Hematologic response at 3 and 6 months to second course of rabbit ATG plus cyclosporine Refractory to first r-ATG/CsA(n=32) 95% CI Relapsed to first r-ATG/CsA(n=5) 95% CI At 3 months no. (%) 5 (16) 3-28 3 (60) 17-100 At 6 months no. (%) 7 (22) 8-36 3 (60) 17-100 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Carrazco Chapa, A., D. C. Rubio Torres, M. E. Corral Trujillo, C. M. Skinner Taylor, L. Pérez Barbosa, I. Pelaez Ballestas, and D. Á. Galarza-Delgado. "AB1808-HPR VIOLENCE: A REALITY IN WOMEN WITH AUTOIMMUNE RHEUMATIC DISEASES?" Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 2136.1–2137. http://dx.doi.org/10.1136/annrheumdis-2023-eular.2844.
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BackgroundIntimate partner violence (IPV) is defined as any aggression that includes physical, psychological and sexual harm by a current or former intimate partner. In Mexico, 39.9% of women aged 15 years or over have experienced IPV throughout their romantic relationships [1].IPV in pregnancy and postpartum can lead to mood disorders, obstetric comorbidities, and low birth weight. Pregnant women with autoimmune rheumatic diseases (ARD) are a high-risk population.Using screening tools to detect women experiencing abuse and explore its severity helps us to intervene appropriately and prevent complications [2].ObjectivesThe aim of this study is to describe the frequency of IPV in patients with ARD.MethodsA descriptive, cross-sectional, exploratory study at the Hospital Universitario “Dr. José Eleuterio González” in Mexico. We included women from the pregnancy and rheumatic diseases clinic (CEER) with a screening of IVP with the HITS scale and categorized them as reproductive-age women and pregnant-postpartum women. We defined reproductive age as the age range of 18-45 years and postpartum up to 1 year after the birth of the last child. The demographic characteristics and ARD data were obtained from the clinical record. Women without ARD were matched (1:1) by age and condition (reproductive age and pregnant-postpartum. A virtual survey was applied including sociodemographic data and the Spanish version of HITS.The Kolmogorov-Smirnov test was used to determine normality. To analyze the differences between groups Mann–Whitney U test, Chi-square or Kruskal–Wallis test were employed. A p < 0.05 was considered statistically significant. The statistical analysis was performed with the statistical program SPSS version 25.Results96 women were included: 48 with ARD and 48 without ARD. The median age was 27 (IQR 24 – 32). In both groups, 24 were reproductive-age women and 24 were pregnant-postpartum women (18/ 75% postpartum and 6/ 25% pregnant). In the ARD group, the most frequent diagnoses were rheumatoid arthritis (22/ 46%) and systemic lupus erythematosus (20/ 42%). The sociodemographic characteristics and HITS results are intable 1.18 (19%) women suffered IVP: 11 (23%) women without ARD and 7 (15%) women with ARD(figure 1); in both the most reported item was being insulted (10 without ARD vs 7 ARD) followed by being screamed (6 without ARD vs 6 ARD). Threatened with harm was reported in 3 ARD women while physical hurt was reported in 3 women without ARD.We found significant differences between the HITS scores of ARD women and women without ARD (p= 0.007). No differences in IVP frequency in women without ARD and in the ARD group were found (p= 0.433). Overall, more pregnant-postpartum women were identified as IPV victims than reproductive-age women (p= 0.433).ConclusionPregnant and postpartum women are prone to report IPV than women of reproductive age. The current rise in IPV requires us to actively participate in research to prevent complications in pregnant and postpartum patients with ARD.References[1] Instituto Nacional de Estadística y Geografía. Encuesta Nacional sobre la Dinámica de las Relaciones en los Hogares (ENDIREH) 2021: INEGI; 2022.[2] Chen P-H, Rovi S, Vega M, Jacobs A, Johnson MS. Screening for domestic violence in a predominantly Hispanic clinical setting. Family Practice. 2005;22(6):617-23.Table 1.Sociodemographic characteristics and HITS resultsPregnant-postpartum ARD women n= 24Reproductive-age ARD women n= 24Pregnant-postpartum without ARD women n= 24Reproductive-age without ARD women n= 24Age, median, (IQR), years28.5(23.3 – 35.0)27.0(23.0 – 32.0)28.5(22.3 – 35.0)27.0(26.0 – 29.0)Marital status, n (%)Single4 (17)20 (83)3 (13)18 (75)Common law marriage9 (38)1 (4)11 (46)2 (8)Married11 (46)3 (13)10 (42)4 (17)Occupation, n (%)Employee7 (29)21 (88)7 (29)21 (88)Housewife14 (58)2 (8)16 (67)-Student3 (13)1 (4)1 (4)3 (13)Years of education, n (%)<9 years10 (42)5 (21)9 (38)->9 years14 (58)19 (33)15 (63)24 (100)HITS score, median, (IQR)4 (4.0 – 4.8)4 (4.0 – 4.0)5 (4.0 – 5.8)4 (4.0 – 5.0)p=0.027IQR: Interquartile range, IPV: Intimate Partner ViolenceAcknowledgements:NIL.Disclosure of InterestsNone Declared.
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Willemze, Roelof, Stefan Suciu, Franco Mandelli, Giovanna Meloni, Boris Labar, Stijn J. M. Halkes, Petra Muus, et al. "High Dose (HD-AraC) Vs Standard Dose Cytosine Arabinoside (SD-AraC) During Induction and IL-2 Vs Observation After Consolidation/Autologous Stem Cell Transplantation in Patients with Acute Myelogenous Leukemia (AML): Final Report of the AML-12 Trial of EORTC and GIMEMA Leukemia Groups on the Value of High Dose AraC." Blood 118, no. 21 (November 18, 2011): 257. http://dx.doi.org/10.1182/blood.v118.21.257.257.
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Abstract Abstract 257 The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/sqm/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm/d for 3 days) and etoposide (50 mg/sqm/d for 5 days) vs SD-AraC (100 mg/sqm/d for 10 days) with the same drugs, in previously untreated AML < 61 year old patients (APL excluded). Patients (pts) in complete remission (CR) had to receive consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization had to be done after evaluation of consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2. The aim of the trial was to detect an 8% treatment difference (from 35% to 43%) in the 5-yr overall survival (OS) rate, corresponding to a hazard ratio (HR) of 0.80 (alpha=5%, power=95%); secondary endpoints were response to induction, toxicity, disease-free survival (DFS) from CR. Randomization was performed centrally; the 1st randomization was stratified for age (<46 vs > 45 yrs), performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 pts from 68 centers were randomized. Due to insufficient reporting, 3 centers, who recruited 63 patients, have been excluded from the analysis. The remaining 1942 pts (872 pts entered by EORTC-LG and 1070 by GIMEMA) 969 were randomized in SD-AraC and 973 in HD-AraC arm; among them 25 and 28, respectively, were ineligible, but kept in the analysis. Both arms were comparable with respect to gender, age (median=45 yrs), disease history, initial leukocyte count, PS, FAB and cytogenetics. At a median follow up of 6 yrs, 1114 pts had died. Results: After 1 or 2 courses of induction, CR was achieved in 1430 pts (73.6%); 684 (71.9%) pts (SD-AraC group) vrs 746 (78.7%) pts (HD-AraC group): p=0.002. Resistance was documented in 173 (18.2%) vrs 123 (13%), and death during induction in 85 (8.9%) vrs 71 (7.5%) pts, respectively. Induction toxicity profile and grade was similar in the 2 arms except for conjunctivitis grade 3: HD-AraC>SD-AraC. CR rates for pts<46 yrs were 74.7% (SD-AraC) and 81.4% (HD-AraC) and for pts>45 yrs 66.4% (SD-AraC) and 71.8% (HD-AraC). 634 pts (SD-AraC and 686 (HD-AraC) received a consolidation cycle. Among 765 CR-pts<46 yrs 284 pts had an HLA identical sibling (<46D) and 481 did not or had not been typed (<46NoD). Among 665 CR-pts>45 yrs 225 pts had an HLA identical sibling (>45D) and 440 did not or had not been typed (>45NoD). In the <46D group 211 underwent an allo-SCT and 11 an auto-SCT. In the <46NoD group 274 underwent an auto-SCT and 29 a MUD-SCT; in the >45D group 147 underwent an allo-SCT and 14 an auto-SCT. In the >45NoD group 244 underwent an auto-SCT and 12 a MUD-SCT. Comparisons of treatments arm regarding OS from randomization, DFS and Survival (S) from CR are indicated in the Table. The impact of age on the treatment difference regarding OS was almost significant (p=0.06). In pts >45 who reached CR, the decrease in the relapse rate in the HD-Ara-C arm vrs SD-Ara-C arm (45.5% vs 49.4%) was counterbalanced by an increase in the death in CR rate (18.4% vs 13.2%). Conclusion: The final evaluation of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 6 years, HD-AraC in the induction treatment leads to a significantly higher CR rate than SD-Ara-C and results in improvement in overall survival but only in pts under the age of 46 years. Disclosures: Muus: Amgen: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen Cilag: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau.
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Olatunji, Akinade S., and Funmilayo Ajay. "Potentially Toxic Contamination of Cultivated Wetlands in Lagos, Nigeria." Journal of Health and Pollution 6, no. 10 (June 1, 2016): 95–102. http://dx.doi.org/10.5696/2156-9614-6.10.95.
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Background. Active cultivation of wetlands without consideration of the quality of the sediment is a common practice in the city of Lagos. Wetlands in several parts of the city have been cleared for growing vegetables and other crops. As a buffer for all surface run-off from the surrounding areas, wetlands are a depository for whatever contaminants are sourced from the catchments; hence the need to ascertain the quality of sediment on which edible crops are grown to determine suitability for agriculture. Methods. Wetland water samples were tested for pH levels, electrical conductivity, and total dissolved solids. Randomly selected core samples from one of the cultivated wetland areas located in the city center were taken to up to 8 cm in depth, then dried, recovered from the barrel and divided into groups of the following depths: 0–2 cm, 2–4 cm, 4–6 cm, and 6–8 cm. The dried and divided samples were subsequently sieved and analyzed for metal content using inductively coupled plasma mass spectrometry. Results for copper (Cu), lead (Pb), zinc (Zn), nickel (Ni), chromium (Cr) and vanadium (V) were geochemically evaluated. Results. The wetland water samples were found to be acidic, ranging from 5.9–6.4. The electrical conductivity was 430–500 μS/cm, and total dissolved solids, 280–320 mg/L. The metal content results (in mg/kg) for samples from 0–2, 2–4, 4–6 and 6–8 cm depths were: Cu (13–861, 12–752, 10–899 and 11–707); Pb (29–1646, 26–2660, 33–2400 and 25–1818); Zn (112–7237, 76–9908, 63–7517 and 47–6579); Ni (3–219, 3–178, 3–186 and 3–176); Cr (10–147, 9–157, 14–160 and 16–147); and V (14–72, 12–75, 17–77 and 19–77). The evaluated results showed that the selected metal concentrations exceeded various guideline values. Calculated geo-accumulation index, metal ratio, and enrichment factor showed marked enrichment of metals in the wetland sediment samples. Discussion. For the majority of the metals observed, the correlation matrix revealed strong positive relationships. For Cu, Pb, Zn, Ni, and Cr, there was a correlation matrix >0.8. This indicates similar origin and sourcing of the sediments. Vanadium, however, displayed a negative correlation with all the other elements. Conclusions. The study revealed that most of the cultivated sediment samples contained elevated levels of potentially toxic elements in the form of Pb, Cu, and Zn. The acidic nature of the wetlands water in the sediment samples also make them unsuitable for cultivation as the possibility of metal dissolution in transpirated water and bio-accumulation of potentially toxic elements in the cultivated vegetables is high.
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Murchison, D., and W. H. Griffith. "High-voltage-activated calcium currents in basal forebrain neurons during aging." Journal of Neurophysiology 76, no. 1 (July 1, 1996): 158–74. http://dx.doi.org/10.1152/jn.1996.76.1.158.
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1. Both conventional whole cell and perforated-patch voltage-clamp recordings were made of high-voltage-activated (HVA) calcium (Ca2+) channel currents in acutely dissociated medical septum and nucleus of the diagonal band neurons from young (1-3.5 mo) and aged (19-26.5 mo) Fischer 344 rats. Barium (Ba2+) was used as the charge carrier to minimize secondary Ca(2+)-induced conductances and Ca(2+)-induced inactivation. 2. When HVA currents generated by voltage ramps from a holding potential (Vh) of-60 mV were recorded within minutes after whole cell formation, no change in peak current density was observed between young (-44.7 +/- 2.5 pA/pF, mean +/- SE, n = 93) and aged (-44.2 +/- 2.1 pA/pF, n = 86) cells. However, currents recorded later with voltage step protocols revealed a reduction in peak current amplitudes and a trend toward larger peak current densities in aged cells. From a Vh of -60 mV and with steps to -10 mV, current densities were -21.5 +/- 1.9 pA/pF in young cells (n = 55) and -25.0 +/- 2.0 pA/pF in aged cells (n = 44). The differences in current densities recorded by the two protocols were explained by nonspecific current rundown and the development of a slow (min) inactivation process. Slow inactivation was different from conventional rundown of HVA currents because it was reversible with the use of perforated-patch recordings. 3. Perforated-patch recordings were used to characterize slow inactivation. There was significantly less slow inactivation in aged cells. When voltage steps (200 ms in duration, from -80 to -10 mV) were delivered at 12-s intervals, slow inactivation reduced the current after 15 min to 63 +/- 7% of control in young cells and 86 +/- 4% in aged cells (P = 0.028). When voltage steps were delivered at 20-s intervals, the current at the 15th step decreased to 93.4 +/- 1.5% of control in aged cells, compared with 86.6 +/- 1.6% in young (P = 0.007). There was less slow inactivation with increased intervals between voltage steps and with shorter step durations. There was also less inactivation with reduced concentration of charge carrier, indicating a current-dependent component to slow inactivation. Additionally, a voltage-dependent component was evident, because slow inactivation was increased at depolarized VhS. 4. Perforated-patch recordings were used to study at least four pharmacologically distinct fractions of HVA currents in both young and aged cells. Nifedipine (10 microM) blocked 16.9 +/- 2.8% and 23.6 +/- 2.5% of the HVA currents in young and aged cells, respectively. omega-Conotoxin GVIA (500 nM) blocked 53.2 +/- 5.8% in young and 53.6 +/- 2.9% in aged cells. In young cells, omega-agatoxin IVA (200-400 nM) blocked 28.4 +/- 2.2% of the HVA current, and it blocked 29.9 +/- 2.8% in aged cells. A fraction of the current (young cells: 13.8 +/- 2.2%; aged cells: 11.4 +/- 1.6%) was resistant to a combination of all three antagonists. Cadmium (100 microM) completely blocked the remaining HVA current. No significant age-related differences in the HVA current fractions were observed. 5. The HVA current density, current-voltage relationship, and voltage-dependent activation were unchanged with age. However, slow inactivation of HVA currents was reduced in aged cells. The age-related difference in HVA Ca2+ currents reported here suggests a possible mechanism by which Ca2+ homeostasis may be altered in aged neurons.
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Morin, Charles M., Si-Jing Chen, Hans Ivers, Simon Beaulieu-Bonneau, Andrew D. Krystal, Bernard Guay, Lynda Bélanger, et al. "Effect of Psychological and Medication Therapies for Insomnia on Daytime Functions." JAMA Network Open 6, no. 12 (December 28, 2023): e2349638. http://dx.doi.org/10.1001/jamanetworkopen.2023.49638.
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ImportanceDaytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for improving daytime functions and how best to proceed with treatment for patients whose insomnia has not remitted.ObjectivesTo compare the efficacy of behavioral therapy (BT) and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluate the added value of a second treatment for patients whose insomnia has not remitted.Design, Setting, and ParticipantsIn this sequential multiple-assignment randomized clinical trial conducted at institutions in Canada and the US, 211 adults with chronic insomnia disorder were enrolled between May 1, 2012, and December 31, 2015, and followed up for 12 months. Statistical analyses were performed on an intention-to-treat basis in April and October 2023.InterventionsParticipants were randomly assigned to either BT or zolpidem as first-stage therapy, and those whose insomnia had not remitted received a second-stage psychological therapy (BT or cognitive therapy) or medication therapy (zolpidem or trazodone).Main Outcomes and MeasuresStudy outcomes were daytime symptoms of insomnia, including mood disturbances, fatigue, functional impairments of insomnia, and scores on the 36-item Short-Form Health Survey (SF-36) physical and mental health components.ResultsAmong 211 adults with insomnia (132 women [63%]; mean [SD] age, 45.6 [14.9] years), 104 were allocated to BT and 107 to zolpidem at the first stage. First-stage treatment with BT or zolpidem yielded significant and equivalent benefits for most of the daytime outcomes, including depressive symptoms (Beck Depression Inventory-II mean score change, −3.5 [95% CI, −4.7 to −2.3] vs −4.3 [95% CI, −5.7 to −2.9]), fatigue (Multidimensional Fatigue Inventory mean score change, −4.7 [95% CI, −7.3 to −2.2] vs −5.2 [95% CI, −7.9 to −2.5]), functional impairments (Work and Social Adjustment Scale mean score change, −5.0 [95% CI, −6.7 to −3.3] vs −5.1 [95% CI, −7.2 to −2.9]), and mental health (SF-36 mental health subscale mean score change, 3.5 [95% CI, 1.9-5.1] vs 2.5 [95% CI, 0.4-4.5]), while BT produced larger improvements for anxiety symptoms relative to zolpidem (State-Trait Anxiety Inventory mean score change, −4.1 [95% CI, –5.8 to –2.4] vs −1.2 [95% CI, −3.0 to 0.5]; P = .02; Cohen d = 0.55). Second-stage therapy produced additional improvements for the 2 conditions starting with zolpidem at posttreatment in fatigue (Multidimensional Fatigue Inventory mean score change: zolpidem plus BT, −3.8 [95% CI, −7.1 to −0.4]; zolpidem plus trazodone, −3.7 [95% CI, −6.3 to −1.1]), functional impairments (Work and Social Adjustment Scale mean score change: zolpidem plus BT, −3.7 [95% CI, −6.4 to −1.0]; zolpidem plus trazodone, −3.3 [95% CI, −5.9 to −0.7]) and mental health (SF-36 mental health subscale mean score change: zolpidem plus BT, 5.3 [95% CI, 2.7-7.9]; zolpidem plus trazodone, 2.0 [95% CI, 0.1-4.0]). Treatment benefits achieved at posttreatment were well maintained throughout the 12-month follow-up, and additional improvements were noted for patients receiving the BT treatment sequences.Conclusions and RelevanceIn this randomized clinical trial of adults with insomnia disorder, BT and zolpidem produced improvements for various daytime symptoms of insomnia that were no different between treatments. Adding a second treatment offered an added value with further improvements of daytime functions.Trial RegistrationClinicalTrials.gov Identifier: NCT01651442
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Maeda, Takeshi, Kimikazu Yakushijin, Yoshitaka Asakura, Nobuhiro Hiramoto, Saiko Kurosawa, Yutaro Kamiyama, Suguru Fukuhara, et al. "Engraftment Syndrome (ES) After Reduced-Intensity Stem Cell Transplantation (RIST): ES May Have a Negative Impact on Survival In Standard-Risk Patients." Blood 116, no. 21 (November 19, 2010): 2318. http://dx.doi.org/10.1182/blood.v116.21.2318.2318.
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Abstract Abstract 2318 Introduction: ES has been well recognized to increase non-relapse mortality (NRM) in autologous hematopoietic cell transplantation (HCT). However, little information is available on ES in allogeneic HCT, particularly after reduced-intensity conditioning. To determine the incidence, risk factors and outcome of ES after RIST, we retrospectively reviewed the medical records of 285 patients (pts) who underwent RIST at our institution between 1999 and 2007. Patients and Methods: After excluding 37 pts who received cord blood transplantation or a second or subsequent allogeneic HCT, and those who experienced primary graft failure, 248 pts (male 153, female 95) with a median age of 55 y (range, 21–68) fulfilled the criteria of this study. The underlying diagnosis included lymphoma (106 pts; 43%), acute myeloid leukemia (59; 24%), myelodysplastic syndrome (51; 21%), and others (32; 13%). Ninety-two pts (37%) had a standard-risk disease such as acute leukemia or lymphoma in CR1, and 156 (63%) had a high-risk disease. The donor and stem cell source were related PBSC in 170 pts (69%), related BM in 8 (3%), and unrelated BM in 70 (28%). All of the pts received reduced-intensity conditioning with a purine analog and a busulfan-based regimen. With the use of G-CSF after HCT, neutrophil engraftment (ANC ≥500/μ l) was achieved at a median of 12 days (range, 5–28). ES was diagnosed when the patient showed at least 2 of the following symptoms within 96 h of neutrophil engraftment: (1) fever (>38.0°C) without an identifiable source of infection, (2) skin rash (>25% of body surface area) that was not due to a drug reaction, (3) weight gain (>2.5% of baseline body weight), and (4) hypoxia (sPO2 <94%) or pulmonary infiltrates. Results: Among the 248 pts, 45 (18%) developed ES at a median of 14 days (6-23) after allogeneic HCT. Symptoms consisted of fever (100%), skin rash (53%), weight gain (62%) and hypoxia (33%). The incidence of ES in recipients of unrelated donor grafts was significantly higher than that in recipients of related donor grafts (28% vs 14%, p=0.02), and male pts had a significantly higher incidence of ES than female pts (22% vs 12%, p=0.04). No significant difference in the incidence of ES was observed between groups stratified according to age, stem cell source, TNC or CD34+ cell dose, disease risk, GVHD prophylaxis, and the timing of engraftment. By a multivariate analysis, use of an unrelated donor (HR 2.3, 95%CI 1.3–4.1, p=0.007), pts with lymphoid malignancy (HR 2.0, 95%CI 1.1–3.7, p=0.03) and male pts (HR 2.0, 95%CI 1.0–4.0, p=0.04) were associated with a significantly increased risk of ES. Among the 40 pts who required systemic corticosteroid therapy, 31 (78%) achieved a complete response, and the remaining 9 (23%) responded partially. There was a trend toward a higher incidence of grade III-IV acute GVHD (27% vs 18%, p=0.10) in pts with ES, and the incidence of extensive chronic GVHD (69% vs 62%, p=0.04) was significantly higher in pts with ES. Overall survival (OS) and non-relapse mortality (NRM) were not significantly different between the two groups, after a median follow-up of 53 months (range, 2–108) in surviving patents. A multivariate analysis showed that pts with high-risk disease (NRM, HR 1.9, 95%CI 1.1–3.3, p=0.01; OS, HR 2.5, 95%CI 1.6–3.8, p<0.001) and those with myeloid malignancy (NRM, HR 2.0, 95%CI 1.2–3.4, p=0.01; OS, HR 1.5, 95%CI 1.0–2.2, p=0.03) were associated with an increased risk of NRM and worse OS after allogeneic HCT, whereas the development of ES did not affect NRM or OS. In a subgroup analysis of 92 pts with standard-risk disease, pts with ES had a significantly worse OS (50% vs 76% at 3 y, p=0.03, Figure, left panel) and a higher NRM (49% vs 20% at 3 y, p=0.03) compared to those without ES. In a subgroup analysis of 156 pts with high-risk disease, however, OS (42% vs 46% at 3 y, p=0.76, Figure, right panel) and NRM (48% vs 39% at 3 y, p=0.84) of pts with ES were equivalent to those of pts without ES. Conclusions: ES is a rather common complication after RIST, especially in recipients of unrelated donor grafts. Although ES shows an initial good response to corticosteroid therapy, ES may have a negative impact on survival, especially in pts with standard-risk disease, and this effect may be related to the occurrence of GVHD. The development of an optimal treatment for ES may improve the outcome of pts who have received RIST by reducing GVHD-related mortality. Disclosures: No relevant conflicts of interest to declare.
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Mena-Vázquez, N., M. Rojas-Giménez, C. M. Romero-Barco, S. Manrique Arija, F. Espildora, M. C. Aguilar-Hurtado, R. Ortega Castro, et al. "POS0211 PREDICTORS OF PROGRESSION AND MORTALITY IN PATIENTS WITH PREVALENT RHEUMATOID ARTHRITIS AND INTERSTITIAL LUNG DISEASE: A PROSPECTIVE COHORT STUDY." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 323.1–323. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1090.
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Objectives:To analyze the effect of disease-modifying antirheumatic drugs (DMARDs) and identify risk factors associated with disease progression and mortality in patients with rheumatoid arthritis associated with interstitial lung disease (RA-ILD).Methods:We performed a multicenter, prospective, observational study of patients with RA-ILD receiving DMARDs between 2015 and 2020. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline and at 60 months. The main outcome measure at 60 months was worsening of FVC >10% or DLCO >15% and radiological progression or death. We recorded demographic and clinical characteristics, lung function, and the incidence of adverse events. A Cox regression analysis was performed to identify factors associated with worsening of ILD.Results:After 60 months, lung disease had stabilized in 66 patients (56.9%), improved in 9 (7.8%), and worsened in 23 (19.8%). Eighteen patients (15.5%) died, with a mean survival of 71.8 (1.9) months. Baseline characteristics of 116 with RA-ILD treated with DMARDs is in table 1.The Cox multivariate analysis revealed the independent predictors of worsening of RA-ILD to be usual interstitial pneumonia (HR, 2.6 [95%CI, 1.0-6.7]), forced vital capacity (%) (HR, 3.8 [95%CI, 1.5-6.7]), anticitrullinated protein antibody titers (HR, 2.8 [95%CI, 1.1-6.8]), smoking (HR, 2.5 [95%CI, 1.1-6.2]), and treatment with abatacept, tocilizumab, or rituximab (HR, 0.4 [95%CI, 0.2-0.8]). During follow-up, 79 patients (68%) experienced an adverse event, mostly infection (61%).Conclusion:Lung function is stable in most patients with RA-ILD receiving treatment with DMARDs, although one third of patients die. Identifying factors of worsening in RA-ILD is important for clinical management.Table 1.Baseline characteristics of 116 with RA-ILD treated with DMARDsVariableTotal=116Epidemiological characteristicsFemale sex, n (%)63 (54.3)Age, years, mean (SD)68.3 (9.9)Clinical and analytical characteristicsCurrent smokerNonsmoker, n (%)57 (49.1)Smoker, n (%)23 (19.8)Exsmoker, n (%)36 (31.0)Time since diagnosis of RA, months, median (p25-p75)148.5 (71.5-217.8)Diagnostic delay, months, median (p25-p75)8.5 (4.9-16.8)Time since diagnosis of ILD, months, median (p25-p75)27.5 (9.8-60.0)Positive rheumatoid factor (>10), n (%)111 (95.7)Positive ACPA titer (>20), n (%)100 (86.2)Erosive disease, n (%)76 (65.5)Treatment Synthetic DMARD100 (86.2) Methotrexate, n (%)51 (44.0) Leflunomide, n (%)30 (25.9) Sulfasalazine, n (%)9 (7.8) Hydroxychloroquine, n (%)21 (18.1)Biologic DMARD50 (43.1) Infliximab, n (%)1 (0.9) Etanercept, n (%)6 (5.2) Adalimumab, n (%)3 (2.6) Golimumab, n (%)3 (2.6) Certolizumab, n (%)3 (2.6) Tocilizumab, n (%)6 (5.2) Abatacept, n (%)15 (12.9) Rituximab, n (%)13 (11.2) Immunosuppressants11 (9.5) Mycophenolate, n (%)7 (6.0) Azathioprine, n (%)4 (3.4) Antifibrotic agents, nintedanib, n (%)1 (0.9) Baseline corticosteroids, n (%)69 (60.0) Dose of baseline corticosteroids, median (p25-p75)5.0 (0.0-7.5)Abbreviations. RA: rheumatoid arthritis; ILD: interstitial lung disease; ACPA: anticyclic citrullinated protein antibody; DMARD: disease-modifying antirheumatic drug; SD: standard deviation.Acknowledgements:Grant for Medical Researchers of the “Fundación Española de Reumatología” 2019. declare.Disclosure of Interests:None declared
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Gossec, L., D. D. Gladman, E. Mcdearmon-Blondell, P. Sewerin, C. T. Ritchlin, D. Feng, A. Lertratanakul, et al. "AB0550 EFFICACY OF UPADACITINIB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS AND A LOW OR HIGH SWOLLEN JOINT COUNT: A SUBGROUP ANALYSIS OF 2 PHASE 3 STUDIES (SELECT-PsA 1 AND SELECT-PsA 2)." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1308.2–1309. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2127.
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Background:Although most patients with psoriatic arthritis (PsA) enrolled in clinical trials have polyarticular arthritis, patients in clinical practice may present with oligoarthritis. Data on the efficacy of Janus kinase inhibitors in patients with PsA with low joint counts are limited.Objectives:To evaluate the efficacy of upadacitinib (UPA) in subgroups of patients with PsA with a low (baseline swollen joint count [SJC] <5) or high (SJC ≥5) SJC (LSJ or HSJ).Methods:Data were pooled across the SELECT-PsA 11 (non-biologic disease-modifying antirheumatic drug [non-bDMARD] inadequate response [IR] or intolerance) and SELECT-PsA 22 (bDMARD IR or intolerance) trials, which both enrolled patients with ≥3 involved joints (SJC ≥3 and tender joint count [TJC] ≥3). Subgroup analysis was performed for patients with LSJ or HSJ treated with UPA 15 mg once daily (QD) or placebo (PBO). Efficacy endpoints included minimal disease activity (MDA), very low disease activity (VLDA), Psoriatic Arthritis Disease Activity Score (PASDAS) low disease activity (LDA; ≤3.2), PASDAS remission (≤1.9), and 20/50/70% improvement in American College of Rheumatology (ACR) criteria (ACR20/50/70), all at Week 24, and Psoriasis Area Severity Index (PASI) 75 and static Investigator Global Assessment of Psoriasis (sIGA) 0/1 at Week 16.Results:At baseline, patients with HSJ (n=1060) had similar demographic characteristics but tended to have higher overall disease activity than patients with LSJ across multiple disease domains (n=215; Table 1). UPA efficacy appeared comparable in patients with LSJ and HSJ, with similar proportions of patients achieving composite (MDA, VLDA, PASDAS LDA, and PASDAS remission) measures at Week 24, and skin endpoints (PASI 75 and sIGA 0/1) at Week 16 (Figure 1). At Week 24, 60.0/36.8/22.1% of patients with LSJ receiving UPA 15 mg achieved ACR20/50/70 vs 40.0/17.5/5.8% in the PBO group; rates were 70.3/49.7/26.2% (UPA 15 mg) and 36.1/15.3/3.3% (PBO) in those with HSJ.Table 1.Baseline characteristicsPBOUPA 15 mg QDTotalLSJn=120HSJn=515LSJn=95HSJn=545LSJn=215HSJn=1060Female, n (%)65 (54.2)266 (51.7)49 (51.6)302 (55.4)114 (53.0)568 (53.6)Age (years), mean (SD)52.2 (12.7)51.5 (12.0)52.0 (10.6)52.0 (12.4)52.1 (11.8)51.8 (12.2)Duration since PsA symptoms (years), mean (SD)10.5 (9.2)11.1 (10.2)9.8 (8.2)10.3 (8.9)10.2 (8.7)10.7 (9.6)BMI, mean (SD)29.7 (6.3)31.1 (7.2)29.8 (6.2)30.7 (6.9)29.7 (6.2)30.9 (7.0)Prior failed bDMARDs, n (%)03 (2.5)15 (2.9)1 (1.1)15 (2.8)4 (1.9)30 (2.8)122 (18.3)113 (21.9)22 (23.2)104 (19.1)44 (20.5)217 (20.5)24 (3.3)31 (6.0)7 (7.4)28 (5.1)11 (5.1)59 (5.6)≥34 (3.3)20 (3.9)7 (7.4)27 (5.0)11 (5.1)47 (4.4)Use of ≥1 non-bDMARD atbaseline, n (%)87 (72.5)360 (69.9)63 (66.3)388 (71.2)150 (69.8)748 (70.6)Dactylitis (LDI >0), n (%)21 (17.5)169 (32.8)15 (15.8)176 (32.3)36 (16.7)345 (32.5)Enthesitis (LEI >0), n (%)60 (50.0)325 (63.1)60 (63.2)343 (62.9)120 (55.8)668 (63.0)TJC68, mean (SD)12.5 (11.3)23.9 (15.8)14.6 (13.5)23.1 (15.8)13.4 (12.3)23.5 (15.8)SJC66, mean (SD)3.5 (0.5)13.2 (8.3)3.6 (0.5)12.9 (9.0)3.6 (0.5)13.0 (8.7)HAQ-DI, mean (SD)1.0 (0.6)1.2 (0.7)0.9 (0.6)1.2 (0.6)0.9 (0.6)1.2 (0.7)hs-CRP > ULN (mg/L), n (%)82 (68.3)363 (70.5)62 (65.3)388 (71.2)144 (67.0)751 (70.8)BSA-Ps, median (range)3.0 (0.1–70.0)4.0 (0.1–95.0)2.0 (0.1–80.0)3.0 (0.1–97.0)3.0 (0.1–80.0)3.0 (0.1–97.0)BSA-Ps ≥ 3%, n (%)57 (47.5)285 (55.3)44 (46.3)300 (55.0)101 (47.0)585 (55.2)PASI (baseline BSA-Ps ≥ 3%), mean (SD)7.7 (7.5)12.1 (11.9)8.2 (7.0)10.2 (10.0)7.9 (7.2)11.1 (11.0)PASI (baseline BSA-Ps ≥ 3%), median (range)5.3 (0.1–39.4)7.9 (0.3–64.8)6.5 (0.2–35.4)6.8 (0.1–70.8)6.0 (0.1–39.4)7.3 (0.1–70.8)Conclusion:UPA efficacy was generally similar in patients with PsA with LSJ or HSJ, with both patient groups showing improvements in composite clinical endpoints and skin responses vs PBO.References:[1]McInnes I, et al. Ann Rheum Dis 2020;79(Suppl. 1):16–17;[2]Mease PJ, et al. Ann Rheum Dis 2020; Epub ahead of print.Acknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Grant Kirkpatrick, MSc of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Laure Gossec Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Dafna D Gladman Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Novartis, Pfizer, and UCB, Erin McDearmon-Blondell Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Philipp Sewerin Consultant of: AbbVie, Amgen, Axiom Health, Biogen, Bristol-Myers Squibb, Celgene, Chugai, Deutscher Psoriasis Bund, Eli Lilly, Fresenius Kabi, Gilead, Hexal, Janssen, Johnson & Johnson, Medi-login, Mediri, Novartis, Onkowissen, Pfizer, Roche, Rheumazentrum Rhein-Ruhr, Sanofi, Swedish Orphan Biovitrum, and UCB, Grant/research support from: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Bundesministerium fuer Bildung und Forschung, Deutsche Forschungsgesellschaft, Deutscher Psoriasis Bund, Eli Lilly, Fresenius Kabi, Gilead, Hexal, Janssen, Novartis, Pfizer, Rheumazentrum Rhein-Ruhr, Roche, Sanofi, and UCB, Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Sun, and UCB, Grant/research support from: AbbVie, Amgen, and UCB, Dai Feng Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Apinya Lertratanakul Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, R Ranza Consultant of: AbbVie, Eli Lilly, Janssen, Novartis, and Pfizer, Grant/research support from: AbbVie, Janssen, Novartis, and Pfizer, Lai-Shan Tam Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen, Pfizer, and Sanofi, Grant/research support from: Amgen, Boehringer Ingelheim, GSK, Janssen, Novartis, and Pfizer, Antonio Marchesoni Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, and UCB, Laura C Coates: None declared., Peter Nash Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB.
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Whitley, Michael J., Joanne Vesci, Michael Holinstat, Leonard C. Edelstein, and Paul F. Bray. "The Common PAR4 Ala120Thr Variant Has a Major Effect on Platelet Reactivity to Thrombin and These Effects Are Enhanced with PAR1 and P2Y12 Inhibition." Blood 128, no. 22 (December 2, 2016): 709. http://dx.doi.org/10.1182/blood.v128.22.709.709.
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Abstract Introduction: Human platelets express two thrombin receptors, protease activated receptor (PAR) 1 and PAR4 with different affinities for thrombin and different signaling properties. PAR1 and PAR4 have non-identical tissue expression patterns and repertoire of protease activators. We have shown a significant difference in activation kinetics and calciummobilization between platelets from healthy white and black subjects stimulated with PAR4-AP (Nat Med 2013). Part of these racial differences appears to be mediated by PAR4 signaling through Gq to Rap1 and PKC (ATVB 2014). Given the importance of platelet thrombus formation in ischemic arterial disease, these findings may contribute to the known worse outcomes in blacks compared to whites after acute coronary syndromes. Genomic approaches demonstrated that ~50% of the racial variance in PAR4-AP-induced platelet aggregation and calcium flux is caused by an Ala120Thr substitution in PAR4 (encoded by rs773902) and that the Thr120 variant is the "hyperreactive" compared to Ala120 (Blood 2014). Importantly, the Thr120 allele frequency is 63% in blacks and 19% in whites. However, the effect of the physiologic activator, thrombin, on this platelet PAR4 variant (independent of race) has not been characterized. The goals of this work were to perform a detailed characterization of the PAR4 Ala120Thr effect on thrombin-induced platelet function, and to assess pharmacogenetic effects of the PAR4 Ala120Thr variant on standard anti-platelet agents and novel PAR4 inhibitors. Results:We recruited 130 healthy, multi-racial donors and genotyped for rs773902. Subjects were excluded who had reduced arachidonic acid aggregation or who had the rare PAR4 Val296 variant. Preliminary studies showed heterozygotes had intermediate phenotypes to all assays, so most comparisons were between washed platelets homozygous for Thr120 or Ala120. The thrombin dose response curve for Thr120 homozygotes was left-shifted relative to Ala120 homozygotes (p=0.022 for genotype effect; n=10 per genotype). The concentration of thrombin required to produce 50% maximal aggregation (ED50) was 17% lower for Thr120 homozygotes than for Ala120 homozygotes (0.041 ± 0.002 U/mL vs. 0.049 ± 0.002 U/mL, respectively; p<0.001). The PAR4-AP dose response for Thr120 homozygotes was also left-shifted compared to Ala120 homozygotes (p<0.0001 for genotype effect; n=11 per genotype), as would be expected for functional variants in PAR4. The PAR4-AP ED50 was 2.5-fold lower for Thr120 homozygotes than for Ala120 homozygotes (41.0 uM ± 5.0 uM vs. 101.0 ± 4.5 uM respectively; p<0.001) Compared to Ala120 homozygotes, Thr120 homozygote platelets showed higher thrombin-induced ATP release and P-selectin exposure, indicating higher levels of dense and alpha granule release, and higher calcium mobilization, indicating Gq coupling (n=4-7 per genotype). Next, washed platelets were incubated with varying concentrations of YD-3 (PAR4 blocker), ASA (COX inhibitor), 2-MeSAMP (P2Y12 antagonist) or the PAR1 antagonist, vorapaxar, and assessed for aggregation after stimulation with 0.1 U/mL thrombin. The concentration of vorapaxar required to inhibit 50% of maximal platelet aggregation (IC50) was 2.6 fold lower for Ala120 homozygotes relative to Thr120 homozygotes (45.5 ± 7.6 nM vs. 118.6 ± 40.9 nM, p<0.0001; n=3 per genotype). The IC50 of 2-MeSAMP was substantially lower for Ala120 homozygotes relative to Thr120 homozygotes (4.0 ± 5.0 uM vs. 10.9 ± 4.8 uM, p=0.056; n=4 per genotype). YD-3 and ASA were unable to inhibit thrombin-induced aggregation regardless of the PAR4 variant. Conclusions: These data indicate that the common Ala120Thr variant alters platelet reactivity to physiologic agonists, that the Thr120 variant has decreased sensitivity to PAR1 and P2Y12 inhibition, and predict the PAR4 Thr120 variant would alter the risk-benefit of PAR1 inhibition. Since current antiplatelet therapy is based largely on platelet studies done with white subjects, novel PAR4 inhibitors may provide improved anti-thrombotic therapy for patients with the Thr120 risk allele. Disclosures No relevant conflicts of interest to declare.
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Bahap, M., E. Duran, A. B. Ekincioğlu, and O. Karadag. "AB1486 ASSESSMENT OF GLUCOCORTICOID-RELATED ADVERSE EVENTS BY THE GLUCOCORTICOID TOXICITY INDEX (GTI) IN RHEUMATIC PATIENTS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1847.2–1847. http://dx.doi.org/10.1136/annrheumdis-2022-eular.5003.
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BackgroundGlucocorticoids (GCs) remain the mainstay treatment for several autoimmune and inflammatory diseases however, its long-term or high-dose usage also has many potential side effects. The glucocorticoid toxicity index (GTI) is a novel global monitoring tool (1) developed to systematically assess glucocorticoid-associated morbidity.ObjectivesTo evaluate GC toxicity by using GTI in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and vasculitis receiving glucocorticoids.MethodsThis descriptive, cross-sectional study included patients who were admitted to the rheumatology clinic between January 2021 and December 2021, were diagnosed with RA, SLE or vasculitis and treated with GCs. A single measurement of GC toxicity was performed using the GTI for each patient. Baseline GTI consists of twelve domains that related to commonly recognized adverse events that result of cumulative GCs exposure: body mass index (BMI), glucose metabolism, blood pressure, lipids, GC-induced myopathy, bone mineral density, skin toxicity, neuropsychiatric effects, infection, ocular, gastrointestinal and endocrine toxicity. The total GTI score ranges from 0 to 538 depending on the increase in toxicity burden.ResultsThe study included 85 patients (55.3% male) with a mean age of 47.5 (±16.0) years (Table 1). Twenty (23.5%) patients had BMI values ≥30 kg/m2 and 63% of the patients were either hypertensive or receiving medications for hypertension. While HbA1c was ≥5.7% in 30 (35.3%) patients, 17 (20.0%) patients had glycated hemoglobin (HbA1c) value of ≥5.7% despite antidiabetic medication. Low density lipoprotein cholesterol (LDL-C) value of 33 (39%) patients was not on target. The median (IQR) GTI score of the study patients was 73 (81.5). Only 10 patients had a score of 0 in the GTI assessment. GTI scores were not correlated with the cumulative steroid doses (r=0.145, p=0.198) however, age was strongly associated with GTI scores (r=0.605, p<0.001).Table 1.Demographics, disease characteristics, and glucocorticoid toxicities of the patientsCharacteristic¶All patients (n=85)RA (n=21)SLE (n=14)Vasculitis* (n=50)Age (years), mean (±SD)47.3 (±17.2)36.4 (±11.0)50.6 (±15.5)Duration of disease (months)12 (12.5)16 (17.8)14 (13.3)Damage and activity indicesDAS-28=2.66 (2.1)SLEDAI=4.0 (6.5)BVAS**=0 (1.0)HAQ=0.07 (0.4)SLICC=0 (1.5)VDI=1.0 (1.0)Cumulative methylprednisolone dose (mg)1458 (1496.9)4646 (9053.5)5604 (5281.5)GTI toxicity domain, n (%)9 (42.8)6 (42.8)24 (48.0)✓ BMI ≥27 kg/m28 (38.1)6 (42.9)33 (68.8)✓ HbA1c ≥5.7%7 (33.3)4 (28.6)26 (53.0)✓ Blood pressure >120/856 (28.5)2 (14.2)25 (51.0)✓ LDL-C >target4 (20.0)011 (24.5)✓Osteoporosis2 (10.0)2 (14.3)13 (26.5)✓ Skin toxicity2 (10.0)3 (21.4)8 (16.3)✓ Neuropsychiatric toxicity2 (10.0)06 (12.2)✓ Ocular toxicity2 (10.0)05 (10.0)✓ Gastrointestinal toxicityGTI score65 (104.5)44 (48.0)87 (76)¶ n (%), if otherwise specified; median (IQR) for numeric values other than ageGTI: Glucocorticoid toxicity index, RA: Rheumatoid arthritis, SLE: Systemic lupus erythematosus, BMI: Body mass index, HbA1c: Glycated hemoglobin, LDL-C: Low density lipoprotein cholesterol*Vasculitis patients include ANCA-associated vasculitis, Giant cell arteritis, Takayasu arteritis, Behcet’s syndrome, Igg4-related disease, Polymyalgia rheumatica and Leukocytoplastic vasculitis patients.***BVAS value given only for ANCA-associated vasculitis (n=19)ConclusionOur study revealed the iceberg of glucocorticoid toxicities in patients with rheumatic disease. Usage of GTI would help management of these possible toxicities. Therefore, it is important to assess GC toxicity at regular intervals during ongoing treatment in order to detect potential differences in the GTI scores.References[1]Miloslavsky EM, Naden RP, Bijlsma JW, Brogan PA, Brown ES, Brunetta P, et al. Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. Ann Rheum Dis. 2017;76(3):543-6.Disclosure of InterestsNone declared
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Kantarjian, Hagop M., Francis Giles, Kapil N. Bhalla, Richard A. Larson, Norbert Gattermann, Oliver G. Ottmann, Ariful Haque, Neil J. Gallagher, Michele Baccarani, and Philipp D. le Coutre. "Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CMLCP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study." Blood 112, no. 11 (November 16, 2008): 3238. http://dx.doi.org/10.1182/blood.v112.11.3238.3238.
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Abstract Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-CP patients resistant or intolerant to imatinib. Imatinib intolerant patients with prior major cytogenetic response (MCyR) on imatinib were not eligible for this trial. Nilotinib was dosed at 400 mg twice daily with the option of dose escalation to 600 mg twice daily if responses were inadequate. Rate of MCyR was the primary endpoint. Secondary endpoints included complete cytogenetic response (CCyR), complete hematological response (CHR), duration of MCyR, survival, and safety. Results: A total of 321 CML-CP patients (71% imatinib-resistant; 29% imatinib-intolerant) were evaluated. Most patients were heavily pretreated with 72% having received more than 600 mg/day of imatinib prior to study entry. Furthermore, imatinib-intolerant patients could not have achieved prior MCyR on imatinib therapy. Median duration of prior imatinib treatment was 33 months (range 0.3–95 months). Dose reductions (25%) and discontinuations (15%) due to adverse events were infrequent on nilotinib therapy and median dose intensity (788 mg/day; range 151–1112 mg/day) closely approximated the planned dose. Median duration of exposure was 465 days (15.5 months). Overall, nilotinib therapy resulted in rapid and durable hematologic and cytogenetic responses. Of all imatinib-resistant and –intolerant patients, 58% achieved MCyR (1 month median time to MCyR), with 72% of patients having a baseline CHR achieving MCyR. The MCyR rate was 63% in imatinibintolerant and 56% in imatinib-resistant patients, respectively. Overall, 42% of patients achieved a CCyR (50% in imatinib-intolerant and 39% in imatinib-resistant patients, respectively). Responses were durable, with 84% of patients maintaining their MCyR at 18 months. Estimated overall survival (OS) rates at 12 and 18 months were 95% and 91%, respectively. Nearly half of all patients (47%) were still receiving nilotinib at the time of cut-off for data analysis. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 biochemical laboratory abnormalities were elevated lipase (16%), hypophosphatemia (15%), hyperglycemia (12%), and elevated total bilirubin (7%). Overall, biochemical laboratory abnormalities were transient and clinically asymptomatic. Grade 3/4 non-hematologic adverse events were infrequent with rash, headache, and diarrhea occurring in only 2% of patients. No pleural or pericardial effusions were documented during nilotinib therapy. The most common grade 3/4 hematological laboratory abnormalities included neutropenia (30%), thrombocytopenia (28%), and anemia (10%). Overall, QTcF changes greater than 60 milliseconds from baseline were infrequent, occurring in only 8 patients (2.5%), and QTcF prolongation >500 milliseconds was uncommon (<1%), occurring in only 3 patients. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: Nilotinib is highly effective and produces rapid and durable responses in CML-CP patients who failed prior therapy including imatinib due to resistance or intolerance and is an important treatment option for this patient population. Nilotinib is well tolerated with minimal occurrence of grade 3/4 adverse events; safety profile has not changed with longer follow-up.
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Lonial, Sagar, Dixil Francis, Chatchada Karanes, Suzanne Trudel, Akari M. Dollard, Fermin Aceo, Engin Gul, et al. "A Phase I Clinical Trial Testing the Combination of Bortezomib and Tipifarnib in Relapsed/Refractory Multiple Myeloma." Blood 114, no. 22 (November 20, 2009): 3851. http://dx.doi.org/10.1182/blood.v114.22.3851.3851.
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Abstract Abstract 3851 Poster Board III-787 Background Preclinical work from our group and others has demonstrated that the combination of a farnesyl transferase inhibitor (FTI) and the proteasome inhibitor bortezomib results in enhanced plasma cell apoptosis and is associated with AKT activation (David, Blood 2005). Sequence of bortezomib followed by a FTI synergistically inhibited cell growth compared to concurrent treatment. More recently, further preclinical data suggests that the mechanism responsible for this profound synergy is due to inhibition of HDAC6 with a resultant inhibition of both the proteasome and aggresome pathway (David ASH 2007). Based upon these observations, with the MMRC, we initiated a phase I trial combining the FTI tipifarnib with bortezomib to clinically evaluate the efficacy of this combination. Methods Patients with relapsed or refractory myeloma were treated with bortezomib at 1.0 mg/m2 or 1.3mg/m2 given on days 1,4,8, and 11 in conjunction with escalating doses of tipifarnib (100-400mg PO BID) given on days 2-15 every 21 days, respectively. Dose escalation was accomplished using an adaptive phase I design (Escalation With Overdose Control (EWOC)). Eligibility criteria included a serum creatinine of <2.5, normal liver function, ANC>500, and platelets >25. Results Twenty-six patients have been enrolled to date: bortezomib 1.0 mg/m2 with tipifarnib 100 mg (n=6), 200mg (n=5), 300mg (n=7), 400mg (n=2) and bortezomib 1.3mg/m2 with tipifarnib 300mg (n=6), 400mg to be enrolled. Median age is 63 (range 42-77). 19/26 patients had received prior high dose therapy. The average number of prior therapies was 4, and, of the 26 patients, 10 were refractory to bortezomib (relapsed on therapy or within 6 months) 11 were bortezomib naïve, and 5 were previously exposed to bortezomib but not refractory. Among these patients with advanced myeloma and refractory disease, 50% had stabilization of disease or better. Maximum number of cycles received was 10. Of note, among the patients achieving clinical benefit, 1 had a stable M-protein, but experienced an 80% reduction in circulating plasma cells while on therapy, and another has had a 75% reduction in the free light chain assay. The most common drug-related toxicities were GI (17.0%) with nausea/vomiting occurring most frequently. Hematologic toxicities were difficult to ascertain as patients had advanced myeloma and many entered with platelet counts of 25-50. Additional grade 3 toxicities included renal insufficiency (related to PD), pneumonia and altered mental status which were all considered due to disease progression. There were no Grade 3- 5 non-hematologic drug related toxicities. There were no cardiac events or DVT, and 1 patient experienced grade 2 peripheral neuropathy who did not have pre- existing PN at baseline. Conclusions The combination of bortezomib and tipifarnib is supported by preclinical rationale and has produced stable disease or better among a group of patients with refractory and advanced myeloma. To date the optimal doses of both tipifarnib and bortezomib have yet to be defined, and additional patients will be enrolled to define the MTD by escalation of tipifarnib to 400 with 1.3mg/m2 of bortezomib. Correlative studies evaluating the effect of the combination on HDAC6 and plasma cell apoptosis will be presented. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Kaufman:Millennium : Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Merck: Research Funding.