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INTRODUCTION: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a protein produced in the lung, is essential for pulmonary host defense and alveolar integrity. Prior studies suggest potential benefits in several pulmonary conditions, including acute respiratory distress syndrome and viral infections. This trial evaluated the effect of the addition of inhaled sargramostim (yeast-derived, glycosylated recombinant human GM-CSF) to standard of care (SOC) on oxygenation and clinical outcomes in patients with COVID-19-associated acute hypoxemia. MATERIALS AND METHODS: A randomized, controlled, open-label trial of hospitalized adults with COVID-19-associated hypoxemia (oxygen saturation <93% on ≥2 L/min oxygen supplementation and/or PaO2/FiO2 <350) randomized 2:1 to inhaled sargramostim (125 mcg twice daily for 5 days) plus SOC versus SOC alone. Institutional SOC before and during the study was not limited. Primary outcomes were change in the alveolar-arterial oxygen gradient (P(A-a)O2) by day 6 and the percentage of patients intubated within 14 days. Safety evaluations included treatment-emergent adverse events. Efficacy analyses were based on the modified intent-to-treat population, the subset of the intent-to-treat population that received ≥1 dose of any study treatment (sargramostim and/or SOC). An analysis of covariance approach was used to analyze changes in oxygenation measures. The intubation rate was analyzed using the chi-squared test. All analyses are considered descriptive. The study was institutional review board approved. RESULTS: In total, 122 patients were treated (sargramostim, n = 78; SOC, n = 44). The sargramostim arm experienced greater improvement in P(A-a)O2 by day 6 compared to SOC alone (least squares [LS] mean change from baseline [SE]: -102.3 [19.4] versus -30.5 [26.9] mmHg; LS mean difference: -71.7 [SE 33.2, 95% CI -137.7 to -5.8]; P = .033; n = 96). By day 14, 11.5% (9/78) of sargramostim and 15.9% (7/44) of SOC arms required intubation (P = .49). The 28-day mortality was 11.5% (9/78) and 13.6% (6/44) in the sargramostim and SOC arms, respectively (hazard ratio 0.85; P = .76). Treatment-emergent adverse events occurred in 67.9% (53/78) and 70.5% (31/44) on the sargramostim and SOC arms, respectively. CONCLUSIONS: The addition of inhaled sargramostim to SOC improved P(A-a)O2, a measure of oxygenation, by day 6 in hospitalized patients with COVID-19-associated acute hypoxemia and was well tolerated. Inhaled sargramostim is delivered directly to the lung, minimizing systemic effects, and is simple to administer making it a feasible treatment option in patients in settings where other therapy routes may be difficult. Although proportionally lower rates of intubation and mortality were observed in sargramostim-treated patients, this study was insufficiently powered to demonstrate significant changes in these outcomes. However, the significant improvement in gas exchange with sargramostim shows this inhalational treatment enhances pulmonary efficiency in this severe respiratory illness. These data provide strong support for further evaluation of sargramostim in high-risk patients with COVID-19.
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Aims: The aim of this publication is to explore occupational exposure trends from biological monitoring data collected over a period of more than 20 years. The data is stored within the HSE database, which holds more than 950,000 results from 120,000 workers in 8,000 companies. The data were collated for all biological monitoring results for lead, mercury, benzene, and hexamethylene diisocyanate exposures where there have been some regulatory drivers within the reported time period of the data searched. Methods: Relevant results from sample analysed were extracted from the database and categorised by year from 1996 to the end of 2019 for individual blood lead results and individual urine results for mercury, benzene, and hexamethylene diisocyanate. Results were classed by broad occupational sector where possible. Data were reported graphically by analytical biomarker result (as 90th percentile (P90)) and number of samples per year as well as with overall summary statistics. To look at longer-term trends, results were also evaluated as P90 over 6-year periods. Results: In the period 1996-2019, 37,474 blood lead, 11,723 urinary mercury, 9,188 urinary S-phenylmercapturic acid (SPMA, benzene metabolite) and 21,955 urinary hexamethylene diamine (HDA, metabolite of hexamethylene diisocyanate, HDI) samples were analysed and reported. Over the time period the blood lead concentrations saw the P90 reduce from 53 µg/dl 1996) to 24 µg/dl in 2019; the P90 urinary mercury levels reduced from 13.7 µmol/mol creatinine to 2.1 µmol/mol creatinine and the P90 urinary SPMA levels reduced from 133.7 µmol/mol creatinine to 1.7 µmol/mol creatinine. For HDI the P90 results reduced from 2 µmol HDA/mol creatinine in 1996-2000 to 0.7 in 2005-2010 but levels have since increased to 1.0 µmol HDA/mol creatinine (2016-2019). Conclusion: There is strong evidence of reductions in exposure of GB workers to lead, benzene and mercury from the data presented here. These reductions may reflect the impact of national, regional and global regulatory action to reduce exposures however, the loss of high exposure industries (from either GB as a whole or just this dataset i.e., samples are being sent elsewhere) and the increase in automation or substitution also need to be considered as potential factors. The results for HDI show that whilst interventions can reduce exposures significantly, such initiatives may need to be refreshed at intervals to maintain the reductions in exposure. We have observed that exposures move between sectors over time. Waste and recycling (lead, mercury) and tunnelling through contaminated land (benzene) were sectors or tasks associated with significant exposures and may be increasingly areas of concern.
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The use of immune checkpoint inhibitors in patients with metastatic melanoma generates clinical benefit, including improved survival. Yet disease resistance and immune-related adverse events persist as unmet needs. Sargramostim, a yeast-derived recombinant human GM-CSF, has shown clinical activity against diverse solid tumors, including metastatic melanoma. Here we review the use of sargramostim for treatment of advanced melanoma. Potential sargramostim applications in melanoma draw on the unique ability of GM-CSF to link innate and adaptive immune responses. We review preclinical and translational data describing the mechanism of action of sargramostim and synergy with immune checkpoint inhibitors to enhance efficacy and reduce treatment-related toxicity.
Lay abstract Immune checkpoint inhibitors are medications that help the immune system to fight cancer. Side effects with these medicines may occur because the immune system may attack healthy cells. Sargramostim is a medication that is similar to a protein in the body (GM-CSF). Studies have shown that sargramostim can fight cancer, including melanoma. When sargramostim is used with immune checkpoint inhibitors, the body's natural defense to fight cancer (the immune system) is boosted and some side effects are reduced. This article reviews how GM-CSF is thought to boost the immune system's response against cancer in the laboratory and in animal models. We also review the use of sargramostim alone and combined with ipilimumab in patients with advanced melanoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Inibidores de Checkpoint Imunológico/administração & dosagem , Melanoma/tratamento farmacológico , Animais , Sinergismo Farmacológico , Humanos , Proteínas Recombinantes/administração & dosagemRESUMO
Purpose: Estrogen receptor-positive (ER+) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ breast cancer.Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER+ breast cancer models, including several patient-derived xenograft models.Results: Elacestrant induces the degradation of ER, inhibits ER-mediated signaling and growth of ER+ breast cancer cell lines in vitro and in vivo, and significantly inhibits tumor growth of multiple PDX models. Furthermore, we demonstrate that elacestrant in combination with palbociclib or everolimus can lead to greater efficacy in certain contexts. Finally, elacestrant exhibits significant antitumor activity both as a single agent and in combination with palbociclib in two patient-derived breast cancer xenograft models harboring ESR1 mutations.Conclusions: These data underscore the potential clinical utility of elacestrant as a single agent and as a combination therapy, for both early- and late-stage ER+ disease. Clin Cancer Res; 23(16); 4793-804. ©2017 AACR.
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Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Tetra-Hidronaftalenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Everolimo/administração & dosagem , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tetra-Hidronaftalenos/administração & dosagem , Carga Tumoral/efeitos dos fármacosRESUMO
Agents that inhibit estrogen production, such as aromatase inhibitors or those that directly block estrogen receptor (ER) activity, such as selective estrogen receptor modulators and selective estrogen receptor degraders, are routinely used in the treatment of ER-positive breast cancers. However, although initial treatment with these agents is often successful, many women eventually relapse with drug-resistant breast cancers. To overcome some of the challenges associated with current endocrine therapies and to combat the development of resistance, there is a need for more durable and more effective ER-targeted therapies. Here we describe and characterize a novel, orally bioavailable small-molecule selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 produced a robust and profound inhibition of tumor growth in MCF-7 xenograft models. In an intracranial MCF-7 model, RAD1901-treated animals survived longer than those treated with either control or fulvestrant, suggesting the potential benefit of RAD1901 in the treatment of ER-positive breast cancer that has metastasized to the brain. Finally, RAD1901 preserved ovariectomy-induced bone loss and prevented the uterotropic effects of E2, suggesting that it may act selectively as an agonist in bone but as an antagonist in breast and uterine tissues. RAD1901 is currently under clinical study in postmenopausal women with ER-positive advanced breast cancer.