Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a ...combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown.
In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg two 300-mg tablets twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival.
The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively).
In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).
Photoisomerization, that is, a photochemical reaction leading to a change of molecular structure after absorption of a photon, can have detrimental effects such as leading to DNA damage under solar ...irradiation, or as a limiting factor for the efficiency of solar cells. Here, we show that strong coupling of organic molecules to a confined light mode can be used to strongly suppress photoisomerization, as well as other photochemical reactions, and thus convert molecules that normally show fast photodegradation into photostable forms. We find this to be especially efficient in the case of collective strong coupling, where the distribution of a single excitation over many molecules and the light mode leads to a collective protection effect that almost completely suppresses the photochemical reaction.
Attribution of trends in streamflow is complex, but essential, in identifying optimal management options for water resources. Disagreement remains on the relative role of climate change and human ...factors, including water ions and land cover change, in driving change in annual streamflow. We construct a very dense network of gauging stations (n = 1,874) from Ireland, the United Kingdom, France, Spain, and Portugal for the period of 1961–2012 to detect and then attribute changes in annual streamflow. Using regression‐based techniques, we show that climate (precipitation and atmospheric evaporative demand) explains many of the observed trends in northwest Europe, while for southwest Europe human disturbances better explain both temporal and spatial trends. For the latter, large increases in irrigated areas, agricultural intensification, and natural revegetation of marginal lands are inferred to be the dominant drivers of decreases in streamflow.
Plain Language Summary
Reduced water resources availability is one of the most serious impacts of climate change since reductions in streamflow may cause noticeable ecological and socioeconomic impacts. However, attribution of streamflow trends to climate change is complex given the influence of other drivers of catchment change, including human and vegetation water uses, agriculture, and land use change. We show that for northwestern Europe most observed trends in annual streamflow are associated with climate change. However, in southwestern Europe there is a clear mismatch between observed trends in river flows and climate, with increasing vegetation and/or irrigated agriculture better explaining observed changes. Our results highlight the importance of human management in explaining large‐scale hydrological trends and the need to carefully evaluate both climate and land use changes to disentangle drivers of streamflow trends.
Key Points
Streamflow trends in countries bordering the northeast Atlantic show a north‐south latitudinal gradient, with strong decreasing trends in southern regions
Climate trends largely explain the evolution of annual streamflow in northwestern Europe
Climate trends cannot fully explain the large reductions in annual streamflow in southwest Europe, with land use changes and water demand from irrigation playing an important additional role
RAS assessment is mandatory for therapy decision in metastatic colorectal cancer (mCRC) patients. This determination is based on tumor tissue, however, genotyping of circulating tumor (ct)DNA offers ...clear advantages as a minimally invasive method that represents tumor heterogeneity. Our study aims to evaluate the use of ctDNA as an alternative for determining baseline RAS status and subsequent monitoring of RAS mutations during therapy as a component of routine clinical practice.
RAS mutational status in plasma was evaluated in mCRC patients by OncoBEAM™ RAS CRC assay. Concordance of results in plasma and tissue was retrospectively evaluated.RAS mutations were also prospectively monitored in longitudinal plasma samples from selected patients.
Analysis of RAS in tissue and plasma samples from 115 mCRC patients showed a 93% overall agreement. Plasma/tissue RAS discrepancies were mainly explained by spatial and temporal tumor heterogeneity. Analysis of clinico-pathological features showed that the site of metastasis (i.e. peritoneal, lung), the histology of the tumor (i.e. mucinous) and administration of treatment previous to blood collection negatively impacted the detection of RAS in ctDNA. In patients with baseline mutant RAS tumors treated with chemotherapy/antiangiogenic, longitudinal analysis of RAS ctDNA mirrored response to treatment, being an early predictor of response. In patients RAS wt, longitudinal monitoring of RAS ctDNA revealed that OncoBEAM was useful to detect emergence of RAS mutations during anti-EGFR treatment.
The high overall agreement in RAS mutational assessment between plasma and tissue supports blood-based testing with OncoBEAM™ as a viable alternative for genotyping RAS of mCRC patients in routine clinical practice. Our study describes practical clinico-pathological specifications to optimize RAS ctDNA determination. Moreover, OncoBEAM™ is useful to monitor RAS in patients undergoing systemic therapy to detect resistance and evaluate the efficacy of particular treatments.
En l’espace d’une cinquantaine d’année, la réglementation a fait de la personne compétente en radioprotection (PCR) l’acteur principal de la radioprotection dans les différents établissements mettant ...en œuvre des rayonnements ionisants pour assurer la protection des travailleurs – mais aussi depuis peu celle du public – notamment lors de l’utilisation de sources non scellées. La réglementation définit le rôle et les missions de la PCR, précise son articulation avec les autres acteurs et fixe les modalités de sa formation. Les fonctions de la PCR ont par ailleurs sensiblement évolué avec la création des conseillers en radioprotection (CRP). L’objectif de cet article est d’analyser et de comprendre l’évolution historique de la fonction de PCR, exercée actuellement par plus de 10 000 personnes en France, pour mieux en dégager les enjeux de demain.
Within fifty years, the regulations have made the person competent in radiation protection (PCR) the main player in radiological protection in the various establishments implementing ionizing radiation to ensure the protection of workers – but also recently that of the public –, in particular when using unsealed sources. The regulations define the role and missions of the PCR, specify its articulation with other players and set the terms of its formation. The functions of the PCR have changed significantly with the creation of radiation protection advisors (CRP), who replace the PCRs. The objective of this article is to analyze and understand the historical evolution of the function of PCR and then that of CRP currently exercised by more than 10 000 people in France, to better identify the challenges of tomorrow.
A
bstract
The European Spallation Source (ESS), presently well on its way to completion, will soon provide the most intense neutron beams for multi-disciplinary science. Fortuitously, it will also ...generate the largest pulsed neutrino flux suitable for the detection of Coherent Elastic Neutrino-Nucleus Scattering (CE
ν
NS), a process recently measured for the first time at ORNL’s Spallation Neutron Source. We describe innovative detector technologies maximally able to profit from the order-of-magnitude increase in neutrino flux provided by the ESS, along with their sensitivity to a rich particle physics phenomenology accessible through high-statistics, precision CE
ν
NS measurements.
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