Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Effects of sea level rise on decomposers in a restored coastal salt marsh

Many southern California coastal salt marshes are urbanized and heavily impacted, but still provide important ecosystem services, including carbon and nutrient cycling. Salt marsh community structure and functions, such as decomposition, are essential for marsh ecosystems and are potentially vulnerable to inundation impacts created by sea level rise (SLR). The saltmarsh communities driving decomposition are comprised of invertebrates, fungi, and bacteria, which may be susceptible to SLR. In this project, inundation of saltmarsh sediments with associated plants and rhizosphere were manipulated using a marsh organ to assess the impacts of SLR on decomposer activity (leaf litter decay, anaerobic respiration) and community structure (bacterial and benthic invertebrate). Marsh organ samples across all inundation treatments showed altered decomposer community diversity and function compared to controls, indicating disturbance. However in some cases there were no significant differences between communities among SLR treatments. However, inundation effects may have been obscured by marsh organ artifacts

Acetaminophen Levels Found in Recycled Wastewater Alter Soil Microbial Community Structure and Functional Diversity

The practice of using recycled wastewater (RWW) has been successfully adopted to address the growing demand for clean water. However, chemicals of emerging concern (CECs) including pharmaceutical products remain in the RWW even after additional cleaning. When RWW is used to irrigate crops or landscapes, these chemicals can enter these and adjacent environments. Unfortunately, the overall composition and concentrations of CECs found in different RWW sources vary, and even the same source can vary over time. Therefore, we selected one compound that is found frequently and in high concentrations in many RWW sources, acetaminophen (APAP), to use for our study. Using greenhouse grown eggplants treated with APAP concentrations within the ranges found in RWW effluents, we investigated the short-term impacts of APAP on the soil bacterial population under agricultural settings. Using Illumina sequencing-based approaches, we showed that APAP has the potential to cause shifts in the microbial community most likely by positively selecting for bacteria that are capable of metabolizing the breakdown products of APAP such as glycosides and carboxylic acids. Community-level physiological profiles of carbon metabolism were evaluated using Biolog EcoPlate as a proxy for community functions. The Biolog plates indicated that the metabolism of amines, amino acids, carbohydrates, carboxylic acids, and polymers was significantly higher in the presence of APAP. Abundance of microorganisms of importance to plant health and productivity was altered by APAP. Our results indicate that the soil microbial community and functions could be altered by APAP at concentrations found in RWW. Our findings contribute to the knowledge base needed to guide policies regulating RWW reuse in agriculture and also highlight the need to further investigate the effects of CECs found in RWW on soil microbiomes

Characterization of chemosynthetic microbial mats associated with intertidal hydrothermal sulfur vents in White Point, San Pedro, CA, USA

The shallow-sea hydrothermal vents at White Point (WP) in Palos Verdes (PV) on the southern California coast support microbial mats and provide easily accessed settings in which to study chemolithoautotrophic sulfur cycling. Previous studies have cultured sulfur-oxidizing bacteria from the WP mats; however, almost nothing is known about the in situ diversity and activity of the microorganisms in these habitats. We studied the diversity, micron-scale spatial associations and metabolic activity of the mat community via sequence analysis of 16S rRNA and aprA genes, Fluorescence in situ Hybridization (FISH) microscopy and sulfate-reduction rate (SRR) measurements. Sequence analysis revealed a diverse group of bacteria, dominated by sulfur cycling gamma-, epsilon- and deltaproteobacterial lineages such as Marithrix, Sulfurovum and Desulfuromusa. FISH microscopy suggests a close physical association between sulfur-oxidizing and sulfur-reducing genotypes, while radiotracer studies showed low, but detectable, SRR. Comparative 16S rRNA gene sequence analyses indicate the WP sulfur vent microbial mat community is similar, but distinct from other hydrothermal vent communities representing a range of biotopes and lithologic settings. These findings suggest a complete biological sulfur cycle is operating in the WP mat ecosystem mediated by diverse bacterial lineages, with some similarity with deep-sea hydrothermal vent communities

Bradyrhizobium japonicum IRAT FA3 promotes salt tolerance through jasmonic acid priming in Arabidopsis thaliana

Abstract Background Plant growth promoting rhizobacteria (PGPR), such as Bradyrhizobium japonicum IRAT FA3, are able to improve seed germination and plant growth under various biotic and abiotic stress conditions, including high salinity stress. PGPR can affect plants’ responses to stress via multiple pathways which are often interconnected but were previously thought to be distinct. Although the overall impacts of PGPR on plant growth and stress tolerance have been well documented, the underlying mechanisms are not fully elucidated. This work contributes to understanding how PGPR promote abiotic stress by revealing major plant pathways triggered by B. japonicum under salt stress. Results The plant growth-promoting rhizobacterial (PGPR) strain Bradyrhizobium japonicum IRAT FA3 reduced the levels of sodium in Arabidopsis thaliana by 37.7%. B. japonicum primed plants as it stimulated an increase in jasmonates (JA) and modulated hydrogen peroxide production shortly after inoculation. B. japonicum-primed plants displayed enhanced shoot biomass, reduced lipid peroxidation and limited sodium accumulation under salt stress conditions. Q(RT)-PCR analysis of JA and abiotic stress-related gene expression in Arabidopsis plants pretreated with B. japonicum and followed by six hours of salt stress revealed differential gene expression compared to non-inoculated plants. Response to Desiccation (RD) gene RD20 and reactive oxygen species scavenging genes CAT3 and MDAR2 were up-regulated in shoots while CAT3 and RD22 were increased in roots by B. japonicum, suggesting roles for these genes in B. japonicum-mediated salt tolerance. B. japonicum also influenced reductions of RD22, MSD1, DHAR and MYC2 in shoots and DHAR, ADC2, RD20, RD29B, GTR1, ANAC055, VSP1 and VSP2 gene expression in roots under salt stress. Conclusion Our data showed that MYC2 and JAR1 are required for B. japonicum-induced shoot growth in both salt stressed and non-stressed plants. The observed microbially influenced reactions to salinity stress in inoculated plants underscore the complexity of the B. japonicum jasmonic acid-mediated plant response salt tolerance