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

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

Santangelo et al., 2015 Botany_Master R script

R script used in analyzing the attached data files. The script contains 4 sections representing 4 separate analyses, each to be used with one of the four datasheets in the .xls file provided

Data from: Fungal endophytes of Festuca rubra increase in frequency following long-term exclusion of rabbits

Plant-fungal endophyte interactions are common in nature and they can shape the ecology of plants. Vertically transmitted endophytes are hypothesized to serve as mutualists, protecting plants from herbivores. If this hypothesis is true then we expect endophytes to be most abundant in the presence of herbivores and least abundant in their absence, assuming endophytes incur a cost to their host. We tested this prediction by studying the effects of intense rabbit (Oryctolagus cuniculus) grazing on grass-endophyte interactions at Silwood Park, UK. We examined seeds of red fescue (Festuca rubra) collected from 15 natural populations that were protected from rabbits for 0.3 to 21 years. Contrary to our prediction, the mean proportion of seeds with endophytes increased 1.84x, from 0.45 to 0.83, following 21 years of rabbit exclusion. To better understand the mechanisms driving this increase in frequency, we conducted a fully factorial greenhouse experiment where we manipulated the presence/absence of endophyte infection, intraspecific competition, and simulated grazing on F. rubra plants. In both damaged and undamaged treatments, infected plants produced approximately twice as much biomass as uninfected plants, and endophytes did not influence tolerance to herbivory. These results suggest that endophytes directly change plant growth but not compensatory responses to damage. In the absence of competitors, infected plants produced 2.17x more biomass than uninfected plants, whereas in the presence of competitors infected plants produced only 1.55x more biomass than uninfected plants. This difference suggests that intraspecific competition might lessen the benefits of endophyte infection. Our results do not support the Defensive Mutualism Hypothesis, but instead suggest that endophyte-induced plant growth is important in shaping the costs and benefits of endophytes in our system

turley_et_al_2017_species_codes_to_species

List of 6-letter species codes and corresponding full scientific names based on up-to-date nomenclature. See read me file for more info

Data from: Dispersal and establishment limitation slows plant community recovery in post-agricultural longleaf pine savannas

Abandoned agricultural lands often have distinct plant communities from areas with no history of agriculture because plant species fail to recolonize. This may be due to dispersal limitation from a lack of seeds, or establishment limitation because of unsuitable environmental conditions. However, few experiments have directly tested how restoration activities may overcome these limitations. We studied longleaf pine savannas in South Carolina abandoned from agriculture >60 years ago that were immediately adjacent to remnant habitats (areas with no history of agriculture). Using 27 sites, we conducted a factorial experiment that sowed seeds of 12 species indicative of remnant communities and conducted restoration thinning of overstorey trees in half of 126, 1-ha patches to mimic canopy density of natural savannas. We also established vegetation transects to examine if restoration promotes spread of remnant species into post-agricultural areas. We found strong evidence for dispersal limitation in post-agricultural areas as over 99% of the occurrences of our focal species were in seed addition plots. Seed additions increased total species richness by 27%. Restoration thinning increased establishment in seed addition plots (measured as richness of sown species) by 126% and increased total richness by 88%. Restoration thinning also increased seed production in remnant habitats by an average of 6506% across our focal species. However, after 4 years, restoration thinning did not facilitate the natural spread of remnant species into adjacent post-agricultural sites. Synthesis and applications. We show that both dispersal and establishment limitation are key factors causing some plant species to be absent from post-agricultural sites. Dense canopy conditions limit seed production in remnant habitats and reduce establishment in post agricultural areas. Restoration thinning helps overcome these limitations and should facilitate the natural spread of species from remnant habitats but natural recovery may still be slow. Our results suggest that accelerating the recovery of post-agricultural habitats will require active restoration that reduces dispersal limitation (seed additions) and reinstates appropriate ecological conditions

Restoration Increases Bee Abundance And Richness But Not Pollination In Remnant And Post-Agricultural Woodlands

Human land use, including agriculture, is a leading contributor to declining biodiversity worldwide and can leave long-lasting legacies on ecosystems after cessation. Ecological restoration is an approach to mitigate these impacts. However, little is known about how animal communities and plant–animal interactions respond to the combined effects of land-use legacies and restoration. We investigated how restoration and agricultural history affect bee (Hymenoptera: Apoidea: Anthophila) communities and pollination function. In 27 paired remnant (no history of agriculture) and post-agricultural longleaf pine (Pinus palustris Mill.) woodlands, we established 4–10 1-ha plots (126 total) and experimentally restored half of them, while the other half were left as unrestored controls. Restoration was accomplished through canopy thinning which reinstates open savanna-like conditions. We collected bees in each plot using a combination of bowl trapping and standardized netting transects. Thinning increased bee abundance by 169% and bee richness by 110%, but agricultural land use had no effect on these variables. Bee community composition was affected by restoration and was marginally affected by agricultural history. To measure pollination function, we conducted a sentinel plant experiment in which potted black mustard (Brassica nigra L.) plants were placed out in a subset of these sites (n = 10) and either bagged to exclude pollinators or left open for pollinator access. Then, we measured fruit and seed set of sentinel plants to compare pollination function among the restoration and land-use history treatments. Seed set and fruit set of sentinel plants were higher in open than bagged plants, indicating that this model system effectively measured pollination, but we found no differences in pollination based on restoration or agricultural history. These results indicate that although pollinator communities may show clear responses to restoration that are largely independent of prior land-use impacts, this does not necessarily translate into differences in pollination function after restoration

turley_et_al_2017_seed_addition_plots_focal_abndances_2015

Counts of focal species in seed addition plots and paired control plots. See read me file for more info

turley_et_al_2017_Plant_Community_data_2010-2015

Plant community data from 10 x 100 m transects. See read me file for more info

turley_et_al_2017_seed_addition_plots_all_species_percent_cover_2015

Plant community data with percent covers of all species within seed addition plots and paired control plots. See read me file for more info