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

A Selection of GMPEs for the United Kingdom Based on Instrumental and Macroseismic Datasets

AbstractIn countries with low‐to‐moderate seismicity, the selection of appropriate ground‐motion prediction equations (GMPEs) to be used in a probabilistic seismic hazard analysis (PSHA) is a challenging step. Empirical observations of ground motion are limited, and GMPEs, when available, are generally based on stochastic simulations or adjusted empirical GMPEs from elsewhere. This article investigates the suitability of recent GMPEs to the United Kingdom. To this end, the spectral accelerations obtained from available instrumental ground‐motion data in the United Kingdom with magnitude lower than 4.5 are compared with the GMPEs’ predictions through the analysis of residuals and the application of statistical tests. To compensate for the scarcity of data for the magnitude range of interest in the PSHA, a macroseismic dataset is also considered. Macroseismic intensities are converted to peak ground acceleration (PGA) and statistically compared with the PGA predicted by the GMPEs. The GMPEs are then compared in terms of median ground‐motion prediction through Sammon’s maps to evaluate their similarities. The analyses from both datasets led to six suitable GMPEs, of which three are from the Next Generation Attenuation‐West2 project, one is European, one is based mainly on a Japanese dataset, and one is a stochastic GMPE developed specifically for the United Kingdom.</jats:p

Localization of SPIO-labeled cells in excised hearts by μCT.

<p>A) Arrows indicate the location of the SPIO nanoparticle-labeled muscle progenitors contained within engineered tissues that were implanted in the AV groove of an adult rat heart for 1 year. Signal from iron is shown as a positive contrast signal (white spot). The asterisk indicates the position of the aorta exiting the heart. Coronal (A), axial (B), and sagittal (C) μCT images are shown. Once again, the panels on the left show individual image slices and the panels on the right show corresponding volumetric renderings. In the absence of signal from bone, soft tissue detail becomes more apparent.</p

Superparamagnetic Iron Oxide Nanoparticles Function as a Long-Term, Multi-Modal Imaging Label for Non-Invasive Tracking of Implanted Progenitor Cells

<div><p>The purpose of this study was to determine the ability of superparamagnetic iron oxide (SPIO) nanoparticles to function as a long-term tracking label for multi-modal imaging of implanted engineered tissues containing muscle-derived progenitor cells using magnetic resonance imaging (MRI) and X-ray micro-computed tomography (μCT). SPIO-labeled primary myoblasts were embedded in fibrin sealant and imaged to obtain intensity data by MRI or radio-opacity information by μCT. Each imaging modality displayed a detection gradient that matched increasing SPIO concentrations. Labeled cells were then incorporated in fibrin sealant, injected into the atrioventricular groove of rat hearts, and imaged <i>in vivo</i> and <i>ex vivo</i> for up to 1 year. Transplanted cells were identified in intact animals and isolated hearts using both imaging modalities. MRI was better able to detect minuscule amounts of SPIO nanoparticles, while μCT more precisely identified the location of heavily-labeled cells. Histological analyses confirmed that iron oxide particles were confined to viable, skeletal muscle-derived cells in the implant at the expected location based on MRI and μCT. These analyses showed no evidence of phagocytosis of labeled cells by macrophages or release of nanoparticles from transplanted cells. In conclusion, we established that SPIO nanoparticles function as a sensitive and specific long-term label for MRI and μCT, respectively. Our findings will enable investigators interested in regenerative therapies to non-invasively and serially acquire complementary, high-resolution images of transplanted cells for one year using a single label.</p></div

<i>In vitro</i> detection of SPIO nanoparticle-labeled muscle progenitor cells by histology, MRI, and μCT.

<p>A) Cells incubated with increasing concentrations of SPIO particles and PLL were fixed and stained with Prussian blue and pararosaniline to identify iron-labeled cells. Slides were imaged using brightfield microscopy. The graph shows the percentage of SPIO-labeled cells at each concentration (mean ± standard error of the mean) as determined by analysis from three blinded observers. B) MRI of SPIO-labeled cell standards incorporated within fibrin sealant in micro-centrifuge tubes. The graphs display T2* relaxation time versus SPIO concentration (left) and average pixel intensity versus SPIO concentration (right) as determined from mean values generated from three different labeling experiments. C) μCT images of the same SPIO-labeled cell standards incorporated within fibrin sealant as depicted in B). The graph displays the number of opaque voxels versus SPIO concentration as determined from values generated from three different labeling experiments. Data represents mean ± standard error of the mean for each.</p

Localization of SPIO-labeled cells within the area of implants by histology.

<p>A) A photograph depicting the fibrin sealant-based implant in a heart excised one year after implantation (left panel), a low magnification image of a Masson's trichrome stained heart section (center panel), and a low magnification image from an adjacent serial section showing Prussian blue iron stain (right panel) of SPIO-labeled cells within the implant. The right atrium (RA), right ventricle (RV), and aorta are depicted along with an outline of the implant (dotted line). Scale bars equal 500 µm. B) Higher magnification brightfield images from the boxed region in A) showing an unprocessed serial section demonstrating iron (brown) can be detected in the cells of the implant and the same Masson's trichrome and Prussian blue stained sections from A). Scale bars equal 50 µm. C) The same section as the left panel from B) immunostained for the presence of macrophages (MAC387 in green), DNA (DAPI in blue), and striated muscle (ACTN in red) (left panel). Adjacent serial sections were immunostained for cardiac troponin T (cTnT in red), DNA (DAPI in blue), and striated muscle (ACTN in green) (middle panel). The right panel shows an image of ACTN, cTnT, and DAPI staining in the right ventricle. Scale bars equal 50 µm. D) Serial sections from a different heart stained for Masson's trichrome (left panel), Prussian blue with pararosaniline (middle panel), and immuno-fluorescence from secondary antibodies detecting binding of cTnT and ACTN antibodies in addition to DAPI staining of DNA. Iron is abundant in implanted cells, but is not apparent in the epicardium or myocardium of the right ventricle. The location of SPIO-labeled cells corresponds to the location of ACTN positive (red), cTnT negative (green) cells. Scale bars equal 50 µm.</p

SPIO nanoparticle-labeled cells located within the implant in three different hearts.

<p>A) Brightfield, fluorescence, and merged images showing iron deposits in progenitor cells contained within the implant (left panel), staining of filamentous actin with phalloidin (green) and DNA (blue) (middle panel) in the same section, and the merged image (right panel). Arrows indicate a few inflammatory cells that are not positive for iron. Scale bars equal 50 µm. B) A different heart showing heavily-labeled cells in the implant using the same staining as described for A). Scale bars equal 25 µm. C) Iron was also evident (brown) within a portion of the implant immediately adjacent to the right ventricular epicardium in a separate tissue section (left panel) that was immunostained for ACTN (red) and DAPI (blue) (middle panel). The right panel shows an overlay of the two images to the left. Scale bars equal 25 µm.</p