Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

BACKGROUND: Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases.

METHODS: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751.

FINDINGS: Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82).

INTERPRETATION: Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases.

FUNDING: Algeta and Bayer HealthCare Pharmaceuticals.

Sir Robert Hart Photo Collection on Flickr

The photographs in this album were selected with the assistance of the Sir Robert Hart Research Project, which is a collaboration between Special Collections & Archives in the Library, the School of Modern History & Anthropology, Queen’s University Belfast, and the Institute of Modern History at the Chinese Academy of Social Sciences (CASS) in Beijing. The research project is creating an annotated photobook from the Sir Robert Hart Photo Collection (originally donated in the 1970s) and the Irons Collection. The photographs here reflect those that will be included in the book.

Delivering a Research-Enabled Multistakeholder Partnership for Enhanced Patient Care at a Population Level: The Northern Ireland Comprehensive Cancer Program

The last 20 years have seen significant advances in cancer care in Northern Ireland, leading to measureable improvements in patient outcomes. Crucial to this transformation has been an ethos that recognizes the primacy role of research in effecting heath care change. The authors' model of a cross-sectoral partnership that unites patients, scientists, health care professionals, hospital trusts, bioindustry, and government agencies can be truly transformative, empowering tripartite clinical-academic-industry efforts that have already yielded significant benefit and will continue to inform strategy and its implementation going forward.

EARLY RADIO AND X-RAY OBSERVATIONS OF THE YOUNGEST NEARBY TYPE Ia SUPERNOVA PTF 11kly (SN 2011fe)

On 2011 August 24 (UT) the Palomar Transient Factory (PTF) discovered PTF11kly (SN 2011fe), the youngest and most nearby Type Ia supernova (SN Ia) in decades. We followed this event up in the radio (centimeter and millimeter bands) and X-ray bands, starting about a day after the estimated explosion time. We present our analysis of the radio and X-ray observations, yielding the tightest constraints yet placed on the pre-explosion mass-loss rate from the progenitor system of this supernova. We find a robust limit of from sensitive X-ray non-detections, as well as a similar limit from radio data, which depends, however, on assumptions about microphysical parameters. We discuss our results in the context of single-degenerate models for SNe Ia and find that our observations modestly disfavor symbiotic progenitor models involving a red giant donor, but cannot constrain systems accreting from main-sequence or sub-giant stars, including the popular supersoft channel. In view of the proximity of PTF11kly and the sensitivity of our prompt observations, we would have to wait for a long time (a decade or longer) in order to more meaningfully probe the circumstellar matter of SNe Ia.

SN 2011dh: DISCOVERY OF A TYPE IIb SUPERNOVA FROM A COMPACT PROGENITOR IN THE NEARBY GALAXY M51

On 2011 May 31 UT a supernova (SN) exploded in the nearby galaxy M51 (the Whirlpool Galaxy). We discovered this event using small telescopes equipped with CCD cameras and also detected it with the Palomar Transient Factory survey, rapidly confirming it to be a Type II SN. Here, we present multi-color ultraviolet through infrared photometry which is used to calculate the bolometric luminosity and a series of spectra. Our early-time observations indicate that SN 2011dh resulted from the explosion of a relatively compact progenitor star. Rapid shock-breakout cooling leads to relatively low temperatures in early-time spectra, compared to explosions of red supergiant stars, as well as a rapid early light curve decline. Optical spectra of SN 2011dh are dominated by H lines out to day 10 after explosion, after which He I lines develop. This SN is likely a member of the cIIb (compact IIb) class, with progenitor radius larger than that of SN 2008ax and smaller than the eIIb (extended IIb) SN 1993J progenitor. Our data imply that the object identified in pre-explosion Hubble Space Telescope images at the SN location is possibly a companion to the progenitor or a blended source, and not the progenitor star itself, as its radius (~1013 cm) would be highly inconsistent with constraints from our post-explosion spectra.

Analysis of the early-time optical spectra of SN 2011fe in M101

The nearby Type Ia supernova SN 2011fe in M101 (cz=241 km s^-1) provides a unique opportunity to study the early evolution of a "normal" Type Ia supernova, its compositional structure, and its elusive progenitor system. We present 18 high signal-to-noise spectra of SN 2011fe during its first month beginning 1.2 days post-explosion and with an average cadence of 1.8 days. This gives a clear picture of how various line-forming species are distributed within the outer layers of the ejecta, including that of unburned material (C+O). We follow the evolution of C II absorption features until they diminish near maximum light, showing overlapping regions of burned and unburned material between ejection velocities of 10,000 and 16,000 km s^-1. This supports the notion that incomplete burning, in addition to progenitor scenarios, is a relevant source of spectroscopic diversity among SNe Ia. The observed evolution of the highly Doppler-shifted O I 7774 absorption features detected within five days post-explosion indicate the presence of O I with expansion velocities from 11,500 to 21,000 km s^-1. The fact that some O I is present above C II suggests that SN 2011fe may have had an appreciable amount of unburned oxygen within the outer layers of the ejecta.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.

METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).

FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.

INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.

FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Le traitement définitoire des noms de plantes herbacées dans le Petit Robert

La présente étude, de type métalexicographique, s'insère dans une perspective de recherche visant à dresser le bilan de la pratique lexicographique réservée aux noms d'espèces naturelles dans les dictionnaires usuels du français. Elle porte sur le traitement définitoire de tous les noms de plantes herbacées répertoriés dans le Petit Robert (édition électronique 1996). Son objectif principal est de décrire très précisément la pratique définitoire en cause. Nous commençons par passer rapidement en revue les différents procédés définitoires illustrés par notre corpus, avant de procéder à l'analyse détaillée du procédé le plus exploité, celui de la définition par inclusion. Notre méthode d'analyse est basée sur la segmentation et l'examen comparatif des différentes composantes sémantiques et formelles présentes dans les définitions par inclusion de notre corpus. Elle permet non seulement de mieux connaître la pratique du Petit Robert , mais aussi d'en extraire un certain savoir-faire. Nous étudions quatre grandes catégories d'éléments descriptifs bien représentées dans notre corpus: les éléments de classification, les éléments de localisation, les éléments de valorisation ainsi que les éléments de morphologie en lien avec ces derniers. Nous donnons, de la métalangue utilisée et des principaux modèles de description exploités, un portrait relativement précis qui pourra alimenter la réflexion des lexicographes et autres linguistes qui s'intéressent à la description des noms d'espèces naturelles en général et des noms de plantes en particulier.