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.

‘It's been hell.’ Italian and British practice educators’ narratives of working with struggling or failing social work students in practice learning settings

Periods of assessed learning in practice settings are common requirements for social work students world wide. The ‘practice learning opportunity’ as it is known in the UK, and ‘tirocinio di servizio sociale’ as it is referred to in Italy, are important sites of gatekeeping in preventing unsuitable people from becoming social workers. The experience of assessing failing students in practice learning settings however, has been found to be particularly stressful and challenging for practice educators. This article documents findings from two qualitative studies that explored field educators’ experiences of working with struggling or failing social work students in Italy and England. The study finds both similarities and differences in the narratives of the assessors from the two countries Similarities include, unpleasant emotional experience of working with a failing student, internalisation of the students failing as the practice educators’ own failing, perceptions that the universities may hide negative information about students and lack of acknowledgement of the gatekeeping function inherent in the practice educator role. Differences include the level of emotionality experienced by educators, the way students are spoken about and the perceived role and responses of the university. Further comparative European research which focuses on practice education is indicated.

Specifying and analysing networks of processes in CSPt (or in search of associativity)

In proposing theories of how we should design and specify networks of processes it is necessary to show that the semantics of any language we use to write down the intended behaviours of a system has several qualities. First in that the meaning of what is written on the page reflects the intention of the designer; second that there are no unexpected behaviours that might arise in a specified system that are hidden from the unsuspecting specifier; and third that the intention for the design of the behaviour of a network of processes can be communicated clearly and intuitively to others. In order to achieve this we have developed a variant of CSP, called CSPt, designed to solve the problems of termination of parallel processes present in the original formulation of CSP. In CSPt we introduced three parallel operators, each with a different kind of termination semantics, which we call synchronous, asynchronous and race. These operators provide specifiers with an expressive and flexible tool kit to define the intended behaviour of a system in such a way that unexpected or unwanted behaviours are guaranteed not to take place. In this paper we extend out analysis of CSPt and introduce the notion of an alphabet diagram that illustrates the different categories of events that can arise in the parallel composition of processes. These alphabet diagrams are then used to analyse networks of three processes in parallel with the aim of identifying sufficient constraints to ensure associativity of their parallel composition. Having achieved this we then proceed to prove associativity laws for the three parallel operators of CSPt. Next, we illustrate how to design and construct a network of three processes that satisfy the associativity law, using the associativity theorem and alphabet diagrams. Finally, we outline how this could be achieved for more general networks of processes.

How to Measure the Deterrence Effects of Merger Policy: Frequency or Composition?

We show that the number of merger proposals (frequency-based deterrence) is a more appropriate indicator of underlying changes in merger policy than the relative anti-competitiveness of merger proposals (composition-based deterrence). This has strong implications for the empirical analysis of the deterrence effects of merger policy enforcement, and potential implications regarding how to reduce anti-competitive merger proposals.

Mutations in the MECP2 Gene Are Not a Major Cause of Rett Syndrome-Like or Related Neurodevelopmental Phenotype in Male Patients

Rett syndrome is a genetic neurodevelopmental disorder that affects mainly girls, but mutations in the causative MECP2 gene have also been identified in boys with classic Rett syndrome and Rett syndrome-like phenotypes. We have studied a group of 28 boys with a neurodevelopmental disorder, 13 of which with a Rett syndrome-like phenotype; the patients had diverse clinical presentations that included perturbations of the autistic spectrum, microcephaly, mental retardation, manual stereotypies, and epilepsy. We analyzed the complete coding region of the MECP2 gene, including the detection of large rearrangements, and we did not detect any pathogenic mutations in the MECP2 gene in these patients, in whom the genetic basis of disease remained unidentified. Thus, additional genes should be screened in this group of patients.

Monoclonal antibodies to murine lipopolysaccharide (LPS)-binding protein (LBP) protect mice from lethal endotoxemia by blocking either the binding of LPS to LBP or the presentation of LPS/LBP complexes to CD14.

Cellular responses to LPS, the major lipid component of the outer membrane of Gram-negative bacteria, are enhanced markedly by the LPS-binding protein (LBP), a plasma protein that transfers LPS to the cell surface CD14 present on cells of the myeloid lineage. LBP has been shown previously to potentiate the host response to LPS. However, experiments performed in mice with a disruption of the LBP gene have yielded discordant results. Whereas one study showed that LBP knockout mice were resistant to endotoxemia, another study did not confirm an important role for LBP in the response of mice challenged in vivo with low doses of LPS. Consequently, we generated rat mAbs to murine LBP to investigate further the contribution of LBP in experimental endotoxemia. Three classes of mAbs were obtained. Class 1 mAbs blocked the binding of LPS to LBP; class 2 mAbs blocked the binding of LPS/LBP complexes to CD14; class 3 mAbs bound LBP but did not suppress LBP activity. In vivo, class 1 and class 2 mAbs suppressed LPS-induced TNF production and protected mice from lethal endotoxemia. These results show that the neutralization of LBP accomplished by blocking either the binding of LPS to LBP or the binding of LPS/LBP complexes to CD14 protects the host from LPS-induced toxicity, confirming that LBP is a critical component of innate immunity.

Pen and sunlight sketches of scenery reached by the Grand Trunk Railway and connections : including Niagara Falls, Thousand Islands, Rapids of the Saint Lawrence, Montreal, Quebec, and the mountains of New England.--

At head of title: "The tourist route of America".

Reflected rays of light upon Freemasonry, or, the Freemason's pocket compendium (1874)

"With an emblematical frontespiece." Inscribed on front free endpaper: A. Graham Barrie 30th Sep 1881.

Utilization of biodiesel-derived glycerol or xylose for increased growth and lipid production by indigenous microalgae

The use of industrial wastes rich in mineral nutrients and carbon sources to increase the final microalgal biomass and lipid yield at a low cost is an important strategy to make algal biofuel technology viable. Using strains from the microalgal collection of the Université de Montréal, this report shows for the first time that microalgal strains can be grown on xylose, the major carbon source found in wastewater streams from pulp and paper industries, with an increase in growth rate of 2.8 fold in comparison to photoautotrophic growth, reaching up to µ=1.1/day. On glycerol, growth rates reached as high as µ=1.52/day. Lipid productivity increased up to 370% on glycerol and 180% on xylose for the strain LB1H10, showing the suitability of this strain for further development for biofuels production through mixotrophic cultivation.

Horns in cattle - implications of keeping horned cattle or not

Literaturreview zum Thema Behornung und Enthornung bei Rindern,Qualitative und quantitative Befragung von Landwirten zur Enthornungspraxis, Untersuchung zur Auswirkung von unterschiedlichen Vorwartehofgrößen auf die Herzfrequenz und die agonistischen Interaktionen von eher ranghohen und eher rangniedrigen horntragenden Milchkühen, Untersuchung zur Auswirkung von zeitlich begrenztem Weidegang auf die Herzfrequenz, die Herzfrequenzvariabilität und die agonistischen Interaktionen von horntragenden Milchkühen im Laufstall