A Randomized, Double-Blind, Dose-Finding, Multicenter, Phase 2 Study of Radium Chloride (Ra 223) in Patients with Bone Metastases and Castration-Resistant Prostate Cancer

BACKGROUND: Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile. OBJECTIVE: To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases. DESIGN, SETTING, AND PARTICIPANTS: In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n=41), 50 kBq/kg (n=39), or 80 kBq/kg (n=42). The study compared the proportion of patients in each dose group who had a confirmed decrease of =50% in baseline prostate-specific antigen (PSA) levels. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups. RESULTS AND LIMITATIONS: The study met its primary end point with a statistically significant dose-response relationship in confirmed =50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p=0.0297). A =50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p

The 1863 Melbourne Shakespeare War: Barry Sullivan, Charles and Ellen Kean, and the Play of Cultural Usurpation on the Australian Stage

This essay investigates an intricate drama of cultural identity in performances of Shakespeare on the nineteenth-century Melbourne stage. It considers the rivalry between Charles and Ellen Kean and their competitor, Barry Sullivan, for the two-month period in 1863 during which their Australian tours overlapped. This Melbourne Shakespeare war was anticipated,augmented, and richly documented in Melbourne’s papers: The Age, The Argus and Melbourne Punch. This essay pursues two seams of inquiry. The first is an investigation of the discourses of cultural and aesthetic value laced through the language of reviews of their Shakespearean roles.The essay identifies how reviewers register affective engagement with the performers in these roles, and suggests how the roles themselves reflected, by accident or design, the terms of the dispute. The second is concerned with the national identity of the actors. Kean, although born in Waterford, Ireland, had held the post of Queen Victoria’s Master of the Revels and identified himself as English. Sullivan, although born in Birmingham, was of Cork parentage and was identified as Irish by both his supporters and his detractors. This essay tracks the development of the actors’ national and artistic identities established prior to Melbourne and ask how they played out on in the context of the particularities of Australian reception. It shows that, in this instance, these actors were implicated in complex debates over national authority and cultural ownership.

‘5 ways to say your prayers’:The Art and Architecture of Curating People, Place and Creativity in a Post-Conflict Context. The Shed, Galway, Ireland 18th June – 23rd July 2013 Includes: 1. Co-Curation of Exhibition with Peter Mutschler, Director of PS² and 2. Morrow’s individual work as part of the exhibition, entitled ‘Departures & Arrivals: Academic Interactions with the Activities, Artists and Archive of PS² ’

This exhibition profiles the curatorial approach of PS² and the work of creative practitioners who have practiced alongside and with the organisation. PS² is a Belfast-based, voluntary arts organisation that initiates projects inside and outside its project space. It seeks to develop a socio-spatial practice that responds to the post-conflict context of Northern Ireland, with particular focus on active intervention and social interaction between local people, creative practitioners, multidisciplinary groups and theorists.<br/>Morrow has collaborated with PS² since its inception in 2005, acting as curatorial advisor specifically on the projects that occur outside PS² . She regards her involvement as a parallel action to her pedagogical explorations within architectural education.<br/><br/>Morrow's personal contribution to the Exhibition aimed to:<br/>-interrogate PS² spatial projects <br/>-contextualise PS² curatorial practice <br/>-open up the analytical framework and extend to similar local practices<br/><br/>The Shed, Galway, Ireland is a joint Galway City Arts and Harbour Company venture. The exhibition subsequently travelled to DarcSpace Gallery, Dublin (Sept 2013).

Assessment of factors that influence physician decision making regarding medication use in patients with dementia at the end of life

Objective<br/>This study aimed to evaluate the extent to which patient-related factors and physicians' country of practice (Northern Ireland [NI] and the Republic of Ireland [RoI]) influenced decision making regarding medication use in patients with end-stage dementia.<br/><br/>Methods<br/>The study utilised a factorial survey design comprising four vignettes to evaluate initiating/withholding or continuing/discontinuing specific medications in patients with dementia nearing death. Questionnaires and vignettes were mailed to all hospital physicians in geriatric medicine and to all general practitioners (GPs) in NI (November 2010) and RoI (December 2010), with a second copy provided 3 weeks after the first mailing. Logistic regression models were constructed to examine the impact of patient-related factors and physicians' country of practice on decision making. Significance was set a priori at p ≤ 0.05. Free text responses to open questions were analysed qualitatively using content analysis.<br/><br/>Results<br/>The response rate was 20.6% (N = 662) [21.1% (N = 245) for GPs and 52.1% (N = 38) for hospital physicians in NI, 18.3% (N = 348) for GPs and 36.0% (N = 31) for hospital physicians in RoI]. There was considerable variability in decision making about initiating/withholding antibiotics and continuing/discontinuing the acetylcholinesterase inhibitor and memantine hydrochloride, and less variability in decision making regarding statins and antipsychotics. Patient place of residence and physician's country of practice had the strongest and most consistent effects on decision making although effect sizes were small.<br/><br/>Conclusions<br/>Further research is required into other factors that may impact upon physicians' prescribing decisions for these vulnerable patients and to clarify how the factors examined in this study influence prescribing decisions.

Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Traces of Peter Rice

A review of the events comprising Peter Rice at Queen's including the Traces of Peter Rice Exhibition at the Naughton Gallery

Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: A prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial

<p>Background: Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. </p><p>Methods: In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. </p><p>Findings: Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56-0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52-0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. </p><p>Interpretation: Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. </p><p>Funding: Algeta ASA and Bayer HealthCare Pharmaceuticals.</p>