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 Unification of Asymmetry Signatures of Type Ia Supernovae

We present a compilation of the geometry measures acquired using optical and IR spectroscopy and optical spectropolarimetry to probe the explosion geometry of Type Ia supernovae (SNe Ia). Polarization measurements are sensitive to asymmetries in the plane of the sky, whereas line profiles in nebular phase spectra are expected to trace asymmetries perpendicular to the plane of the sky. The combination of these two measures can overcome their respective projection effects, completely probing the structures of these events. For nine normal SNe Ia, we find that the polarization of Si II ?6355 at 5 days before maximum (p Si II ) is well correlated with its velocity evolution (\dot{v}_Si II), implying that \dot{v}_Si II is predominantly due to the asymmetry of the SNe. We find only a weak correlation between the polarization of Si II and the reported velocities (v neb) for peak emission of optical Fe II and Ni II lines in nebular spectra. Our sample is biased, with polarization measurements being only available for normal SNe that subsequently exhibited positive (i.e., redshifted) v neb. In unison these indicators are consistent with an explosion in which the outer layers are dominated by a spherical oxygen layer, mixed with an asymmetric distribution of intermediate-mass elements. The combination of spectroscopic and spectropolarimetric indicators suggests a single geometric configuration for normal SNe Ia, with some of the diversity of observed properties arising from orientation effects.

A randomised double-blind placebo-controlled phase II study of AGI004 for control of chemotherapy-induced diarrhoea

Background: AGI004 is a controlled-release transdermal patch preparation of mecamylamine. We conducted a randomised placebo-controlled phase II study of two dose levels of AGI004 in chemotherapy-induced diarrhoea (CID).

Methods: Adult patients receiving chemotherapy who had experienced diarrhoea (NCI grade 1-2) during previous cycles of chemotherapy were eligible. In all, 64 patients were randomised to receive AGI004 4mg then 8mg per 24 h transdermal patch or placebo for two sequential cycles of chemotherapy. Patients' severity of diarrhoea was physician-assessed using NCI grade of diarrhoea and patient-assessed using information recorded in daily diaries of bowel movements.

Results: Overall AGI004 doubled the odds of a response to treatment on the first day of chemotherapy based on physician assessment of NCI grade of diarrhoea compared with placebo (odds ratio = 2.0, 90% confidence interval: 0.9-4.5) and there was a trend to improved response rates for AGI004 for the full treatment cycle although these results were not statistically significant. There was also evidence of significantly improved response rates based on patient assessment of diarrhoea both overall (P = 0.05) and at the 8-mg dose level (P = 0.02) compared with placebo.

Conclusion: AGI004 demonstrated effectiveness in reducing chemotherapy-associated diarrhoea, with results suggesting response across multiple measurements of diarrhoea. Treatment was well tolerated with no drug-related adverse events. Further evaluation of this agent in the management of CID is warranted.

RADIATIVE SIGNATURES OF RELATIVISTIC SHOCKS

Particle-in-cell simulations of relativistic, weakly magnetized collisionless shocks show that particles can gain energy by repeatedly crossing the shock front. This requires scattering off self-generated small length-scale magnetic fluctuations. The radiative signature of this first-order Fermi acceleration mechanism is important for models of both the prompt and afterglow emission in gamma-ray bursts and depends on the strength parameter a = lambda e/delta B/mc(2) of the fluctuations (lambda is the length scale and vertical bar delta B vertical bar is the magnitude of the fluctuations). For electrons (and positrons), acceleration saturates when the radiative losses produced by the scattering cannot be compensated by the energy gained on crossing the shock. We show that this sets an upper limit on both the electron Lorentz factor gamma <10(6) (n/1 cm(-3))(-1/6)(-1/6) and on the energy of the photons radiated during the scattering process h omega(max) <40Max(a, 1)(n/1 cm(-3))(1/6)(-1/6) eV, where n is the number density of the plasma and (gamma) over bar is the thermal Lorentz factor of the downstream plasma, provided a <a(crit) similar to 10(6). This rules out "jitter" radiation on self-excited fluctuations with a <I as a source of gamma rays, although high-energy photons might still be produced when the jitter photons are upscattered in an analog of the synchrotron self-Compton process. In fluctuations with a > 1, radiation is generated by the standard synchrotron mechanism, and the maximum photon energy rises linearly with a, until saturating at 70 MeV, when a = a(crit).

Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin:a randomized, double-blind, placebo-controlled trial

To evaluate the dose-response relationship of lixisenatide (AVE0010), a glucagon-like peptide-1 (GLP-1) receptor agonist, in metformin-treated patients with Type 2 diabetes.

Knowledge work: Gender-blind or gender-biased?

Knowledge-intensive firms (KIFs) have been the subject of growing interest from researchers. However, investigations into the comparative experiences of men and women in KIFs remain sparse, and little is known about women's participation in the processes of innovation and knowledge exchange and combination that are core features of KIFs. The article reports on the findings of a study in the UK and Ireland involving 498 male and female knowledge workers in KIFs. Despite equal levels of qualification and experience, women are more likely to be in lower status and less secure jobs. They also predominantly occupy roles featuring less variety and autonomy than men and, despite comparable levels of knowledge exchange and combination, are less likely to be in a position to translate this into the innovative work behaviours necessary for career advancement. The findings suggest that women's experiences of and participation in knowledge processes within KIFs differ fundamentally from men's. © The Author(s) 2012.

Risks to patient confidentiality when communicating health information to blind and partially sighted patients.

The research reports on a survey of 228 blind and partially sighted persons in 15 health authorities across Scotland. The survey reports data on patient experience of receiving health information in accessible reading formats. Data indicated that about 90% of blind and partially sighted persons did not receive communications from various NHS health departments in a format that they could read by themselves. The implications for patient privacy, confidentiality and wider impact on life and health care are highlighted. The implications for professional ethical medical practice and for public policy are also discussed. Recommendations for improved practice are made.

Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial

Aromatase inhibitors effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. We assessed the efficacy and safety of the aromatase inhibitor anastrozole for prevention of breast cancer in postmenopausal women who are at high risk of the disease.

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

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. 

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. 

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. 

Interpretation: Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. 

Funding: Algeta ASA and Bayer HealthCare Pharmaceuticals.