Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both

Importance Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival. Objective To determine clinical effectiveness and cost-effectiveness of combining docetaxel, ZA, and Sr89, all having palliative benefits and used in bony metastatic CRPC to control bone symptoms and, for docetaxel, to prolong survival. Design, Setting, and Participants The TRAPEZE trial is a 2 × 2 factorial trial comparing docetaxel alone or with ZA, Sr89, or both. A cohort of 757 participants were recruited between February 2005 and February 2012 from hospitals in the United Kingdom. Overall, 169 participants (45%) had received palliative radiotherapy, and the median (IQR) prostate-specific antigen level was 146 (51-354). Follow-ups were performed for at least 12 months. Interventions Up to 10 cycles of docetaxel alone; docetaxel with ZA; docetaxel with a single Sr89 dose after 6 cycles; or docetaxel with both ZA and Sr89. Main Outcomes and Measures Primary outcomes included clinical progression-free survival (CPFS) (pain progression, skeletal-related events [SREs], or death) and cost-effectiveness. Secondary outcomes included SRE-free interval, pain progression–free interval, total SREs, and overall survival (OS). Results Overall, of 757 participants, 349 (46%) completed docetaxel treatment. Median (IQR) age was 68 (63-73) years. Clinical progression-free survival did not reach statistical significance for either Sr89 or ZA. Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (hazard ratio [HR], 0.85; 95% CI, 0.73-0.99; P = .03) and confirmed no effect of ZA (HR, 0.98; 95% CI, 0.85-1.14; P = .81); ZA had a significant effect on SRE-free interval (HR, 0.78; 95% CI, 0.65-0.95; P = .01). For OS, there was no effect of either Sr89 (HR, 0.92; 95% CI, 0.79-1.08; P = 0.34) or ZA (HR, 0.99; 95% CI, 0.84-1.16; P = 0.91). Conclusions and Relevance Strontium-89 combined with docetaxel improved CPFS but did not improve OS, SRE-free interval, or total SREs; ZA did not improve CPFS or OS but did significantly improve median SRE-free interval and reduced total SREs by around one-third, suggesting a role as postchemotherapy maintenance therapy

Tune in to your emotions: a robust personalized affective music player

The emotional power of music is exploited in a personalized affective music player (AMP) that selects music for mood enhancement. A biosignal approach is used to measure listeners’ personal emotional reactions to their own music as input for affective user models. Regression and kernel density estimation are applied to model the physiological changes the music elicits. Using these models, personalized music selections based on an affective goal state can be made. The AMP was validated in real-world trials over the course of several weeks. Results show that our models can cope with noisy situations and handle large inter-individual differences in the music domain. The AMP augments music listening where its techniques enable automated affect guidance. Our approach provides valuable insights for affective computing and user modeling, for which the AMP is a suitable carrier application

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer : long-term survival results from the STAMPEDE trial

Background STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. Methods We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. Results Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69–0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57–0.76, P  0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). Conclusions The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden

Spatially heterogeneous ages in glassy dynamics

We construct a framework for the study of fluctuations in the nonequilibrium relaxation of glassy systems with and without quenched disorder. We study two types of two-time local correlators with the aim of characterizing the heterogeneous evolution: in one case we average the local correlators over histories of the thermal noise, in the other case we simply coarse-grain the local correlators. We explain why the former describe the fingerprint of quenched disorder when it exists, while the latter are linked to noise-induced mesoscopic fluctuations. We predict constraints on the pdfs of the fluctuations of the coarse-grained quantities. We show that locally defined correlations and responses are connected by a generalized local out-of-equilibrium fluctuation-dissipation relation. We argue that large-size heterogeneities in the age of the system survive in the long-time limit. The invariance of the theory under reparametrizations of time underlies these results. We relate the pdfs of local coarse-grained quantities and the theory of dynamic random manifolds. We define a two-time dependent correlation length from the spatial decay of the fluctuations in the two-time local functions. We present numerical tests performed on disordered spin models in finite and infinite dimensions. Finally, we explain how these ideas can be applied to the analysis of the dynamics of other glassy systems that can be either spin models without disorder or atomic and molecular glassy systems.Comment: 47 pages, 60 Fig

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Machine Learning Education for Artists, Musicians, and Other Creative Practitioners

This article aims to lay a foundation for the research and practice of machine learning education for creative practitioners. It begins by arguing that it is important to teach machine learning to creative practitioners and to conduct research about this teaching, drawing on related work in creative machine learning, creative computing education, and machine learning education. It then draws on research about design processes in engineering and creative practice to motivate a set of learning objectives for students who wish to design new creative artifacts with machine learning. The article then draws on education research and knowledge of creative computing practices to propose a set of teaching strategies that can be used to support creative computing students in achieving these objectives. Explanations of these strategies are accompanied by concrete descriptions of how they have been employed to develop new lectures and activities, and to design new experiential learning and scaffolding technologies, for teaching some of the first courses in the world focused on teaching machine learning to creative practitioners. The article subsequently draws on data collected from these courses—an online course as well as undergraduate and masters-level courses taught at a university—to begin to understand how this curriculum supported student learning, to understand learners’ challenges and mistakes, and to inform future teaching and research