Accumulation of copy number alterations and clinical progression across advanced prostate cancer.

BACKGROUND: Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown. METHODS: We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression. RESULTS: The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10-6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov-Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037). CONCLUSIONS: Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00268476 , registered on December 22, 2005. EudraCT  2004-000193-31 , registered on October 4, 2004

Centrosome misorientation reduces stem cell division during ageing

Asymmetric division of adult stem cells generates one self- renewing stem cell and one differentiating cell, thereby maintaining tissue homeostasis. A decline in stem cell function has been proposed to contribute to tissue ageing, although the underlying mechanism is poorly understood. Here we show that changes in the stem cell orientation with respect to the niche during ageing contribute to the decline in spermatogenesis in the male germ line of Drosophila. Throughout the cell cycle, centrosomes in germline stem cells ( GSCs) are oriented within their niche and this ensures asymmetric division. We found that GSCs containing misoriented centrosomes accumulate with age and that these GSCs are arrested or delayed in the cell cycle. The cell cycle arrest is transient, and GSCs appear to re- enter the cell cycle on correction of centrosome orientation. On the basis of these findings, we propose that cell cycle arrest associated with centrosome misorientation functions as a mechanism to ensure asymmetric stem cell division, and that the inability of stem cells to maintain correct orientation during ageing contributes to the decline in spermatogenesis. We also show that some of the misoriented GSCs probably originate from dedifferentiation of spermatogonia.University of Michigan ; March of Dimes Basil O'Conner Starter Scholar Research Award ; Searle Scholar Program ; NIH [P01 DK53074, R01GM072006]We thank C. Gonzalez, D. McKearin, N. Rusan, M. Peifer and the Bloomington Stock Center for fly stocks; R. Lehmann, C. Field and the Developmental Studies Hybridoma Bank for antibodies; M. Kiel and D. Nakada for help with X-ray irradiation; and S. Morrison and T. Mahowald for comments on the manuscript. This research was supported by a University of Michigan start-up fund, March of Dimes Basil O'Conner Starter Scholar Research Award and the Searle Scholar Program (to Y.M.Y.), and NIH grants P01 DK53074 (to M.T.F.) and R01GM072006 (to A.J.H.).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62879/1/nature07386.pd

Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial

PURPOSE: Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS: A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS: Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION: Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial.

BACKGROUND: STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). METHODS AND FINDINGS: Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. CONCLUSIONS: Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. TRIAL REGISTRATION: ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544

Efficiency of Spermatogonial Dedifferentiation during Aging

Adult stem cells are critical for tissue homeostasis; therefore, the mechanisms utilized to maintain an adequate stem cell pool are important for the survival of an individual. In Drosophila, one mechanism utilized to replace lost germline stem cells (GSCs) is dedifferentiation of early progenitor cells. However, the average number of male GSCs decreases with age, suggesting that stem cell replacement may become compromised in older flies.Using a temperature sensitive allelic combination of Stat92E to control dedifferentiation, we found that germline dedifferentiation is remarkably efficient in older males; somatic cells are also effectively replaced. Surprisingly, although the number of somatic cyst cells also declines with age, the proliferation rate of early somatic cells, including cyst stem cells (CySCs) increases.These data indicate that defects in spermatogonial dedifferentiation are not likely to contribute significantly to an aging-related decline in GSCs. In addition, our findings highlight differences in the ways GSCs and CySCs age. Strategies to initiate or enhance the ability of endogenous, differentiating progenitor cells to replace lost stem cells could provide a powerful and novel strategy for maintaining tissue homeostasis and an alternative to tissue replacement therapy in older individuals

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol

BACKGROUND: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. METHODS: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0-2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544. FINDINGS: Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63-73) and median PSA 34 ng/ml (14·7-47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60-84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]-NE) than in the control groups (not reached, 97-NE; hazard ratio [HR] 0·53, 95% CI 0·44-0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79-85) in the combination-therapy group and 69% (66-72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70-1·50, p=0·91) and no evidence of between-trial heterogeneity (I2 p=0·90). Overall survival (median not reached [IQR NE-NE] in the combination-therapy groups vs not reached [103-NE] in the control groups; HR 0·60, 95% CI 0·48-0·73, p<0·0001), prostate cancer-specific survival (not reached [NE-NE] vs not reached [NE-NE]; 0·49, 0·37-0·65, p<0·0001), biochemical failure-free-survival (not reached [NE-NE] vs 86 months [83-NE]; 0·39, 0·33-0·47, p<0·0001), and progression-free-survival (not reached [NE-NE] vs not reached [103-NE]; 0·44, 0·36-0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death). INTERPRETATION: Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas

Designing clinical trials for assessing the effects of cognitive training and physical activity interventions on cognitive outcomes: The Seniors Health and Activity Research Program Pilot (SHARP-P) Study, a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>The efficacy of non-pharmacological intervention approaches such as physical activity, strength, and cognitive training for improving brain health has not been established. Before definitive trials are mounted, important design questions on participation/adherence, training and interventions effects must be answered to more fully inform a full-scale trial.</p> <p>Methods</p> <p>SHARP-P was a single-blinded randomized controlled pilot trial of a 4-month physical activity training intervention (PA) and/or cognitive training intervention (CT) in a 2 × 2 factorial design with a health education control condition in 73 community-dwelling persons, aged 70-85 years, who were at risk for cognitive decline but did not have mild cognitive impairment.</p> <p>Results</p> <p>Intervention attendance rates were higher in the CT and PACT groups: CT: 96%, PA: 76%, PACT: 90% (p=0.004), the interventions produced marked changes in cognitive and physical performance measures (p≤0.05), and retention rates exceeded 90%. There were no statistically significant differences in 4-month changes in composite scores of cognitive, executive, and episodic memory function among arms. Four-month improvements in the composite measure increased with age among participants assigned to physical activity training but decreased with age for other participants (intervention*age interaction p = 0.01). Depending on the choice of outcome, two-armed full-scale trials may require fewer than 1,000 participants (continuous outcome) or 2,000 participants (categorical outcome).</p> <p>Conclusions</p> <p>Good levels of participation, adherence, and retention appear to be achievable for participants through age 85 years. Care should be taken to ensure that an attention control condition does not attenuate intervention effects. Depending on the choice of outcome measures, the necessary sample sizes to conduct four-year trials appear to be feasible.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00688155">NCT00688155</a></p

Milk Lacking α-Casein Leads to Permanent Reduction in Body Size in Mice

The major physiological function of milk is the transport of amino acids, carbohydrates, lipids and minerals to mammalian offspring. Caseins, the major milk proteins, are secreted in the form of a micelle consisting of protein and calcium-phosphate