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Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Background Understanding how polygenic scores for ageing-related traits interact with diet in determining a future dementia including Alzheimer’s diagnosis (AD) would increase our understanding of mechanisms underlying dementia onset. Methods Using 6784 population representative adults aged ≥50 years from the English Longitudinal Study of Ageing, we employed accelerated failure time survival model to investigate interactions between polygenic scores for AD (AD-PGS), schizophrenia (SZ-PGS) and general cognition (GC-PGS) and the baseline daily fruit and vegetable intake in association with dementia diagnosis during a 10-year follow-up. The baseline sample was obtained from waves 3–4 (2006–2009); follow-up data came from wave 5 (2010–2011) to wave 8 (2016–2017). Results Consuming < 5 portions of fruit and vegetables a day was associated with 33–37% greater risk for dementia in the following 10 years depending on an individual polygenic propensity. One standard deviation (1-SD) increase in AD-PGS was associated with 24% higher risk of dementia and 47% higher risk for AD diagnosis. 1-SD increase in SZ-PGS was associated with an increased risk of AD diagnosis by 66%(95%CI = 1.05–2.64) in participants who consumed < 5 portions of fruit or vegetables. There was a significant additive interaction between GC-PGS and < 5 portions of the baseline daily intake of fruit and vegetables in association with AD diagnosis during the 10-year follow-up (RERI = 0.70, 95%CI = 0.09–4.82; AP = 0.36, 95%CI = 0.17–0.66). Conclusion A diet rich in fruit and vegetables is an important factor influencing the subsequent risk of dementia in the 10 years follow-up, especially in the context of polygenetic predisposition to AD, schizophrenia, and general cognition.

Reducing hospitalisation and length of stay (LOS) in hospital following first episode psychosis (FEP) is important, yet reliable measures of these outcomes and their moderators are lacking. We conducted a systematic review and meta-analysis to investigate the proportion of FEP cases who were hospitalised after their first contact with services and the LOS in a hospital during follow-up. Studies were identified from a systematic search across major electronic databases from inception to October 2017. Random effects meta-analyses and meta-regression analyses were conducted. 81 longitudinal studies encompassing data for 23 280 FEP patients with an average follow-up length of 7 years were included. 55% (95% CI 50.3-60.5%) of FEP cases were hospitalised at least once during follow-up with the pooled average LOS of 116.7 days (95% CI 95.1-138.3). Older age of illness onset and being in a stable relationship were associated with a lower proportion of people who were hospitalised. While the proportion of hospitalised patients has not decreased over time, LOS has, with the sharpest reduction in the latest time period. The proportion of patients hospitalised during follow-up was highest in Australia and New Zealand (78.4%) compared to Europe (58.1%) and North America (48.0%); and lowest in Asia (32.5%). Black ethnicity and longer duration of untreated psychosis were associated with longer LOS; while less severe psychotic symptoms at baseline were associated with shorter LOS. One in two FEP cases required hospitalisation at least once during a 7-year follow-up with an average length of hospitalisation of 4 months during this period. LOS has declined over time, particularly in those countries in which it was previously longest.

Abstract Background The Clinical Record Interactive Search (CRIS) database provides anonymised data from the full electronic health records of all patients at the South London and Maudsley NHS Foundation Trust, a large provider of secondary mental health care. We have previously shown how the large volumes of available CRIS data pertaining to outcomes can be mined and integrated with patient data collected by historical research interview. The applications of this futuristic translational research model are yet to be fully explored. The aim of this study is to determine whether transcriptomic profiles at the onset of psychosis can discern the likely trajectory symptoms over the subsequent 5 years of illness. Methods The study sample consists of 200 first-episode psychosis cases (ICD-10 codes: F20-F29 or F30-F33) aged 18–65 years who presented to SLAM (South London and Maudsley NHS Trust) mental health services between the 1st of January 2010 and the 1st of January 2015. Patients were subsequently recruited to the GAP study. Patients were followed-up electronically for 5 years post recruitment using the CRIS research platform. RNA samples were collected at the baseline timepoint via PAXgene blood tubes and interrogates, using the Illumina HumanHT-12.v4 beadchip array. Samples were run at the National Institute for Health Research’s (NIHR) Biomedical Research Centre for Mental Health (BRC-MH) at the Institute of Psychiatry, Psychology and Neuroscience. A total of 4756 probes passed a stringent quality control across the 200 samples. Results CRIS data pertaining to the GAP cohort was interrogated for information on clinical symptoms over a 5-year period using text-mining and natural language processing apps that represent over 70 different dictionary definitions of psychotic and affective symptoms. Confirmatory factor analysis was used to reduce this to a much smaller set of orthogonal symptom dimensions which were then the subject of a genetic interrogation using gene expression data. The analysis was conducted using a statistical learning framework which combines Elastic net penalised regression methodology with K-fold cross-validation (via the GLMnet package in R). This identified gene transcripts that were predictive of longer term symptom trajectories in half of the available sample. The veracity of the model was further validated using the second withheld portion of the sample. Discussion The results of this discovery phase may provide a rationale for subsequent multi-modal investigations whose aims will be to further enrich the biomarker signature and to also understand the molecular mechanisms that sustain them.