Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background 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. Methods 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. Findings 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. Interpretation 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

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background 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. Methods 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 . Findings 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. Interpretation 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. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

An investigation of the interaction of carbonyl compounds with the snowpack

Measurements of formaldehyde, acetaldehyde, and acetone in ambient and snowpack air were conducted as a part of the SNOW99 study in northern Michigan. Vertical profiles of ambient and snowpack air illustrate large concentration gradients through the top ~10 cm of the snowpack, implying a positive flux of these species from the surface. Snow chamber experiments that involved flushing a snow-filled 34L Teflon-lined chamber with zero air at 20 slpm indicated that release from the snow followed first order kinetics, with decay constants of 0.19, 0.44, and 0.34 hr-1 for formaldehyde, acetaldehyde, and acetone, respectively. Although it is likely that temperature dependent adsorption/desorption processes play a role, the data are not inconsistent with loss from the snowpack via snow grain metamorphism. The data also imply that formaldehyde is not hydrated in the snow grain surface layer

The Common Architecture of Cross-beta Amyloid.

Amyloid fibril deposition is central to the pathology of more than 30 unrelated diseases including Alzheimer's disease and Type 2 diabetes. It is generally accepted that amyloid fibrils share common structural features despite each disease being characterised by the deposition of an unrelated protein or peptide. The structure of amyloid fibrils has been studied using X-ray fibre diffraction and crystallography, solid-state NMR and electron paramagnetic resonance, and many different, sometimes opposing, models have been suggested. Many of these models are based on the original interpretation of the cross-beta diffraction pattern for cross-beta silk in which beta-strands run perpendicular to the fibre axis, although alternative models include p-helices and natively structured proteins. Here, we have analysed opposing model structures and examined the necessary structural elements within the amyloid core structure, as well as producing idealised models to test the limits of the core conformation. Our work supports the view that amyloid fibrils share a number of common structural features, resulting in characteristic diffraction patterns. This pattern may be satisfied by structures in which the strands align close to perpendicular to the fibre axis and are regularly arranged to form beta-sheet ribbons. Furthermore, the fibril structure contains several beta-sheets that associate via side-chain packing to form the final protofilament structure

Do schizotypy dimensions reflect the symptoms of schizophrenia?

OBJECTIVE: The personality characteristics and symptoms observed in schizophrenia are postulated to lie on a continuum, with non-clinical manifestations referred to as schizotypy. High schizotypy behaviours are argued to correspond with the three main clusters of symptoms in schizophrenia: positive, negative and cognitive/disorganised symptoms, yet there is limited empirical evidence to support this. This study aimed to investigate whether schizotypy dimensions significantly correlate with their respective schizophrenia symptomatology in the largest sample to date. METHODS: A total of 361 adults (103 patients with schizophrenia/schizoaffective disorder and 258 healthy controls) were assessed for schizotypy using the Oxford-Liverpool Inventory of Feelings and Experiences. The MATRICS Consensus Cognitive Battery supplemented by the Stroop task and Wisconsin Card Sorting Test was administered to all participants to obtain objective measurements of cognition. Schizophrenia symptomatology was assessed using the Positive and Negative Syndrome Scale in patients only. RESULTS: The results demonstrated significant correlations between the Oxford-Liverpool Inventory of Feelings and Experiences positive and negative subscales and their respective Positive and Negative Syndrome Scale subscales only, indicating that positive and negative schizotypy dimensions across patients and controls accurately reflect the respective schizophrenia symptomatology observed in patients. Cognitive performance did not correlate with cognitive/disorganised symptom dimensions of the Oxford-Liverpool Inventory of Feelings and Experiences or the Positive and Negative Syndrome Scale, indicating that cognitive impairment is an independent symptom dimension that requires objective cognitive testing. CONCLUSION: Collectively, the findings provide empirical evidence for the continuum theory and support the use of schizotypy as a model for investigating schizophrenia

Supplementary_final – Supplemental material for Do schizotypy dimensions reflect the symptoms of schizophrenia?

<p>Supplemental material, Supplementary_final for Do schizotypy dimensions reflect the symptoms of schizophrenia? by Elizabeth HX Thomas, Susan L Rossell, Eric J Tan, Erica Neill, Tamsyn E Van Rheenen, Sean P Carruthers, Philip J Sumner, Stephanie Louise, Kiymet Bozaoglu and Caroline Gurvich in Australian & New Zealand Journal of Psychiatry</p

Neither vaginal nor buccal administration of 800 μg misoprostol alters mucosal and systemic immune activation or the cervicovaginal microbiome: a pilot study

<p><b>Objectives:</b> The aim of the study was to assess the extent to which misoprostol alters mucosal or systemic immune responses following either buccal or vaginal administration.</p> <p><b>Methods:</b> This was a prospective, crossover pilot study of 15 healthy, reproductive-age women. Women first received 800 μg misoprostol either via buccal or vaginal administration and were crossed over 1 month later to receive the drug via the other route. Cervicovaginal lavage samples, cervical Cytobrush samples, cervicovaginal swabs, urine and blood were obtained immediately prior to drug administration and the following day. Parameters assessed included urine and cervicovaginal misoprostol levels, whole blood cytokine responses (by ELISA) to immune stimulation with lipopolysaccharide, peripheral blood and cervical lymphocyte phenotyping by flow cytometry, cervicovaginal antimicrobial peptide measurement by ELISA and vaginal microbial ecology assessment by 16S rRNA sequencing.</p> <p><b>Results:</b> Neither buccal nor vaginal misoprostol significantly altered local or systemic immune and microbiological parameters.</p> <p><b>Conclusion:</b> In this pilot study, we did not observe significant alteration of mucosal or systemic immunology or vaginal microbial ecology 1 day after drug administration following either the buccal or vaginal route.</p