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

Supplementary materials: Indirect treatment comparison of anifrolumab efficacy versus belimumab in adults with systemic lupus erythematosus

These are peer-reviewed supplementary materials for the article 'Indirect treatment comparison of anifrolumab efficacy versus belimumab in adults with systemic lupus erythematosus' published in the Journal of Comparative Effectiveness Research.Appendix A: Systematic Literature ReviewTable S1: Summary of inclusion and exclusion criteria for the systematic literature review.Appendix B: PRISMA Flow DiagramFigure S1: PRISMA flow diagram. Appendix C: Feasibility AssessmentTable S2: Overview of feasibility assessment by outcome.Appendix D: STC Analysis: Additional Details and Sensitivity AnalysesTable S3: Factors adjusted in each base case STC analysis.Figure S2: SLEDAI reduction STC sensitivity analysis: Inclusion of MUSEFigure S3: SRI(4) response STC sensitivity analysis: Inclusion of MUSEFigure S4: BILAG flares STC sensitivity analysis: Inclusion of MUSEFigure S5: OCS reduction STC sensitivity analysis: Inclusion of MUSEAim: Assess the comparative efficacy of anifrolumab 300 mg versus belimumab 10 mg/kg in adults with moderate-to-severe systemic lupus erythematosus (SLE) receiving standard therapy. Patients and methods: Population-adjusted simulated treatment comparisons (primary analyses) and matching-adjusted indirect comparisons (supporting analyses) were conducted using individual patient data from TULIP-1/TULIP-2 and summary-level data from BLISS-52/BLISS-76. Results: Compared with belimumab-treated patients, anifrolumab-treated patients were more than twice as likely to achieve a reduction of four or more points in SLE Disease Activity Index 2000 score (simulated treatment comparison odds ratio: 2.47; 95% CI: 1.16–5.25) and SLE Responder Index-4 response (odds ratio: 2.61; 95% CI: 1.22–5.58) at 52 weeks. Conclusion: Patients with moderate-to-severe SLE are more likely to achieve an improvement in disease activity with anifrolumab than with belimumab.</p

High fat diet induced resistance to helminth infection via alternative induction of Type 2 immunity

Gastrointestinal nematode infections cause morbidity and socio-economic loss in the most deprived communities. The shift in context of obesity has led to spatial overlap with endemic gastrointestinal nematode regions resulting in the emergence of a novel comorbidity. Despite this, the impact of high fat diet (HFD) on immune-regulated protection against gastrointestinal infections remains largely unknown. We employed the murine model of nematode infection, Trichuris muris, to investigate the effect of a HFD on the immune response against chronic infection. Surprisingly, diet induced obesity drove parasite expulsion in both single and repeated trickle low doses of T. muris eggs. Mechanistically, a HFD increased expression of the ST2 receptor on CD4+ T-cells priming an enhanced Th2 cytokine production following IL-33 stimulation ex vivo. Despite IL-33-/- mice demonstrating that IL-33 is not critical for host protective immunity to T. muris under a conventional diet, HFD fed T-cell deplete mice adoptively transferred with ST2-/- CD4 T-cells were unable to expel a T. muris infection unlike those transferred with ST2 sufficient cells. Collectively, this study demonstrates a HFD primes CD4+ T-cells to utilise the IL-33-ST2 axis in a novel induction of Type 2 immunity, providing insights into the emerging comorbidities of obesity and nematode infection

Translation and Validation of a Bahasa Malaysia (Malay) Version of the Functionality Appreciation Scale

The Functionality Appreciation Scale (FAS; Alleva, Tylka, & Kroon Van Diest, 2017) is a 7-item measure of an individual’s appreciation of their body for what it can do and is capable of doing. To date, its psychometric properties have not been examined beyond the parent study and outside English-speaking samples. To rectify this, we examined the psychometric properties of a Bahasa Malaysia (Malay) translation of the FAS. An online sample of 815 Malaysia citizens completed a Malay translation of the FAS, along with validated measures of body appreciation, weight discrepancy, drive for muscularity, perceived pressure from and internalisation of appearance ideals, self-esteem, and trait mindfulness. Exploratory factor analyses supported a 1-dimensional factor structure of FAS scores, which was upheld using confirmatory factor analysis. FAS scores were also invariant across sex and there was no significant sex difference in scores. Construct validity was generally supported through significant associations with the additional measures included in the study. Incremental validity was also established insofar as functionality appreciation predicted self-esteem over-and-above the variance accounted for by other body image measures. The availability of the Malay FAS will be of use to scholars in Malaysia, but establishing cross-linguistic invariance will be an important next step

Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Abstract: Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers