Apalutamide plus Androgen Deprivation Therapy for Metastatic Castration-Sensitive Prostate Cancer: Analysis of Pain and Fatigue in the Phase 3 TITAN Study

PURPOSE: We performed an exploratory analysis of prostate cancer-related pain and fatigue on health-related quality of life in patients with metastatic castration-sensitive prostate cancer receiving apalutamide (240 mg/day) or placebo, with continuous androgen deprivation therapy (ADT), in the phase 3, randomized, double-blind, placebo controlled TITAN trial (NCT02489318). MATERIALS AND METHODS: Patient-reported outcomes for pain and fatigue were evaluated using the Brief Pain Inventory-Short Form and Brief Fatigue Inventory. Time to deterioration (TTD) was estimated by Kaplan-Meier method; hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards model. General estimating equations for logistic regression estimated treatment-related differences in the likelihood of worsening pain or fatigue. RESULTS: Compliance for completing the Brief Pain Inventory-Short Form and Brief Fatigue Inventory was high (96% to 97%) in the first year. Median followup times were similar between treatments (19 to 22 months). Median pain TTD was longer with apalutamide than placebo for "pain at its least in the last 24 hours" (28.7 vs 21.8 months, respectively; p=0.0146), "pain interfered with mood" (not estimable vs 22.4 months; p=0.0017), "pain interfered with walking ability" (28.7 vs 20.2 months; p=0.0027), "pain interfered with relations" (not estimable vs 23.0 months; p=0.0139) and "pain interfered with sleep" (28.7 vs 20.9 months; p=0.0167). Likelihood for fatigue and worsening fatigue were similar between groups. CONCLUSIONS: Patients with metastatic castration-sensitive prostate cancer receiving apalutamide plus ADT vs placebo plus ADT reported consistently favorable TTD of pain. No difference for change in fatigue was observed with apalutamide vs placebo

Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study

Background: In the phase 3 TITAN study, the addition of apalutamide to androgen deprivation therapy (ADT) significantly improved the primary endpoints of overall survival and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer. We aimed to assess health-related quality of life (HRQOL) in TITAN, including pain and fatigue. Methods: In this randomised, placebo-controlled, double-blind, phase 3 study, patients with metastatic castration-sensitive prostate cancer (defined as not receiving ADT at the time of metastatic disease progression) aged 18 years and older, receiving continuous ADT (selected at the investigator's discretion), and with an Eastern Cooperative Oncology Group performance status score of 0 or 1 were randomly assigned (1:1), using an interactive web response system, to receive oral apalutamide (four 60 mg tablets, once daily) or matching placebo. Previous localised disease treatment or previous docetaxel for metastatic castration-sensitive prostate cancer were allowed. Randomisation was stratified by Gleason score at diagnosis, region, and previous docetaxel treatment. Randomisation was done using randomly permuted blocks (block size of four). Investigators, research staff, sponsor study team, and patients were masked to the identities of test and control treatments. Patient-reported outcomes were prespecified exploratory endpoints and were the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EuroQoL 5D questionnaire 5 level (EQ-5D-5L). BPI and BFI were completed for 7 consecutive days (days −6 to 1 inclusive of each cycle visit), then at months 4, 8, and 12 in follow-up. FACT-P and EQ-5D-5L were completed during cycles 1–7, then every other cycle until the end of treatment, and at months 4, 8, and 12 in follow-up. Analyses were based on the intention-to-treat population. Missing patient-reported outcome assessments were calculated as the expected number of assessments for a visit minus the actual number of assessments received for that visit. For time-to-event endpoints, when median values could not be calculated because less than 50% of patients had degradation, 25th percentiles were compared. This study is registered with ClinicalTrials.gov, number NCT02489318, and is ongoing. Findings: Between Dec 9, 2015, and July 25, 2017, 1052 eligible patients were enrolled randomly assigned to apalutamide (n=525) or placebo (n=527). Data cutoff for this analysis of patient-reported outcomes was Nov 23, 2018. Median follow-up for time to pain-related endpoints ranged from 19·4 to 22·1 months. Patients were mostly asymptomatic at baseline: on the BPI-SF pain severity scale of 0–10, median pain scores (indicating worst pain in the past 24 h) were 1·14 (IQR 0–3·17) in the apalutamide group and 1·00 (0–2·86) in the placebo group, and median worst fatigue scores on the BFI were 1·29 (IQR 0–3·29) in the apalutamide group and 1·43 (0·14–3·14) in the placebo group. Patient experience of pain and fatigue (intensity and interference) did not differ between the groups for the duration of treatment. Median time to worst pain intensity progression was 19·09 months (95% CI 11·04–not reached) in the apalutamide group versus 11·99 months (8·28–18·46) in the placebo group (HR 0·89 [95% CI 0·75–1·06]; p=0·20). Median time to pain interference progression was not reached in either group (95% CI 28·58–not reached in the apalutamide group; not reached–not reached in the placebo group). 25th percentiles for time to pain interference progression were 9·17 months (5·55–11·96) in the apalutamide group and 6·24 months (4·63–7·43) in the placebo group (HR 0·90 [95% CI 0·73–1·10]; p=0·29). FACT-P total scores and EQ-5D-5L data showed preservation of HRQOL in both groups. The median time to deterioration as determined by FACT-P total score was 8·87 months (95% CI 4·70–11·10) in the apalutamide group and 9·23 months (7·39–12·91) in the placebo group (HR 1·02 [95% CI 0·85–1·22]; p=0·85). Interpretation: Apalutamide with ADT is a well-tolerated and effective option for men with metastatic castration-sensitive prostate cancer. The combination significantly improves survival outcomes compared with ADT alone while maintaining HRQOL despite additive androgen blockade. Funding: Janssen Research & Development

World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions.

BACKGROUND: To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions. METHODS: In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40-80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance. FINDINGS: Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0·685 (95% CI 0·629-0·741) to 0·833 (0·783-0·882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a 60-year-old male smoker without diabetes and with systolic blood pressure of 140 mm Hg and total cholesterol of 5 mmol/L ranged from 11% in Andean Latin America to 30% in central Asia. When applied to data from 79 countries (mostly low-income and middle-income countries), the proportion of individuals aged 40-64 years estimated to be at greater than 20% risk ranged from less than 1% in Uganda to more than 16% in Egypt. INTERPRETATION: We have derived, calibrated, and validated new WHO risk prediction models to estimate cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide. FUNDING: World Health Organization, British Heart Foundation (BHF), BHF Cambridge Centre for Research Excellence, UK Medical Research Council, and National Institute for Health Research

Measurement of the total cross section and ρ -parameter from elastic scattering in pp collisions at √s=13 TeV with the ATLAS detector

In a special run of the LHC with β⋆=2.5 km, proton–proton elastic-scattering events were recorded at s√=13 TeV with an integrated luminosity of 340 μb−1 using the ALFA subdetector of ATLAS in 2016. The elastic cross section was measured differentially in the Mandelstam t variable in the range from −t=2.5⋅10−4 GeV2 to −t=0.46 GeV2 using 6.9 million elastic-scattering candidates. This paper presents measurements of the total cross section σtot, parameters of the nuclear slope, and the ρ-parameter defined as the ratio of the real part to the imaginary part of the elastic-scattering amplitude in the limit t→0. These parameters are determined from a fit to the differential elastic cross section using the optical theorem and different parameterizations of the t-dependence. The results for σtot and ρ are σtot(pp→X)=104.7±1.1 mb ,ρ=0.098±0.011. The uncertainty in σtot is dominated by the luminosity measurement, and in ρ by imperfect knowledge of the detector alignment and by modelling of the nuclear amplitude.publishedVersio

Search for new heavy resonances decaying to WW, WZ, ZZ, WH, or ZH boson pairs in the all-jets final state in proton-proton collisions at s=13TeV

A search for new heavy resonances decaying to WW, WZ, ZZ, WH, or ZH boson pairs in the all-jets final state is presented. The analysis is based on proton-proton collision data recorded by the CMS detector in 2016–2018 at a centre-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 138 fb−1. The search is sensitive to resonances with masses between 1.3 and 6TeV, decaying to bosons that are highly Lorentz-boosted such that each of the bosons forms a single large-radius jet. Machine learning techniques are employed to identify such jets. No significant excess over the estimated standard model background is observed. A maximum local significance of 3.6 standard deviations, corresponding to a global significance of 2.3 standard deviations, is observed at masses of 2.1 and 2.9 TeV. In a heavy vector triplet model, spin-1 Z′ and W′ resonances with masses below 4.8TeV are excluded at the 95% confidence level (CL). These limits are the most stringent to date. In a bulk graviton model, spin-2 gravitons and spin-0 radions with masses below 1.4 and 2.7TeV, respectively, are excluded at 95% CL. Production of heavy resonances through vector boson fusion is constrained with upper cross section limits at 95% CL as low as 0.1 fb. © 2023 The Author(s

Search for a heavy composite Majorana neutrino in events with dilepton signatures from proton-proton collisions at √s=13 Tev

Results are presented of a search for a heavy Majorana neutrino N ⠃ decaying into two same-flavor leptons ⠃ (electrons or muons) and a quark-pair jet. A model is considered in which the N ⠃ is an excited neutrino in a compositeness scenario. The analysis is performed using a sample of proton-proton collisions at & RADIC;s = 13 TeV recorded by the CMS experiment at the CERN LHC, corresponding to an integrated luminosity of 138 fb-1. The data are found to be in agreement with the standard model prediction. For the process in which the N ⠃ is produced in association with a lepton, followed by the decay of the N ⠃ to a same-flavor lepton and a quark pair, an upper limit at 95% confidence level on the product of the cross section and branching fraction is obtained as a function of the N ⠃ mass mN ⠃ and the compositeness scale ⠄. For this model the data exclude the existence of Ne (N & mu;) for mN ⠃ below 6.0 (6.1) TeV, at the limit where mN ⠃ is equal to ⠄. For mN ⠃ N 1 TeV, values of ⠄ less than 20 (23) TeV are excluded. These results represent a considerable improvement in sensitivity, covering a larger parameter space than previous searches in pp collisions at 13 TeV.& COPY; 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons .org /licenses /by /4 .0/). Funded by SCOAP3

Measurement of prompt D0^{0} and D‾\overline{D}0^{0} meson azimuthal anisotropy and search for strong electric fields in PbPb collisions at root SNN\sqrt{S_{NN}} = 5.02 TeV

The strong Coulomb field created in ultrarelativistic heavy ion collisions is expected to produce a rapiditydependent difference (Av2) in the second Fourier coefficient of the azimuthal distribution (elliptic flow, v2) between D0 (uc) and D0 (uc) mesons. Motivated by the search for evidence of this field, the CMS detector at the LHC is used to perform the first measurement of Av2. The rapidity-averaged value is found to be (Av2) = 0.001 ? 0.001 (stat)? 0.003 (syst) in PbPb collisions at ?sNN = 5.02 TeV. In addition, the influence of the collision geometry is explored by measuring the D0 and D0mesons v2 and triangular flow coefficient (v3) as functions of rapidity, transverse momentum (pT), and event centrality (a measure of the overlap of the two Pb nuclei). A clear centrality dependence of prompt D0 meson v2 values is observed, while the v3 is largely independent of centrality. These trends are consistent with expectations of flow driven by the initial-state geometry. ? 2021 The Author. Published by Elsevier B.V. This is an open access article under the CC BY licens

Observation of electroweak production of Wγ with two jets in proton-proton collisions at √s = 13 TeV

A first observation is presented for the electroweak production of a W boson, a photon, and two jets in proton-proton collisions. The W boson decays are selected by requiring one identified electron or muon and an imbalance in transverse momentum. The two jets are required to have a high dijet mass and a large separation in pseudorapidity. The measurement is based on data collected with the CMS detector at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb$^{-1}$. The observed (expected) significance for this process is 4.9 (4.6) standard deviations. After combining with previously reported CMS results at 8 TeV, the observed (expected) significance is 5.3 (4.8) standard deviations. The cross section for the electroweak W$_{γjj}$ production in a restricted fiducial region is measured as 20.4 +/- 4.5 fb and the total cross section for W$_{γ}$ production in association with 2 jets in the same fiducial region is 108 +/- 16 fb. All results are in good agreement with recent theoretical predictions. Constraints are placed on anomalous quartic gauge couplings in terms of dimension-8 effective field theory operators

Long COVID and cardiovascular disease: a prospective cohort study

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known. Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors. Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health. Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86). Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need