Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for... Show moreBackground: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Delta 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Delta 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Delta 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 35 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDES and DDFS with no new safety signals. Show less
Objective This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods We carried out a genome-wide association study,... Show moreObjective This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 x 10(-17), odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 x 10(-17), OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 x 10(-8), OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 x 10(-8), OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021 Show less
BACKGROUNDPoly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce... Show moreBACKGROUNDPoly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer.METHODSWe conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival.RESULTSA total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P=0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest.CONCLUSIONSAmong patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. Show less
Improved data on biosphere-atmosphere exchange are fundamental to understanding the production and fate of ammonia (NH3) in the atmosphere. The GRAMINAE Integrated Experiment combined novel... Show moreImproved data on biosphere-atmosphere exchange are fundamental to understanding the production and fate of ammonia (NH3) in the atmosphere. The GRAMINAE Integrated Experiment combined novel measurement and modelling approaches to provide the most comprehensive analysis of the interactions to date. Major inter-comparisons of micrometeorological parameters and NH3 flux measurements using the aerodynamic gradient method and relaxed eddy accumulation (REA) were conducted. These showed close agreement, though the REA systems proved insufficiently precise to investigate vertical flux divergence. Grassland management had a large effect on fluxes: emissions increased after grass cutting (-50 to 700 ng m(-2) s(-1) NH3) and after N-fertilization (0 to 3800 ng m(-2) s(-1)) compared with before the cut (-60 to 40 ng m(-2) s(-1)).Effects of advection and air chemistry were investigated using horizontal NH3 profiles, acid gas and particle flux measurements. Inverse modelling of NH3 emission from an experimental farm agreed closely with inventory estimates, while advection errors were used to correct measured grassland fluxes. Advection effects were caused both by the farm and by emissions from the field, with an inverse dispersion-deposition model providing a reliable new approach to estimate net NH3 fluxes. Effects of aerosol chemistry on net NH3 fluxes were small, while the measurements allowed NH3-induced particle growth rates to be calculated and aerosol fluxes to be corrected.Bioassays estimated the emission potential I" = [NH4+]/[H+] for different plant pools, with the apoplast having the smallest values (30-1000). The main within-canopy sources of NH3 emission appeared to be leaf litter and the soil surface, with I" up to 3 million and 300 000, respectively. Cuvette and within-canopy analyses confirmed the role of leaf litter NH3 emission, which, prior to cutting, was mostly recaptured within the canopy.Measured ammonia fluxes were compared with three models: an ecosystem model (PaSim), a soil vegetation atmosphere transfer model (SURFATM-NH3) and a dynamic leaf chemistry model (DCC model). The different models each reproduced the main temporal dynamics in the flux, highlighting the importance of canopy temperature dynamics (Surfatm-NH3), interactions with ecosystem nitrogen cycling (PaSim) and the role of leaf surface chemistry (DCC model). Overall, net above-canopy fluxes were mostly determined by stomatal and cuticular uptake (before the cut), leaf litter emissions (after the cut) and fertilizer and litter emissions (after fertilization). The dynamics of ammonia emission from leaf litter are identified as a priority for future research. Show less
