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
Slenders, L.; Landsmeer, L.P.L.; Cui, K.; Depuydt, M.A.C.; Verwer, M.; Mekke, J.; ... ; Laan, S.W. van den, Mokry, M. 2021
Genome-wide association studies (GWASs) have discovered hundreds of common genetic variants for atherosclerotic disease and cardiovascular risk factors. The translation of susceptibility loci into... Show moreGenome-wide association studies (GWASs) have discovered hundreds of common genetic variants for atherosclerotic disease and cardiovascular risk factors. The translation of susceptibility loci into biological mechanisms and targets for drug discovery remains challenging. Intersecting genetic and gene expression data has led to the identification of candidate genes. However, previously studied tissues are often non-diseased and heterogeneous in cell composition, hindering accurate candidate prioritization. Therefore, we analysed single-cell transcriptomics from atherosclerotic plaques for cell-type-specific expression to identify atherosclerosis-associated candidate gene-cell pairs.\nWe applied gene-based analyses using GWAS summary statistics from 46 atherosclerotic and cardiovascular disease, risk factors, and other traits. We then intersected these candidates with single-cell RNA sequencing (scRNA-seq) data to identify genes specific for individual cell (sub)populations in atherosclerotic plaques. The coronary artery disease (CAD) loci demonstrated a prominent signal in plaque smooth muscle cells (SMCs) (SKI, KANK2, and SORT1) P-adj. = 0.0012, and endothelial cells (ECs) (SLC44A1, ATP2B1) P-adj. = 0.0011. Finally, we used liver-derived scRNA-seq data and showed hepatocyte-specific enrichment of genes involved in serum lipid levels.\nWe discovered novel and known gene-cell pairs pointing to new biological mechanisms of atherosclerotic disease. We highlight that loci associated with CAD reveal prominent association levels in mainly plaque SMC and EC populations. We present an intuitive single-cell transcriptomics-driven workflow rooted in human large-scale genetic studies to identify putative candidate genes and affected cells associated with cardiovascular traits. Collectively, our workflow allows for the identification of cell-specific targets relevant for atherosclerosis and can be universally applied to other complex genetic diseases and traits. Show less
Background: Accurate on-line assessments of vessel dimensions are of utmost importance for selecting the appropriate stent size in coronary interventions. Recently a new three-dimensional... Show moreBackground: Accurate on-line assessments of vessel dimensions are of utmost importance for selecting the appropriate stent size in coronary interventions. Recently a new three-dimensional quantitative coronary angiography (3D QCA) analytical software package was developed to accurately assess the vessel dimensions for the planning and guidance of such coronary interventions. This study aimed to validate the 3D QCA software package for assessing arterial segment length by comparing with intravascular ultrasound (IVUS). In addition, the difference in the two measurements from 3D QCA and IVUS for curved segments was studied. Methods: A retrospective study including 20 patients undergoing both coronary angiography and IVUS examinations of the left coronary artery was set up for the validation. The same vessel segments of interest between proximal and distal markers were identified and measured on both angiographic and IVUS images, by the 3D QCA software and by a quantitative IVUS software package, respectively. In addition, the curvature of each of the segments of interest was assessed and the correlation between the accumulated curvature of the segment and the difference in segment lengths measured from the two imaging modalities was analyzed. Results: 37 vessel segments of interest were identified from both angiographic and IVUS images. The 3D QCA segment length was slightly longer than the IVUS segment length (15.42 +/- 6.02 mm vs. 15.12 +/- 5.81 mm, P = 0.040). The linear correlation of the two measurements was: 3D QCA Length = -0.09 + 1.03 x IVUS Length (r(2) = 0.98, P < 0.001). Bland-Altman plot showed that the difference in the two measurements was not correlated with the average of the two measurements (P = 0.141), but with the accumulated curvature of the segment (P = 0.015). After refining the difference by the correlation, the average difference of the two measurements decreased from 0.30 +/- 0.86 mm (P = 0.040) to 0.00 +/- 0.78 mm (P = 0.977). Conclusions: The 3D QCA software package can accurately assess the actual arterial segment length. The difference in segment lengths measured from 3D CICA and IVUS was correlated with the accumulated curvature of the segment. (C) 2010 Wiley-Liss, Inc. Show less
