BACKGROUND:Diffuse gastric cancer (DGC) is the most common manifestation in germline CTNNA1 variant carriers, with one study estimating a 49-57% lifetime risk by age 80. Knowledge on CTNNA1-associated hereditary diffuse gastric cancer (HDGC), loss-of-function mechanisms, variant-type causality, disease spectrum and cancer risks remains scarce. OBJECTIVE:Explore CTNNA1 genotype-phenotype associations to improve genetic testing criteria, surveillance and risk-reduction recommendations for carriers. DESIGN:Using molecular, clinical and population data from 1308 individuals from 351 CTNNA1-variant carrier families and 37 428 non-carriers from European and American ancestries, we analysed genotype-phenotype associations with multivariable logistic regression. With CRISPR/Cas9 CTNNA1-knockout gastric cancer (GC) cells and CTNNA1-humanised Drosophila, we assessed CTNNA1-associated loss-of-function mechanisms. RESULTS:CTNNA1-truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD), and DGCs from germline CTNNA1-truncating carriers lose αE-catenin. These transcripts are non-functional in Drosophila, in contrast to non-truncating transcripts. DGC risk is eightfold higher in truncating, compared with non-truncating carriers. The risk of GC and lobular breast cancer (LBC) development in CTNNA1-truncating variant carriers is fivefold and eightfold lower than in CDH1 pathogenic/likely pathogenic variant carriers, respectively. Compared with wild-type individuals, GC risk is 7-fold higher in CTNNA1-truncating and 38-fold higher in CDH1-truncating variant carriers. LBC is recurrent among CTNNA1-truncating carriers, some lacking HDGC criteria. Simplification of previous criteria for CTNNA1 genetic testing produced the 'Porto' criteria, which increased CTNNA1-carrier families' pick-up rate by 9%, without performance loss compared with the HDGC 2020 clinical guidelines. Macular dystrophy patterned-2 was positively associated with non-truncating variants, specifically in the αE-catenin M-fragment. CONCLUSION:We provide compelling evidence supporting that CTNNA1-truncating variants positively associate with DGC and LBC, and NMD as the pathophysiological mechanism leading to CTNNA1 downregulation. We demonstrate that compared with CDH1, CTNNA1 is a moderate penetrance HDGC gene. This new knowledge is essential to define surveillance and/or prophylactic measures for CTNNA1-carrier individuals and families.
BACKGROUND:There is a lack of contemporary studies addressing the prevalence rates and antifungal susceptibility of bloodstream infections (BSI) caused by rare yeasts (RY) from the Saccharomycotina subphylum. OBJECTIVES:This 16-year multicentre study (2007-2023) aimed to assess the prevalence and antifungal susceptibility of rare yeasts isolated from BSIs in 28 Brazilian tertiary care hospitals. METHODS:Yeasts from the Saccharomycotina subphylum, excluding common Candida species and Basidiomycota, were selected from BSI episodes. Species were identified using proteomics and molecular methods. Antifungal susceptibility testing was performed by EUCAST broth microdilution. RESULTS:Among 2655 BSI episodes, 100 (3.76%) involved rare yeasts. Prevalence showed a slight, non-significant increase from 3.16% (2007-2015) to 4.17% (2016-2023; p = 0.183). A total of 11 genera and 20 species were identified, with Clavispora lusitaniae (20%), Wickerhamomyces anomalus (16%), Candida haemulonii (14%) and Candida duobushaemulonii (12%) being the most frequent species. Eight species, including Pichia kluyveri and Kodamaea ohmeri, appeared only in the latter period. Most rare yeasts showed low MICs to amphotericin B and anidulafungin, except for Clavispora lusitaniae, Candida haemulonii and Candida duobushaemulonii, which were less susceptible to amphotericin B. Wickerhamomyces anomalus and Candida duobushaemulonii also showed reduced susceptibility to fluconazole. CONCLUSIONS:This study provides valuable insights into the prevalence rates, species distribution and antifungal susceptibility of rare yeasts causing BSIs in tertiary care hospitals. Our findings highlight the need for continuous surveillance, incorporation of new diagnostic and tailored therapeutic strategies to mitigate morbidity and mortality due to invasive infections caused by emerging fungal pathogens.
Purpose Conventional multiparametric magnetic resonance imaging (mpMRI) parameters have limited ability to identify prostate cancer (PCa) patients harboring BRCA1/2 mutations. We investigated whether radiomic features extracted from apparent diffusion coefficient (ADC) maps can non-invasively discriminate BRCA-mutated from doubly negative (BRCA−) PCa patients. Materials and Methods This prospective cohort study with retrospective imaging analysis included 107 PCa patients (58 BRCA-positive [BRCA+], confirmed by germline and/or somatic testing; 49 doubly negative controls [BRCA−]) at a quaternary referral center (2021–2024). Patients with a negative result in one genetic pathway who were not tested in the other were excluded. Conventional mpMRI parameters (lesion size, mean ADC, zonal location, PI-RADS category, prostate volume) were compared between groups. Radiomic features were extracted from ADC maps using PyRadiomics (107 features; 33 retained after morphological robustness filtering). Twenty-five machine-learning algorithm families were evaluated with stratified k-fold cross-validation. The primary endpoint was area under the precision-recall curve (PR-AUC); secondary endpoint was ROC-AUC. Results No significant differences were found in conventional mpMRI parameters between BRCA + and BRCA− groups (mean ADC: 0.631 ± 0.153 vs. 0.675 ± 0.177 × 10⁻³ mm²/s, p = 0.19; lesion size, PI-RADS, zonal location: all p > 0.10). For radiomic analysis (n = 98; 51 BRCA+, 47 BRCA−), the best overall model was CatBoost applied to robustness-filtered radiomic features (PR-AUC = 0.6936; ROC-AUC = 0.6612). Restricting analysis to lesions ≥ 500 voxels (n = 31) improved performance (PR-AUC = 0.778; ROC-AUC = 0.615). Conclusion Conventional mpMRI parameters cannot distinguish BRCA-mutated from non-mutated PCa. ADC map radiomics combined with machine learning demonstrated intermediate yet promising discriminatory performance, suggesting that quantitative imaging features may capture biologically relevant information associated with BRCA mutational status. Larger multicenter validation studies are warranted. Clinical trial number : not applicable.
Background The primary analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 1333/PEACE-3 study demonstrated that enzalutamide plus radium-223 (Ra223) improved radiological progression-free survival (rPFS) compared with enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint was rPFS, while overall survival (OS) was a key secondary endpoint. Interim OS results were reported at the time of primary analysis. Here, we report the final OS analysis. Patients and methods From November 2015 to March 2023, 446 patients were randomly assigned to receive enzalutamide alone or enzalutamide combined with six cycles of Ra223. Co-administration of bone-protecting agents (BPAs) became mandatory for all patients from March 2018. Final analysis of OS was triggered on 1 May 2025. Results With a median follow-up of 58 months and 317 reported deaths, the hazard ratio (HR) was 0.76 [95% confidence interval (CI) 0.60-0.96, P = 0.0096] for OS in favor of the enzalutamide + Ra223 arm, reaching the predefined level of statistical significance of <0.0248. Median OS was 32.6 months (95% CI 29.3-38.2 months) in the enzalutamide arm (n = 224) and 38.2 months (95% CI 33.1-44.8 months) in the combination arm (n = 222). The HR for rPFS was 0.71 (95% CI 0.57-0.89). Grade ≥3 treatment-emergent adverse events (TEAEs) increased from 57.6% to 69.3% in the combination arm, as did treatment-related grade ≥3 TEAEs (18.8% versus 28.9%), with the most frequent being hypertension. Conclusions The final analysis of this study confirmed that the combination of enzalutamide with Ra223 significantly improved not only rPFS but also OS as first-line therapy for mCRPC versus enzalutamide alone. Co-administration of a BPA is required to reduce skeletal complications.
