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.
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.
Objetivo: Relatar um caso raro de sarcoma histiocítico (SH) com apresentação cutânea seguida de disseminação linfonodal e pulmonar, abordando a dificuldade de se proceder ao diagnóstico e a importância da imuno-histoquímica (IHQ) nesse contexto. Relato de caso: Paciente feminina, 54 anos, em 2021 notou o aparecimento de hematomas em membro inferior direito e evoluiu com surgimento de massa em membro inferior contralateral. A ressonância magnética realizada suscitou a hipótese de sarcoma. Solicitada a ressecção cirúrgica (8,5 x 4,4 x 4,8 cm) e o anatomopatológico, confirmando o diagnóstico de sarcoma histiocítico e realizado radioterapia. Após quatro meses, houve progressão da doença, com acometimento nodal inguinal esquerdo, procedendo-se à ressecção nodal. Após dois anos, a paciente evoluiu com nódulo em lobo pulmonar inferior direito, com captação importante em PET-CT. A biópsia dessa lesão evidenciou células atípicas suspeitas para neoplasia em meio a infiltrado linfoplasmocitário, em associação com IHQ com CD68, CD163 e CD4 positivos, compatíveis com recidiva de sarcoma histiocítico e realizado lobectomia inferior direita. Atualmente, a paciente apresentou novos nódulos pleurais em pulmão direito, sendo encaminhada para a radiointervenção para nova biópsia por suspeita de recidiva. Discussão: O sarcoma histiocítico consiste em uma neoplasia maligna de origem histiocítica/dendrítica, rara e de difícil diagnóstico, com etiologia indefinida. Acomete mais frequentemente homens, em qualquer faixa etária. Sua manifestação clínica é variável, de forma localizada ou disseminada, e com achado histológico de células histiocitoides, fundo linfoplasmocitário e necrose. A IHQ é essencial ao diagnóstico, auxiliando no diagnóstico diferencial e na confirmação dos marcadores, sendo expressos CD68, CD163, PU.1, além de CD31, CD4 e CD45RO. O diagnóstico diferencial oncológico deve ser feito com linfomas, carcinomas pouco diferenciados e melanomas. No caso relatado, o diagnóstico apresentava desafios por mimetizar quadros vasculares (hematomas pós-trombose) e linfomas (padrão histológico com infiltrado linfoplasmocitário). Ademais, a recidiva da doença em sítio pulmonar apontava para a necessidade de novo estudo imuno-histoquímico. Conclusão: O sarcoma histiocítico é, portanto, neoplasia rara e de difícil diagnóstico, devido à sobreposição com outras condições clínicas. A importância da IHQ está consolidada na definição diagnóstica e, mesmo em caso de recidiva, é indispensável solicitá-la, haja vista a variedade de diagnósticos diferenciais possíveis e a baixa prevalência do SH.
Background: Myelodysplastic neoplasms (MDS) comprise a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, ineffective hematopoiesis, and a variable risk of progression to acute myeloid leukemia. Although conventional cytogenetic abnormalities are widely used for prognostic stratification, a substantial proportion of patients present with normal karyotypes, suggesting the involvement of submicroscopic genomic alterations. Aim: To evaluate the genomic profile of copy number variations (CNVs) in Brazilian patients with MDS and investigate their associations with clinical, cytogenetic, and ancestry-related characteristics. Materials and methods: This retro-prospective study included 94 patients diagnosed with MDS at a tertiary referral center in Northeastern Brazil and 94 cancer-free controls. CNVs were identified using high-density SNP microarrays (Axiom™ Precision Medicine Diversity Array), covering approximately 870,000 markers. Analyses included genomic burden assessment, chromosomal distribution, clinicopathological associations, and ancestry inference using ADMIXTURE. Quality control filters were applied to retain high-confidence CNVs, including exclusion of diploid regions, events < 10 kb, segments supported by fewer than 20 markers, and low-intensity signals. Results: A total of 44,072 CNVs were identified across the evaluated autosomal chromosomes. Patients with MDS exhibited a significantly higher overall CNV burden than controls (p = 0.01), mainly driven by an increased number of copy number gains (p = 0.01). CNVs in MDS patients also displayed significantly larger genomic sizes (p < 0.05). Copy number gains were more frequently observed on chromosomes 1, 3, 6, 7, 12, 14, 15, 16, 17, 19, and 22, whereas copy number losses predominated on chromosomes 2, 5, 7, and 18. The presence of dysmegakaryopoiesis was associated with a higher total CNV burden (p = 0.019) and increased copy number gains (p = 0.011). Patients with abnormal karyotypes exhibited a greater number of copy number losses (p = 0.002) and larger CNV sizes (p = 0.001). Among the WHO 2022 MDS subtypes, cases harboring del(5q) showed the highest burden of CNVs and genomic losses. Individuals with intermediate levels of Asian ancestry presented a higher overall CNV burden compared with those with low Asian ancestry (p = 0.046). However, no significant differences in ancestry proportions were observed between patients with MDS and controls. Discussion: These findings demonstrate increased genomic instability in MDS, with non-random CNV distribution and significant associations with morphological and cytogenetic features. Collectively, the data support CNV burden as a marker of genomic complexity and suggest that genome-wide CNV profiling may complement conventional approaches for biological characterization and risk assessment in MDS. Conclusion: Brazilian patients with MDS exhibit a significantly increased CNV burden and larger genomic alterations, with specific chromosomal patterns and associations with clinical and cytogenetic features. Comprehensive genomic profiling may contribute to the identification of novel diagnostic and prognostic biomarkers in MDS. Funding: This study was supported by the National Institute of Science and Technology (INCT), through the INCT T-Bio² – Translational Biodiscovery and Biomodels (grant no. 408566/2024-8).
