ABSTRACT Intrinsic biological processes and carcinogenic exposures leave cumulative DNA methylation (DNAme) imprints in epithelial cells. These changes reflect cellular composition, replicative/mitotic age and impaired differentiation capacity, and arise long before clinically detectable cancer, consistent with the concept of field cancerisation. Importantly, such epigenetic alterations are not confined to the tissue of origin but extend to anatomically distant epithelia that share developmental lineage and/or carcinogen exposure/susceptibility, thereby serving as field defect indicators. Notably, these signatures are dynamic and responsive to preventive interventions, enabling both risk assessment and real‐time monitoring of prevention efficacy. The epithelial epigenome is thus emerging as a unified, minimally invasive platform for personalised, multi‐cancer prevention.
ABSTRACT The extent and direction of the impact of COVID‐19 pandemic disruptions on cancer mortality remain unclear. We assessed observed versus expected cancer mortality from 2020 to 2023 across 54 countries in 14 regions, by cancer type. Using WHO Mortality Database, we calculated age‐standardized mortality rates (ASMRs) for adults (≥ 20 years) from all cancers combined and specifically for lung, pancreatic, breast, and leukemia. Expected ASMRs for 2020–2023 were projected from 2015 to 2019 using Estimated Annual Percent Change. Rate ratios (RRs) of observed versus expected ASMRs were stratified by year, age group, cancer type, country, and region. The analysis included over 2.3 million annual cancer deaths across 54 countries. Lung cancer was the leading cause of death in 45 countries. Eastern Europe had the highest mortality in 2020–2023, with Hungary reporting the highest ASMR (222.6/100,000). Overall, observed mortality was lower than expected (RR < 1). Differences were modest in 2020 but widened by 2023. The largest discrepancies were for breast cancer (RR 0.62–1.19) and leukemia (0.67–1.18), while lung (0.87–1.16) and pancreatic cancers (0.91–1.20) showed smaller differences. Regional variation was notable, with Western Asia showing the widest difference from expected. Differences in expected mortality were limited for poor‐prognosis cancers, while breast cancer and leukemia were more affected during long‐term healthcare disruptions. Regional disparities illustrate the negative impact of compounding crises on cancer mortality and underscore the need for resilient systems to protect cancer care during emergencies.
Dedifferentiated liposarcoma (DDLPS) is a rare soft tissue sarcoma with limited real-world epidemiologic data. This nationwide retrospective study describes the epidemiology, management, and outcomes of DDLPS in France using the NETSARC+ national sarcoma registry. A total of 1451 adults with histologically confirmed DDLPS diagnosed between 2010 and 2021 across 14 expert centers were included. The median age at diagnosis was 67 years, with a male predominance (M/F ratio 1.84). The retroperitoneum was the most frequent site (51.6%), and tumors were large (median 150 mm) and FNCLCC Grade 2-3 in 82.6%. MDM2 amplification was confirmed in 97.4% of tested cases. Surgery was performed in 91% of localized cases and was the strongest independent prognostic factor for overall survival (OS). After a median follow-up of 78.4 months, median OS was 90.3 months (95% CI 82.7-101.0). Among metastatic patients, the median first-line progression-free survival (PFS1) was 4.1 months, and second-line PFS (PFS2) was 3.1 months, with stable disease as the most common best response (40.6%) and 12% of partial response. Doxorubicin-based chemotherapy remained the predominant systemic treatment but yielded only modest activity, with no difference compared to other regimens in terms of response rate. Independent predictors of improved OS included younger age, smaller tumor size, good performance status, lower grade and absence of metastasis at diagnosis. This large, population-based study provides the most comprehensive real-world characterization of DDLPS in France, validating known prognostic factors, emphasizing the central role of surgery, and underscoring the persistent and unmet need for more effective systemic therapies.
Intraductal carcinoma of the prostate (IDC-P) has been associated with increased homologous recombination deficiency (HRD). We evaluated the association between IDC-P and the efficacy of olaparib plus novel hormonal therapy (NHT) in metastatic castration-resistant prostate cancer (mCRPC) after progression on prior NHT. A total of 64 consecutive patients were analyzed, including 33 with IDC-P and 31 with prostate adenocarcinoma (PAC). An external validation cohort of 36 patients from two additional centers was also included. Primary outcomes were progression-free survival (PFS), while treatment-change free survival (TFS), prostate-specific antigen response, overall survival, and adverse events were additionally assessed. After a median follow-up of 35.0 months, IDC-P was associated with longer PFS and TFS than PAC (PFS, 6.2 vs. 3.0 months; TFS, 10.0 vs. 6.3 months; both p < 0.01). This association remained significant in patients with BRCA1/2 mutations and after multivariable adjustment for BRCA1/2 mutation status. In the validation cohort, IDC-P status was associated with longer PFS (6.1 vs. 3.1 months, p = 0.02). In an independent cohort of 187 patients with prostate cancer, IDC-P was associated with higher HRD scores than PAC in the BRCA1/2-mutated subgroup, with a nonsignificant trend in the BRCA1/2-wild-type subgroup, suggesting a possible biological context for the observed outcome association. These findings suggest that IDC-P may serve as a practical pathological biomarker associated with improved outcomes following PARP inhibitor-based therapy in mCRPC, although further large-scale prospective validation is warranted.
