Nicolò Lentini

Background Over the past decades, cancer mortality has declined in many high-income countries owing to reductions in exposure to tobacco and other risk factors, screening programs, and advances in diagnosis and treatment. However, ongoing changes in environmental, behavioral, and metabolic risk factors continue to reshape the epidemiology of cancer. Objectives To provide a comprehensive assessment of long-term cancer incidence and mortality trends in Italy and investigate cohort patterns through age-period-cohort (APC) analyses. Methods We used certified mortality data for the period 1980-2023 from the World Health Organization and the Italian National Institute of Statistics databases, incidence data for 1995-2018 from the European Cancer Information System. We computed age-standardized mortality rates (ASMRs) and age-standardized incidence rates (ASIRs) using the Segi-Doll world standard population. We described long-term trends using locally estimated scatterplot smoothing (LOESS) regression. We quantified overall percentage changes between 2023-2010 for mortality and between 2018-2008 for incidence, with 95% confidence intervals (CI) derived from a parametric bootstrap assuming Poisson-distributed counts. We performed APC analyses using generalized additive models with a quasi-Poisson specification. Age, period, and cohort effects were modeled using cubic regression splines, allowing flexible estimation of nonlinear temporal patterns while addressing the identifiability problem inherent to APC models. Results Between 2010 and 2023, overall mortality declined by 25.5% (95%CI: -26.3%; -24.6%) in males (to 103.5/100,000) and 13.9% (95%CI: -14.9%; -12.7%) in females (to 71.4/100,000), with major reductions for stomach (~35%), lung (~30%) (except for a 15.4% increase in females aged 50+), and colorectal cancers (~33%). Mortality increased for testicular (8.3%), uterine (2.8%), and pancreatic cancer in both sexes (2.0% males, 6.9% females). Among young adults (25-49 years), mortality from all cancers declined by 22.1% (95%CI: -26.5%; -17.6%) in males and 19.2% (95%CI: -23.2%; -14.9%) in females but increased in testicular (36.6%), and uterine cancer (16.6%). In this age group pancreatic cancer decreased by 21.1%, whereas it remained stable in males (2.0%). APC analyses showed declining cohort-specific risks for most cancers among cohorts born after approximately 1925. Pancreatic cancer exhibited largely stable cohort risks, whereas female lung cancer risk increased up to the 1960 birth cohort before declining in more recent generations. Between 2008 and 2018, overall cancer incidence decreased by 10.9% (95%CI: -11.8%; -10.0%) in males (to 305.7/100,000) but increased by 2.9% (95%CI: 2.0%; 4.1%) in females (to 273.7/100,000), with rising trends for skin (~70%), thyroid (~25%), testicular (24.2%), and lung cancer in females aged 50+ (27.2%). Rates were stable for pancreatic cancer (0.3% in males, 6.7% in females) and increased modestly for breast cancer (3.9%). Among young adults, incidence increased in both males by (3.6%, 95%CI: -0.4%; 7.7%) and females (10.3%, 95%CI: 7.0%; 13.3%). Conclusions Cancer mortality in Italy has declined substantially over recent decades, reflecting the combined effects of smoking cessation in men, screening, and therapeutic advances. Nevertheless, less favorable trends persist for selected cancers, particularly pancreatic cancer and lung cancer among older women. The increasing incidence of cancers associated with metabolic, environmental, and lifestyle-related factors highlights emerging public health challenges.

Background: Cancer screening programmes apply uniform criteria irrespective of inherited risk. Polygenic risk scores (PRSs) have been proposed as a promising tool to stratify individual cancer risk and tailor screening strategies. However, whether PRS-informed strategies improve health outcomes compared with current practices remains uncertain. We aimed to synthesise the available evidence on the projected clinical utility of PRS-stratified cancer screening across six malignancies.Methods: We searched PubMed, Scopus, and Web of Science from inception to March 15, 2026, for studies evaluating PRS-stratified screening for breast, colorectal, prostate, lung, gastric, or cervical cancer. Eligible outcomes included cancer-specific mortality, life-years gained (LYG), quality-adjusted life-years (QALYs), overdiagnosis, and false-positive rates. Risk of bias was assessed using the ISPOR-SMDM checklist for modelling studies and ROBINS-I for observational studies. Certainty of evidence was appraised using the GRADE framework.Findings: Of 8,454 records identified, 25 studies were included (22 decision-analytic modelling studies, 3 observational studies) covering five malignancies; no eligible studies were identified for cervical cancer. PRS-stratified strategies were associated with improvements in QALYs for breast, colorectal, gastric, and lung cancer, whereas results for prostate cancer were heterogeneous. Mortality reductions were observed for colorectal, gastric, and lung cancer, although evidence for the latter two rested on single studies. For breast cancer, mortality outcomes were inconsistent and dependent on comparator intensity. For prostate cancer, the principal benefit was a reduction in overdiagnosis rather than mortality improvement. Across all cancer sites, the absolute magnitude of incremental benefit over non-stratified screening was modest. Harms increased in high-risk groups receiving intensified surveillance. The certainty of evidence was rated very low for all outcomes across all cancer types, driven by serious risk of bias and very serious indirectness, reflecting limited transferability across populations and healthcare systems.Interpretation: PRS-stratified screening shows consistent but modest potential to improve the efficiency of cancer screening, particularly for breast, colorectal, and prostate cancer, although the certainty of evidence remains very low. PRS-stratified screening should remain investigational pending validation through prospective trials powered for clinical endpoints, conducted in ancestrally diverse populations, and incorporating equity-sensitive implementation frameworks.

Background: Cancer screening programmes apply uniform criteria irrespective of inherited risk. Polygenic risk scores (PRSs) have been proposed as a promising tool to stratify individual cancer risk and tailor screening strategies. However, whether PRS-informed strategies improve health outcomes compared with current practices remains uncertain. We aimed to synthesise the available evidence on the projected clinical utility of PRS-stratified cancer screening across six malignancies. Methods: We searched PubMed, Scopus, and Web of Science from inception to March 15, 2026, for studies evaluating PRS-stratified screening for breast, colorectal, prostate, lung, gastric, or cervical cancer. Eligible outcomes included cancer-specific mortality, life-years gained (LYG), quality-adjusted life-years (QALYs), overdiagnosis, and false-positive rates. Risk of bias was assessed using the ISPOR-SMDM checklist for modelling studies and ROBINS-I for observational studies. Certainty of evidence was appraised using the GRADE framework. Findings: Of 8,454 records identified, 25 studies were included (22 decision-analytic modelling studies, 3 observational studies) covering five malignancies; no eligible studies were identified for cervical cancer. PRS-stratified strategies were associated with improvements in QALYs for breast, colorectal, gastric, and lung cancer, whereas results for prostate cancer were heterogeneous. Mortality reductions were observed for colorectal, gastric, and lung cancer, although evidence for the latter two rested on single studies. For breast cancer, mortality outcomes were inconsistent and dependent on comparator intensity. For prostate cancer, the principal benefit was a reduction in overdiagnosis rather than mortality improvement. Across all cancer sites, the absolute magnitude of incremental benefit over non-stratified screening was modest. Harms increased in high-risk groups receiving intensified surveillance. The certainty of evidence was rated very low for all outcomes across all cancer types, driven by serious risk of bias and very serious indirectness, reflecting limited transferability across populations and healthcare systems. Interpretation: PRS-stratified screening shows consistent but modest potential to improve the efficiency of cancer screening, particularly for breast, colorectal, and prostate cancer, although the certainty of evidence remains very low. PRS-stratified screening should remain investigational pending validation through prospective trials powered for clinical endpoints, conducted in ancestrally diverse populations, and incorporating equity-sensitive implementation frameworks.

Objective: To summarise the evidence so far from all randomised controlled trials on the efficacy of communication of polygenic risk scores in changing health outcomes. Design: Systematic review and meta-analysis. Data sources: Cochrane Central Register of Controlled Trials (CENTRAL) and Pubmed, from inception to 1 March 2025. Eligibility criteria for selecting studies: Randomised controlled trials in human participants; articles published or accepted for publication in peer reviewed journals, or with available results on ClinicalTrials.gov, without time restriction in any language; and randomised controlled trials comparing the disclosure of inherited genetic risk obtained through the polygenic risk score for any phenotype (intervention group) with scenarios where no genetic information was provided (comparator group). Results: Of 7830 articles retrieved, 27 randomised controlled trials were eligible for inclusion in the analysis. Polygenic risk scores mainly predicted risks for cancer (n=9 randomised controlled trials), cardiovascular diseases (n=8), and diabetes (n=6). 21 randomised controlled trials targeted mainly healthy populations, three targeted at-risk populations, and three trials targeted individuals who had already developed a disease and the polygenic risk score predicted complications. Most randomised controlled trials (15/27) concluded in their abstracts with favourable claims about the polygenic risk score, with only 5/15 trials justifying the score with any significant results. Nine of the 27 randomised controlled trials had a high risk of bias. Meta-analysis showed no significant effects on any of the 22 outcomes tested in two or more trials. Standardised mean differences for dietary outcomes were −0.11 (95% confidence interval (CI) −0.22 to 0.01) for daily energy intake, 0.03 (−0.18 to 0.25) for daily fat intake, and −0.11 (−0.28 to 0.06) for alcohol consumption. For physical activity, standardised mean difference was −0.01 (95% CI −0.13 to 0.11). Relative risks were 1.12 (95% CI 0.77 to 1.61) for screening attendance, 1.50 (0.98 to 2.29) for use of statins, and 0.95 (0.32 to 2.79) for incidence of disease. For psychological outcomes, standardised mean differences were −0.02 (95% CI −0.13 to 0.08) for anxiety, −0.06 (−0.23 to 0.10) for worry, −0.04 (−0.21 to 0.13) for perceived risk, and −0.05 (−0.23 to 0.13) for depression. For clinical outcomes, mean differences were −2.01 (95% CI −8.27 to 4.26) for total cholesterol, −3.64 (−7.88 to 0.60) for low density lipoprotein cholesterol, −0.21 (−2.65 to 2.23) for high density lipoprotein cholesterol, −1.88 (−4.17 to 0.42) for diastolic blood pressure, −1.26 (−4.44 to 1.92) for systolic blood pressure, −0.12 (−0.63 to 0.39) for body mass index, and −0.33 (−0.87 to 0.20) for weight. 80 outcomes were reported across multiple studies, with each outcome reported in a single trial only. 19 of 80 were primary outcomes, and of these two had significant results (P<0.05), as did three secondary outcomes. Conclusions: Overall, despite frequent promising claims, disclosure of polygenic risk scores did not result in meaningful changes in behavioural, psychological, or clinical measures for the outcomes examined. Although when interpreting the findings the heterogeneity and methodological limitations of the available trials should be considered, communication of polygenic risk scores did not show consistent improvements in preventive behaviours or risk factor modification. Systematic review registration: Open Science Framework doi.org/10.17605/OSF.IO/28V6J

Background: Molecular Tumor Boards (MTBs) bring together multidisciplinary experts to translate genomic data into clinical decisions in oncology, however, their overall clinical impact remains unclear. The aim of this systematic review is to assess the clinical impact of MTB-recommended therapies on patients with cancer outcomes. Methods and findings: In this systematic review and meta-analysis, we searched PubMed, Embase, Scopus, and CENTRAL up to July 2025. We included studies of any design, both single-arm studies and studies with a comparator group, that reported the clinical impact of MTBs in patients who received MTB-guided therapy. Meta-analyses were performed separately by study design, using hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), relative risks (RRs) for objective response rate (ORR) and disease control rate (DCR), and pooled proportions for PFS ratio ≥1.3. All meta-analyses were conducted using random-effects models based on the inverse variance method. We evaluated the risk of bias using the RoB 2.0 for RCTs and ROBINS-I for non-randomized studies. From 6,846 records, 78 studies (9,195 patients; 4,569 treated per MTB recommendations) were included. MTB-guided therapies were associated with reduced risk of death (HR 0.87; 95% CI [0.76, 1.01]; p = 0.069; I ² = 0.0% in RCTs; 0.62 in retrospective studies) and disease progression (HR 0.73; 95% CI [0.64, 0.84]; p < 0.001; I ² = 0.0% in RCTs; 0.63 in retrospective studies), as well as improved ORR (RR 1.75; 95% CI [1.24, 2.47]; p = 0.001; I ² = 0.0% in RCTs; 3.32 in retrospective studies) and DCR (RR 1.20; 95% CI [1.03, 1.40]; p = 0.018; I ² = 19.9% in RCTs; 1.65 in retrospective studies). Between 33% and 43% of patients achieved a PFS ratio ≥1.3. While the risk of bias for RCTs was low, except for one study that was rated as having some concerns, the overall risk of bias for non-randomized studies was rated as “serious” in most of the studies ( n = 54). Limitations include substantial heterogeneity, predominance of non-randomized studies with risk of bias, and limitations in data reporting, which restrict causal inference. Conclusions: This meta-analysis provides robust evidence from RCTs supporting the clinical benefit of MTBs, although limited for OS. Methodological heterogeneity and study limitations from observational studies warrant cautious interpretation. Future high-quality RCTs and standardized reporting are needed to confirm these findings and guide the integration of MTBs into routine clinical practice and health system strategies.

BACKGROUND: The impact of proportionality to heart valve regurgitation has been widely investigated in mitral regurgitation, helping to better characterize the best candidates for therapies. However, it has never been studied in tricuspid regurgitation (TR). The aim of the present study is to investigate the impact of the proportionality of TR on outcomes. METHODS: Patients undergoing tricuspid transcatheter edge-to-edge repair were selected from the TRIVALVE registry (International Multisite Transcatheter Tricuspid Valve Therapies Registry). Patients were divided according to the ratio between effective regurgitant orifice area (EROA) and right ventricular (RV) end diastolic diameter (RVEDD) into tertiles: patients with low EROA/RVEDD (RV, dominant); intermediate EROA/RVEDD (RV and TR, RV-TR, codominant), and high EROA/RVEDD (TR, dominant). The primary outcome was all-cause mortality. Median follow-up was 9.7 months (4.2–12.0). RESULTS: A total of 204 patients were included in the present study: 67 for the RV dominant, 68 for the RV-TR codominant, and 69 for the TR dominant group. The 3 groups presented different baseline characteristics. Survival analysis among the 3 groups showed a trend towards worse prognosis for the RV-dominant group, as compared with the RV-TR codominant and TR dominant groups. CONCLUSIONS: The conceptual framework of proportionality is applicable to TR with EROA/RVEDD, defining a higher risk RV-dominant phenotype with a trend towards worse survival after tricuspid transcatheter edge-to-edge repair.