Background RADICAL PC-2 (RAndomizeD Intervention for CArdiovascular and Lifestyle Risk Factors in Prostate Cancer Patients) was a pragmatic randomized controlled trial that tested whether routine referral to a cardiologist or an internist for cardiovascular (CV) risk-factor and lifestyle modification improves outcomes in patients with prostate cancer or receiving androgen-deprivation therapy. The intervention group had more favorable outcomes overall, driven by improved cholesterol control, with no differences in rates of CV death, myocardial infarction (MI), stroke, or heart failure (HF). Objectives The authors aim to identify patient subgroups more likely to benefit from routine CV care referral. Methods Prespecified subgroup analyses were used to assess whether patients at higher CV risk derived greater benefit from specialist referral, with treatment-effect heterogeneity assessed using interaction tests. The first primary outcome was a hierarchical composite of CV death, MI, stroke, HF, suboptimal cholesterol, and systolic blood pressure (SBP) control, evaluated using the win ratio. The second primary outcome was time to CV death, MI, stroke, or HF. Results Among 2487 participants, treatment effect differed by baseline total cholesterol ≤4 mmol/L vs >4 mmol/L (interaction P = 0.016), with respective win ratios of 1.21 (95% CI: 0.89-1.64) and 1.75 (95% CI: 1.51-2.03), and by baseline BP status (SBP ≥130 mm Hg or diastolic BP ≥80 mm Hg vs BP <130/80 mm Hg; interaction P = 0.003), with respective subdistribution HRs (sHRs) for CV death, MI, stroke, or HF of 0.86 (95% CI: 0.61-1.21) and 4.85 (95% CI: 1.65-14.26). The interaction for diabetes did not reach statistical significance (interaction P = 0.054) although the intervention effect estimates suggested a potential difference by diabetes status, with sHRs of 0.53 (95% CI: 0.24-1.15) among participants with diabetes and 1.25 (95% CI: 0.88-1.78) among participants without diabetes. The win ratio was higher among participants with total cholesterol >4 mmol/L, and sHRs were numerically lower among those with SBP ≥130 mm Hg or diastolic BP ≥80 mm Hg and diabetes. Conclusions Uncontrolled modifiable CV risk factors may identify patients with prostate cancer who are more likely to benefit from routine CV care referral.
Anthracyclines such as doxorubicin remain central to cancer therapy, but their clinical utility is constrained by dose-limiting cardiotoxicity and long-term cardiovascular sequelae. Although traditionally attributed to cardiomyocyte-intrinsic mechanisms, including mitochondrial dysfunction, oxidative stress, and DNA damage, emerging evidence demonstrates that these initial injuries rapidly activate the immune system, transforming doxorubicin-induced cardiotoxicity (DIC) into a multicellular inflammatory process. Release of mitochondrial and nuclear danger signals triggers innate immune pathways and recruitment of neutrophils, monocytes, and lymphocytes, whose sustained activation promotes maladaptive remodeling, fibrosis, and chronic dysfunction. Conversely, specific immune subsets exert context-dependent cardioprotective effects, underscoring the dual role of immune responses in disease progression. This review frames DIC within a cardioimmunology paradigm, highlighting the intersection of mitochondrial stress, sterile inflammation, and adaptive immunity across acute and chronic phases of injury. We discuss emerging therapeutic strategies that extend beyond cardiomyocyte protection, including immune recalibration rather than broad immunosuppression, immune-targeted interventions, and biomarker-guided monitoring, to enable mechanism-based, individualized cardioprotection without compromising anticancer efficacy.
BACKGROUND:Immune checkpoint inhibitor (ICI) myocarditis typically develops soon after treatment initiation (<90 days) but may also occur as a delayed complication after discontinuation of ICI therapy. The clinical and histopathologic differences between early- and late-manifestation ICI myocarditis remain unclear. OBJECTIVES:This study sought to compare the clinical features and myocardial histopathology of early- versus late-manifestation ICI myocarditis. METHODS:We conducted a retrospective national cohort study of patients diagnosed with myocarditis after ICI initiation who underwent endomyocardial biopsy. Biopsy samples were analyzed for inflammatory cell infiltration, severity of myocardial inflammation, and collagen volume fraction. RESULTS:Among 35 patients (mean age: 66 ± 13 years; 71.4% male), 26 (74.3%) developed early-manifestation myocarditis (<90 days), whereas 9 (25.7%) had late-manifestation myocarditis (≥90 days). Early-manifestation cases showed significantly more severe myocardial inflammation; higher levels (median [Q1-Q3]) of CD3+ T cells (432 [173-1,381] vs 121 [43-400] cells/mm2; P = 0.036), CD8+ T cells (289 [73-994] vs 86 [21-168] cells/mm2; P = 0.019), and CD 68+ macrophages (307 [116-841] vs 57 [36-200] cells/mm2; P = 0.008); and higher CD4+ T-cell levels that did not reach statistical significance (P = 0.054). There were no significant differences in regulatory T cells or collagen volume. Clinically, early-manifestation myocarditis was characterized by higher cardiac biomarker levels and older age, whereas left ventricular ejection fraction was similar between groups. Mortality due to myocarditis occurred in 2 early-manifestation cases and in no late-manifestation cases. Conversely, cancer-related mortality was more frequent in the late-manifestation group (n = 3) than in the early-manifestation group (n = 2). ICI therapy was reinitiated in only 2 patients overall. CONCLUSIONS:Late-manifestation ICI myocarditis may represent a temporally distinct or partially attenuated inflammatory phase. Despite a milder inflammatory profile, higher cancer-related mortality was observed, suggesting that cautious ICI reinitiation may warrant consideration in selected patients within this subgroup.
BACKGROUND:Cardiovascular-kidney-metabolic (CKM) syndrome is an emerging integrative framework and a critical determinant of overall disease risk; however, its relationship with cancer risk and underlying mechanisms remains poorly understood. OBJECTIVES:This study sought to investigate the association between CKM staging and incident cancer and elucidate mediators underlying this association, thereby uncovering pathways and potential targets for risk mitigation based on multiomics analysis. METHODS:UK Biobank participants were categorized into CKM stages 0 to 4 according to the American Heart Association staging framework based on International Classification of Diseases, 10th Revision codes. Cox regression was conducted to evaluate associations between CKM staging and overall cancer incidence. Proteomic and metabolomic mediators linking adjacent stages and cancer were identified using Cox regression, logistic regression, and mediation analysis and underwent Gene Ontology enrichment and interaction network analyses. RESULTS:Overall cancer risk increased stepwise from CKM stages 1 to 3, with slight attenuation but persistent elevation in stage 4. Stage-specific mediators and mechanisms were identified: leukocyte/lymphocyte activation and cell-cell adhesion in stage 1; T cell-related immunity and emerging immune tolerance induction in stage 2; emerging natural killer (NK) cell tolerance induction and respiratory burst involved in the inflammatory response in stage 3; and dominant NK cell tolerance induction and tissue-resident chronic pathology in stage 4. Dominant metabolomic mediation evolved from high-density lipoproteins (HDLs) and triglyceride-rich lipoproteins (TRLs) to low-density lipoproteins (LDLs). Protein-metabolite interaction networks revealed distinct profiles for each stage, including angiopoietin-like protein 1/HDL and asialoglycoprotein receptor 1/TRL interactions in early stages and phospholipid transfer protein/HDL, apolipoprotein M/LDL, and fibroblast growth factor-binding protein 1/intermediate-density lipoprotein/LDL correlations in advanced stages. CONCLUSIONS:CKM staging is associated with incremental cancer risk and stage-specific immune-metabolic pathways, highlighting potential prevention targets.
Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, often fatal disease caused by transthyretin (TTR) tetramer destabilization, leading to amyloid deposition from either age-related wild type TTR or pathogenic TTR variants. TTR variants are less stable than wild type TTR, leading to lower serum TTR (sTTR) and worse clinical outcomes. TTR stabilizers, tafamidis and acoramidis, are approved for treatment of patients with ATTR-CM. Objectives The aim of this study was to evaluate the differences in stabilizing effect and magnitude of sTTR increases for acoramidis and tafamidis using data from the ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy) trial. Methods Stabilizing potency was analyzed using sTTR as an in vivo readout and by applying 2 orthogonal pharmacodynamic assays: Western blot and fluorescent probe exclusion. In vitro analyses used blood samples from patients with variant ATTR-CM at clinically relevant concentrations of acoramidis (10 μM) and tafamidis (16-26 μM). Results In ATTRibute-CM, treatment with acoramidis (n = 234) resulted in a greater rise in sTTR from baseline to month 30 vs placebo plus tafamidis (n = 34). Acoramidis achieved greater TTR stabilization than placebo plus tafamidis at month 30 by Western blot (90.2% [n = 83] vs 60.6% [n = 6]) and fluorescent probe exclusion (99.7% [n = 71] vs 68.0% [n = 4]), although this was limited by a small sample size. Subsequent in vitro analysis corroborated acoramidis was a more effective TTR stabilizer than tafamidis across all 51 individual participant samples tested, representing 17 unique variants. Conclusions Acoramidis is a near-complete stabilizer of wild type and variant TTR. Although in vitro comparisons between acoramidis and tafamidis suggest greater stabilization by acoramidis, randomized prospective trial data comparing these TTR stabilizers are lacking, and further investigation is warranted. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935)
BACKGROUND:Immune checkpoint inhibitor-associated myocarditis (ICI-My) is rare but potentially life-threatening. Biomarkers that distinguish myocarditis-related inflammation from background immune activation induced by ICIs remain needed. OBJECTIVES:This study sought to define the circulating inflammatory and cellular immune landscape of ICI-My, relate these findings to clinical severity, and explore the feasibility of interleukin-6 receptor (IL-6R) blockade in selected steroid-refractory cases. METHODS:In this single-center retrospective cohort (January 2018 to June 2024), we performed biomarker profiling including multiplex cytokine profiling in 33 patients with ICI-My (7 severe and 26 nonsevere, 28 cytokines profiles) and 68 ICI-treated patients without myocarditis or other immune-related adverse events. Mass cytometry analyses compared 16 patients with ICI-My with 72 ICI-treated patients without myocarditis or other immune-related adverse events. We also describe eight steroid-refractory patients treated with tocilizumab on a compassionate-use basis. RESULTS:Compared with ICI-treated controls, ICI-My was associated with higher circulating IL-6, CCL3, CCL4, CCL5, CXCL9, CXCL10, CXCL13, and VEGF-A. Mass cytometry analyses showed qualitative immune-cell differences, including higher proportions of immature neutrophils and activated HLA-DR+CD38+ CD4+ and CD8+ T cells, lower CXCR5+ memory B- and T-cell populations, contraction of switched and unswitched memory B-cell compartments, and lower CXCR3 expression across memory T-cell subsets. No clear systemic complement activation signal was observed. High-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, aspartate aminotransferase, and alanine aminotransferase discriminated severe from nonsevere myocarditis more consistently than individual cytokines. In eight steroid-refractory cases, tocilizumab administration was feasible, but this uncontrolled series cannot establish efficacy. CONCLUSIONS:Peripheral immune profiling identifies an IL-6-centered and chemokine-centered inflammatory signature in ICI-My beyond background ICI exposure. Conventional cardiac biomarkers remain more informative than single cytokines for severity assessment in this cohort. IL-6R blockade appears biologically plausible and clinically feasible in selected steroid-refractory cases and warrants prospective evaluation.
Background Patients with cancer-associated venous thromboembolism (VTE) are at a high risk of major bleeding during anticoagulant therapy, emphasizing the need for bleeding risk assessment in the era of direct oral anticoagulants (DOACs). However, few bleeding risk scores have been specifically developed and validated for this population. Objectives The aim of this study was to develop and validate a novel bleeding risk score (ONCO-DOAC BLEED score) for patients with cancer-associated VTE receiving DOAC therapy. Methods We derived the bleeding risk prediction score using 1,166 patients with cancer-associated VTE treated with DOAC therapy from the COMMAND VTE (Contemporary Management and Outcomes in Patients with Venous Thromboembolism) Registry-2 and externally validated its performance in an independent cohort from the ONCO deep vein thrombosis and ONCO pulmonary embolism studies. Results Over a median follow-up of 163 days, 127 patients (10.9%) experienced major bleeding. In multivariable analysis, a history of major bleeding, chronic kidney disease, nonsteroidal anti-inflammatory drug use, distant metastatic cancer, terminal cancer, upper gastrointestinal cancer, pancreatic cancer, and uterine cancer were independently associated with major bleeding. Based on these risk factors, the ONCO-DOAC BLEED score was constructed. This score demonstrated moderate discrimination for major bleeding in the derivation cohort (Harrell's C-index 0.68; Uno's C-index 0.67) and validation cohort (Harrell's C-index 0.62; Uno's C-index 0.63), with higher discrimination in the derivation cohort and comparable performance in the validation cohort compared with the VTE-BLEED, RIETE, CAT-BLEED, and Perform scores. Conclusions The ONCO-DOAC BLEED score provides clinically relevant stratification of major bleeding risk in patients with cancer-associated VTE receiving DOAC therapy and may support individualized therapeutic decision-making in routine practice. (Optimal Duration of Anticoagulation Therapy for Isolated Distal Deep Vein Thrombosis in Patients With Cancer Study [ONCO DVT]; NCT03895502 and Optimal Duration of Anticoagulation Therapy for Low-risk Pulmonary Embolism Patients With Cancer [ONCO PE]; NCT04724460)
