Background and Objectives: Dose-dense anthracycline-based chemotherapy has emerged as a critical strategy in managing high-risk breast cancer, offering survival benefits through increased dose intensity or shortened intervals. While short-term studies report preserved left ventricular ejection fraction (LVEF), the long-term cardiotoxicity of such regimens, especially at accelerated intervals, remains inadequately explored. Aim of this study was to evaluate the long-term cardiac safety of dose-dense anthracycline-based chemotherapy compared to conventional protocols in patients with non-metastatic breast cancer. Methods: This retrospective study included 101 breast cancer patients treated at the National Center for Tumor Diseases, Heidelberg, between 2007 and 2014. Patients were classified into dose-dense (n=44) or conventional therapy (n=57) groups. Long-term follow-up (7–10 years post-treatment) comprised echocardiography with global longitudinal strain (GLS), electrocardiography, and cardiac biomarkers. Statistical analyses were conducted using Cox regression, and competing risks models. Results: Left ventricular systolic function was preserved in both groups, with no significant differences in LVEF (58.1±5.4% in the dose-dense group and 59.6±3.7% in the conventional therapy group, p=0.341) or GLS. Diastolic dysfunction affected 28.6% of the dose-dense group and 47.4% of the conventional group, with age (odds ratio [OR], 1.14 per year; p=0.038) and hypertension (OR, 10.50; p=0.011) emerging as key predictors. Only one case of anthracycline-induced heart failure was reported. Mortality was primarily tumor-related, highlighting limited cardiac contributions to overall survival. Conclusions Dose-dense anthracycline therapy demonstrated comparable long-term cardiac safety to conventional regimens, with preserved systolic function and minimal heart failure incidence. These findings underscore the importance of individualized risk assessment and comprehensive cardiac monitoring in breast cancer management.

MicroRNA (miRNA) levels in serum have recently emerged as potential novel biomarkers for various diseases. miRNAs are routinely measured by standard quantitative real-time PCR (qPCR); however, the high sensitivity of qPCR demands appropriate normalization to correct for nonbiological variation. Presently, RNU6B (U6) is used for data normalization of circulating miRNAs in many studies. However, it was suggested that serum levels of U6 themselves might differ between individuals. Therefore, no consensus has been reached on the best normalization strategy in 'circulating miRNA'. We analyzed U6 levels as well as levels of spiked-in SV40-RNA in sera of 44 healthy volunteers, 203 intensive care unit patients and 64 patients with liver fibrosis. Levels of U6 demonstrated a high variability in sera of healthy donors, patients with critical illness and liver fibrosis. This high variability could also be confirmed in sera of mice after the cecal ligation and puncture procedure. Most importantly, levels of circulating U6 were significantly upregulated in sera of patients with critical illness and sepsis compared with controls and correlated with established markers of inflammation. In patients with liver fibrosis, U6 levels were significantly downregulated. In contrast, levels of spiked-in SV40 displayed a significantly higher stability both in human cohorts (healthy, critical illness, liver fibrosis) and in mice. Thus, we conclude that U6 levels in the serum are dysregulated in a disease-specific manner. Therefore, U6 should not be used for data normalization of circulating miRNAs in inflammatory diseases and previous studies using this approach should be interpreted with caution. Further studies are warranted to identify specific regulatory processes of U6 levels in sepsis and liver fibrosis.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Animals ; Antigens, Polyomavirus Transforming/blood ; Case-Control Studies ; Down-Regulation ; Female ; Humans ; Liver Cirrhosis/*blood/diagnosis ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; RNA, Small Nuclear/*blood ; Reference Values ; Sepsis/*blood/diagnosis