Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol

Aims: Contemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the {beta}-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation. Methods and results: In a 2 x 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the {beta}-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed. Conclusion: In patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function

Using machine learning model explanations to identify proteins related to severity of meibomian gland dysfunction

Abstract Meibomian gland dysfunction is the most common cause of dry eye disease and leads to significantly reduced quality of life and social burdens. Because meibomian gland dysfunction results in impaired function of the tear film lipid layer, studying the expression of tear proteins might increase the understanding of the etiology of the condition. Machine learning is able to detect patterns in complex data. This study applied machine learning to classify levels of meibomian gland dysfunction from tear proteins. The aim was to investigate proteomic changes between groups with different severity levels of meibomian gland dysfunction, as opposed to only separating patients with and without this condition. An established feature importance method was used to identify the most important proteins for the resulting models. Moreover, a new method that can take the uncertainty of the models into account when creating explanations was proposed. By examining the identified proteins, potential biomarkers for meibomian gland dysfunction were discovered. The overall findings are largely confirmatory, indicating that the presented machine learning approaches are promising for detecting clinically relevant proteins. While this study provides valuable insights into proteomic changes associated with varying severity levels of meibomian gland dysfunction, it should be noted that it was conducted without a healthy control group. Future research could benefit from including such a comparison to further validate and extend the findings presented here

Effect of candesartan and metoprolol on myocardial tissue composition during anthracycline treatment: the PRADA trial

Aims: Anthracycline treatment may cause myocyte loss and expansion of the myocardial extracellular volume (ECV) fraction by oedema and fibrosis. We tested the hypotheses that adjuvant treatment for early breast cancer with the anthracycline epirubicin is dose dependently associated with increased ECV fraction and total ECV, as well as reduced total myocardial cellular volume, and that these changes could be prevented by concomitant angiotensin or beta-adrenergic blockade. Methods and results: PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) was a 2 × 2 factorial, placebo-controlled, double-blinded trial of candesartan and metoprolol. Sixty-nine women had valid ECV measurements. ECV fraction, total ECV, and total cellular volume were measured by cardiovascular magnetic resonance before and at the completion of anthracycline therapy. ECV fraction increased from 27.5 ± 2.7% to 28.6 ± 2.9% (P = 0.002). A cumulative doxorubicin equivalent dose of 268 mg/m2 was associated with greater increase in ECV fraction than doses <268 mg/m2 (mean change 3.4% [95% confidence interval (CI) 1.2, 5.5] vs. 0.7% [95% CI 0.0, 1.5], P = 0.006), as well as greater increase in total ECV (1.9 mL [95% CI 0.4, 3.5] vs. 0.1 mL [95% CI -0.6, 0.8], P = 0.04). In patients receiving candesartan, total cellular volume decreased (-3.5 mL [95% CI - 4.7, -2.2], P < 0.001) while in patients not receiving candesartan, it remained unchanged (P = 0.45; between group difference P = 0.003). Conclusions: Anthracycline therapy is associated with dose-dependent increase in ECV fraction and total ECV. Concomitant treatment with candesartan reduces left ventricular total cellular volume