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BACKGROUND: Cardiotoxicity is a recognized complication in breast cancer (BC) patients undergoing chemotherapy with anthracyclines with or without trastuzumab. However, the prognostic value of heart rate variability (HRV) indexes for early cardiotoxicity development remains unknown. METHODS: Fifty BC patients underwent TTE assessment before and three months after chemotherapy. HRV indexes were obtained from continuous electrocardiograms in supine position with spontaneous breathing, active standing, and supine position with controlled breathing. The magnitude of change (Δ) between supine-standing and supine-controlled breathing was calculated. Variables were compared using t-test or ANOVA. Cardiotoxicity predictive value was assessed by ROC curve analysis. A p value of < 0.05 was considered significant. RESULTS: TTE revealed reduced left atrial conduit strain in the cardiotoxicity group. Mean heart rate increased during all maneuvers at follow-up, with no differences in HRV indexes between patients with or without cardiotoxicity. However, a lower Δ in supine-controlled breathing of several HRV indexes predicted early cardiotoxicity identified by echocardiography (e.g. SDNN ≤ -8.44 ms: Sensitivity = 75%, Specificity = 69%). CONCLUSIONS: BC patients treated with chemotherapy maintain cardiac autonomic responses to physiological stimuli after 3 months of chemotherapy. However, a lower Δ during active standing and controlled breathing before chemotherapy may predict early cardiotoxicity.

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INTRODUCTION: Several interventions have been tested for cardio-protection against anthracycline-induced cancer therapy-related cardiovascular dysfunction (CTRCD). The role of statins in this setting remains unclear. METHODS: We systematically searched PubMed, Embase, Cochrane Library, Clinicaltrials.gov, and Web of Science for randomized controlled trials (RCTs) comparing statins versus control (placebo or no intervention) for preventing anthracycline-induced CTRCD. We applied a random-effects model to pool risk ratios (RR) and mean differences (MD) with 95 % confidence intervals (CI). RESULTS: We included seven RCTs comprising 887 patients with planned chemotherapy with anthracycline-based regimens, of whom 49.8 % were randomized to statins. Relative to placebo, statins significantly reduced the incidence of cardiotoxicity/CTRCD (RR 0.46; 95 % CI 0.29 to 0.72; p < 0.001). The left ventricular end-systolic volume was also lower in patients treated with statin (MD -3.12 mL; 95 % CI -6.13 to -0.12 mL; p = 0.042). There was no significant difference between groups in post-anthracycline left ventricular ejection fraction (LVEF) overall. CONCLUSION: In this meta-analysis of RCTs, statins were significantly associated with a lower incidence of anthracycline-induced CTRCD and attenuated changes in the left ventricular end-systolic volume. Thus, our findings suggest that statins should be considered as a cardio-protection strategy for patients with planned anthracycline-based chemotherapy.

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Dysregulated A>I(G) RNA editing, which is mainly catalyzed by ADAR1 and is a type of post-transcriptional modification, has been linked to cancer. A low response to therapy in breast cancer (BC) is a significant contributor to mortality. However, it remains unclear if there is an association between A>I(G) RNA-edited sites and sensitivity to genotoxic drugs. To address this issue, we employed a stringent bioinformatics approach to identify differentially RNA-edited sites (DESs) associated with low or high sensitivity (FDR 0.1, log2 fold change 2.5) according to the IC50 of PARP inhibitors, anthracyclines, and alkylating agents using WGS/RNA-seq data in BC cell lines. We then validated these findings in patients with basal subtype BC. These DESs are mainly located in non-coding regions, but a lesser proportion in coding regions showed predicted deleterious consequences. Notably, some of these DESs are previously reported as oncogenic variants, and in genes related to DNA damage repair, drug metabolism, gene regulation, the cell cycle, and immune response. In patients with BC, we uncovered DESs predominantly in immune response genes, and a subset with a significant association (log-rank test p < 0.05) between RNA editing level in LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 genes, and progression-free survival. Our findings provide a landscape of RNA-edited sites that may be involved in drug response mechanisms, highlighting the value of A>I(G) RNA editing in clinical outcomes for BC.

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Evidences on the effects of chemotherapy treatment cycles on measures of muscle, mental state, social and cognitive performance are scarce. The objective of this study was to analyze the effects of chemotherapy cycles on muscle strength and activation, functional capacity, quality of life, fatigue and anxiety of women with breast cancer. Therefore, twenty-two women divided into a treatment group (n = 10; 46.6 ± 9.6 years) and control group (n = 12; 51.6 ± 7.0 years) participated in the study. Analysis of muscle performance, quality of life, fatigue and anxiety after the 2nd and 4th cycle of chemotherapy with anthracyclines were performed in women with breast cancer (TRA) and compared to healthy women (CTR). Two-way ANOVA was used to compare the variance of the means and the significance level was set as P≤0.05. The results showed Differences in the muscular activation of the vastus mediallis between the groups at post time (P = 0.038), as well as in the sit and stand test in the baseline (P<0.001) and post moment (P<0.001). Functional capacity performance was different between baseline (P<0.001) and post-time (P<0.001) groups. Additionally, the TRA group worsened the quality of life in the domains of functional capacity (P<0.001) and limitation of physical aspects (P = 0.002), besides presenting negative changes in fatigue. Thus, anthracycline chemotherapy cycles reduce muscular performance and affect biopsychosocial variables in women with breast cancer.

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Resumo Fundamento: A introdução das antraciclinas no tratamento do câncer infantojuvenil propiciou um aumento significativo na sobrevida, mas também nas taxas de morbimortalidade devido às complicações cardiovasculares (CVs). Objetivos: Conhecer o perfil cardiológico de pacientes pediátricos tratados com antraciclinas em um centro oncológico no Brasil e a incidência das complicações CVs. Métodos: Foram coletados, de prontuários de pacientes de ambos os sexos com idade até 19 anos - frequência e forma de apresentação clínica das complicações CVs Gerais (G1) e relacionadas à Disfunção Ventricular (G2) - e correlacionados com fatores de risco, faixa etária e estado vital, medicações cardiológicas e cardioprotetoras. Um valor de p < 0,05 foi considerado significativo. Resultados: Foram incluídos 326 pacientes, destes, 214 (65,6%) eram menores de 10 anos e 192 (58,89%) do sexo masculino. As complicações do G1 ocorreram em 141 (43,3%) pacientes e a mais frequente foi a hipertensão arterial sistêmica; as complicações do G2 ocorreram em 84 pacientes (25,76%). Uma Dose Cumulativa (DC) das antraciclinas > 250mg/m2 foi usada em 26,7% dos pacientes e a associação de complicações do G2 com essa DC não mostrou significância estatística (p=0,305; RC=1,330 e [95% IC= 0,770- 2,296]). As medicações cardiológicas mais usadas foram os diuréticos em 34,7% dos pacientes. Conclusões: O estudo mostrou, como na literatura, uma alta incidência de complicações CVs no tratamento do câncer infantojuvenil, sendo as do G1 as mais frequentes.

Abstract Background: The introduction of anthracyclines in the treatment of children and adolescents with cancer has promoted a significant increase in survival, but also in morbidity and mortality rates due to cardiovascular (CV) complications. Objectives: To determine the cardiovascular profile of pediatric patients treated with anthracyclines at a cancer center in Brazil and the incidence of CV complications. Methods: The following data were collected from the medical records of patients of both sexes, aged younger than 19 years - frequency and form of clinical presentation of general CV complications (G1) and CV complications related to ventricular dysfunction (G2) - and correlated with risk factors, age range and vital status, cardiovascular and cardioprotective medications. A p<0.05 was considered statistically significant. Results: A total of 326 patients were included, 214 (65.6%) were younger than 10 years and 192 (58.9%) of male sex. G1 complications occurred in 141 (43.3%) patients, and the most frequent was systemic arterial hypertension; G2 complications occurred in 84 patients (25.8%). Cumulative dose (CD) of anthracyclines > 250mg/m2 was used in 26.7% of patients and the association of G2 complications with this CD was not statistically significant (p=0.305; OR=1.330 and [95% CI = 0.770- 2.296]). The most used cardiac medications were diuretics (34.7% of patients). Conclusions: In accordance with literature, the study showed a high incidence of CV complications in the treatment of children and adolescents with cancer, with general CV complications as the most prevalent.

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SUMMARY BACKGROUND: Chemotherapy with doxorubicin may lead to left ventricular dysfunction. There is a controversial recommendation that biomarkers can predict ventricular dysfunction, which is one of the most feared manifestations of anthracycline cardiotoxicity. OBJECTIVE: The aim of this study was to evaluate the behavior of biomarkers such as Troponin I, type B natriuretic peptide, creatine phosphokinase fraction MB, and myoglobin in predicting cardiotoxicity in a cohort of women with breast cancer undergoing chemotherapy with anthracycline. METHODS: This is an observational, prospective, longitudinal, unicentric study, which included 40 women with breast cancer, whose therapeutic proposal included treatment with doxorubicin. The protocol had a clinical follow-up of 12 months. Biomarkers such as Troponin I, type B natriuretic peptide, creatine phosphokinase fraction MB, and myoglobin were measured pre-chemotherapy and after the first, third, fourth, and sixth cycles of chemotherapy. RESULTS: There was a progressive increase in type B natriuretic peptide and myoglobin values in all chemotherapy cycles. Although creatine phosphokinase fraction MB showed a sustained increase, this increase was not statistically significant. Troponin, type B natriuretic peptide, myoglobin, and creatine phosphokinase fraction MB were the cardiotoxicity markers with the earliest changes, with a significant increase after the first chemotherapy session. However, they were not able to predict cardiotoxicity. CONCLUSION: Troponin I, type B natriuretic peptide, myoglobin, and creatine phosphokinase fraction MB are elevated during chemotherapy with doxorubicin, but they were not able to predict cardiotoxicity according to established clinical and echocardiographic criteria. The incidence of subclinical cardiotoxicity resulting from the administration of doxorubicin was 12.5%.

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ABSTRACT Introduction: Acute promyelocytic leukemia currently presents an excellent chance of cure with protocols based on all-trans-retinoic acid (ATRA) and anthracycline or only differentiation agents. However, high early mortality rates continue to be reported Methods: Between 2000 and 2018, patients were enrolled and retrospectively analyzed by medical records. A modified AIDA protocol, with a 1-year shortening of the treatment duration, reduction in the number of drugs and a strategy to reduce early mortality by the postponement of the initiation of anthracyclines were employed. Overall and event-free survival rates and toxicity were analyzed Results: Thirty-two patients were enrolled, of whom 56% were female, with a median age of 12 years and 34% belonged to the high-risk group. Two patients had the hypogranular variant and three had another cytogenetic alteration, in addition to the t(15;17). The median start of the first anthracycline dose was 7 days. There were two early deaths (6%) due to central nervous system (CNS) bleeding. All patients achieved molecular remission after the consolidation phase. Two children relapsed and were rescued by arsenic trioxide and hematopoietic stem cell transplantation. The presence of disseminated intravascular coagulation (DIC) at diagnosis (p = 0.03) was the only factor with survival impact. The five-year event-free survival (EFS) was 84% and 5-year overall survival (OS) was 90% Conclusion: The survival results were comparable to those found in the AIDA protocol, with a low rate of early mortality in relation to the Brazilian reality.

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Despite advances in chemotherapy, the drugs used in cancer treatment remain rather harmful to the cardiovascular system, causing structural and functional cardiotoxic changes. Positron-emission tomography associated with computed tomography (PET/CT) has emerged like a promising technique in the early diagnosis of these adverse drug effects as the myocardial tissue uptake of fluorodeoxyglucose labeled with fluorine-18 (18F-FDG), a glucose analog, is increased after their use. Among these drugs, anthracyclines are the most frequently associated with cardiotoxicity because they promote heart damage through DNA breaks, and induction of an oxidative, proinflammatory, and toxic environment. This review aimed to present the scientific evidence available so far regarding the use of 18F-FDG PET/CT as an early biomarker of anthracycline-related cardiotoxicity. Thus, it discusses the physiological basis for its uptake, hypotheses to justify its increase in the myocardium affected by anthracyclines, importance of 18F-FDG PET/CT findings for cardio-oncology, and primary challenges of incorporating this technique in standard clinical oncology practice.

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INTRODUCTION: Acute promyelocytic leukemia currently presents an excellent chance of cure with protocols based on all-trans-retinoic acid (ATRA) and anthracycline or only differentiation agents. However, high early mortality rates continue to be reported METHODS: Between 2000 and 2018, patients were enrolled and retrospectively analyzed by medical records. A modified AIDA protocol, with a 1-year shortening of the treatment duration, reduction in the number of drugs and a strategy to reduce early mortality by the postponement of the initiation of anthracyclines were employed. Overall and event-free survival rates and toxicity were analyzed RESULTS: Thirty-two patients were enrolled, of whom 56% were female, with a median age of 12 years and 34% belonged to the high-risk group. Two patients had the hypogranular variant and three had another cytogenetic alteration, in addition to the t(15;17). The median start of the first anthracycline dose was 7 days. There were two early deaths (6%) due to central nervous system (CNS) bleeding. All patients achieved molecular remission after the consolidation phase. Two children relapsed and were rescued by arsenic trioxide and hematopoietic stem cell transplantation. The presence of disseminated intravascular coagulation (DIC) at diagnosis (p = 0.03) was the only factor with survival impact. The five-year event-free survival (EFS) was 84% and 5-year overall survival (OS) was 90% CONCLUSION: The survival results were comparable to those found in the AIDA protocol, with a low rate of early mortality in relation to the Brazilian reality.