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ABSTRACT Gemtuzumab ozogamicin (GO) is a CD33‐targeting antibody‐drug conjugate approved for the treatment of CD33‐positive de novo and relapsed and refractory acute myeloid leukemia (AML). Subset analyses have demonstrated improved clinical outcomes in patients with favorable‐risk disease. It is unclear whether the addition of GO to cytarabine and anthracycline chemotherapy (7+3) improves clinical outcomes compared with other conventional regimens for AML. We evaluated the real‐world experience with GO added to 7+3 chemotherapy for patients with favorable risk AML. This retrospective analysis included 174 patients with de novo favorable risk AML undergoing induction chemotherapy between 2010 and 2020. The primary outcome was overall survival (OS) and secondary outcomes included rates of remission, measurable residual disease (MRD), and toxicity. Eighteen patients received GO, 37 received a high‐dose (HD) anthracycline, and 119 received an intermediate‐dose anthracycline. Composite complete remission was achieved in 162 patients (93.1%). Among the 54 patients who were assessed for MRD at remission, 66.7% were undetectable. An improvement in OS was seen for patients who received GO and those treated with HD anthracycline, which was better explained by differences in patient performance status and comorbidities. Patients who received GO did not show increased toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: Doxorubicin is a widely used chemotherapeutic agent for breast cancer but is accompanied by significant side effects due to its systemic delivery. The expression of the transient receptor potential canonical 1 (TRPC1) cation channel subunit correlates with breast cancer progression. This study showed that brief magnetic exposure (10 min) increased doxorubicin uptake into breast cancer cells without harming healthy cells. Heightened TRPC1 expression was correlated with more advanced breast cancer grades as well as with greater doxorubicin uptake. Pharmacologically or genetically silencing TRPC1 activity reduced magnetically induced doxorubicin uptake, whereas overexpression of TRPC1 amplified doxorubicin uptake and increased cancer cell death. This study described a localized and non-invasive magnetic therapy paradigm that could potentially improve breast cancer chemotherapeutic efficacy with less systemically delivered doxorubicin. The loading of TRPC1-enriched cell-derived vesicles with doxorubicin upon magnetic exposure underscored the contribution of TRPC1 in the stimulated uptake of doxorubicin in a minimalized model system. Background/Objectives: Doxorubicin (DOX) is commonly used as a chemotherapeutic agent for the treatment of breast cancer. Nonetheless, its systemic delivery via intravenous injection and toxicity towards healthy tissues commonly result in a broad range of detrimental side effects. Breast cancer severity was previously shown to be correlated with TRPC1 channel expression that conferred upon it enhanced vulnerability to pulsed electromagnetic field (PEMF) therapy. PEMF therapy was also previously shown to enhance breast cancer cell vulnerability to DOX in vitro and in vivo that correlated with TRPC1 expression and mitochondrial respiratory rates. Methods: DOX uptake was assessed by measuring its innate autofluorescence within murine 4T1 or human MCF7 breast cancer cells following magnetic exposure. Cellular vulnerability to doxorubicin uptake was assessed by monitoring mitochondrial activity and cellular DNA content. Results: Here, we demonstrate that 10 min of PEMF exposure could augment DOX uptake into 4T1 and MCF7 breast cancer cells. DOX uptake could be increased by TRPC1 overexpression, whereas inhibiting the activity of TRPC1 channels with SKF-96356 or genetic knockdown, precluded DOX uptake. PEMF exposure enhances DOX-mediated killing of breast cancer cells, reducing the IC50 value of DOX by half, whereas muscle cells, representative of collateral tissues, were less sensitive to PEMF-enhanced DOX-mediated cytotoxicity. Vesicular loading of DOX correlated with TRPC1 expression. Conclusions: This study presents a novel TRPC1-mediated mechanism through which PEMF therapy may enhance DOX cytotoxicity in breast cancer cells, paving the way for the development of localized non-invasive PEMF platforms to improve cancer outcomes with lower systemic levels of DOX. [ABSTRACT FROM AUTHOR]

Background: Trastuzumab has improved breast cancer (BC) prognosis and reduced anthracycline use. However, the characteristic changes of anthracycline-related cardiomyopathy (ARCM) in patients with BC remain unclear. We aimed to update our understanding of ARCM in the trastuzumab era. METHODS: This retrospective observational cohort study included 2959 patients with BC treated with anthracyclines at three regional cancer centers in Niigata City between 1990 and 2020. Seventy-five patients (2.5%) developed ARCM and were categorized into two groups: pre- 2007 (early phase) and post-2007 (late phase), corresponding to before and during the trastuzumab era in Japan. Results: ARCM incidence peaked at 6% in the 1990s, then decreased and stabilized at 2% until the 2010s. Survivors of anthracycline-treated BC increased more rapidly in the late phase, with four times as many patients with ARCM compared to the end of the early phase (26 and six, respectively). Although the rate of change in accumulation from the early phase to the late phase was slight in the anthracycline-treated BC group, it was more pronounced in the ARCM group (P < 0.001). Mean anthracycline use in the late phase was significantly lower than in the early phase (307 vs. 525 mg/m2, P < 0.001). Five-year survival rates in the late phase tended to be higher than early phase (45% and 28%, respectively. P = 0.058). Human epidermal growth factor receptor type 2 (HER2) positivity with trastuzumab therapy in the late phase was an independent predictor for mortality within 10 years (hazard ratio = 0.24, 95% confidence interval: 0.10–0.56; P = 0.001). Conclusions: HER2-positive patients with ARCM receiving trastuzumab therapy had a better prognosis than HER2-positive and HER2-negative patients with ARCM not receiving trastuzumab therapy, and this trend has been increasing in the trastuzumab era. These findings highlight the importance of HER2-targeted treatments in improving prognosis for BC patients with ARCM. [ABSTRACT FROM AUTHOR]

Objectives: Several studies have indicated that dietary interventions may offer protection against the development of cardiac damage in the case of anthracycline-induced cardiomyopathy (AIC). The goal of this study was to assess whether an evidence-based cardioprotective diet can be effective in preventing AIC in patients with breast cancer. Design: Randomized, open-label, controlled trial. The study period was set for 18 weeks, and the data were analyzed by generalized estimating equation modeling and one-way repeated measures analysis of variance. Setting/Location: Shahid Rajaie Hospital affiliated (Tehran, Iran). Subjects: Fifty anthracycline-treated patients with breast cancer. Interventions: Patients were randomized to receive either a 2-hour training in evidence-based cardio-protective diet or Carvedilol 6.25 mg bid. Outcome Measures: The primary outcome was the number of patients with abnormal left ventricular ejection fraction (LVEF) after 18 weeks. Results: At week 18, 12 (48%) out of 25 participants in the cardioprotective diet group had abnormal LVEF in comparison with 21 (84%) out of 25 in the carvedilol group (p = 0.007). Also, 2 (8%) out of 25 in the cardioprotective diet group compared with 7 (28%) out of 25 participants in the carvedilol group had abnormal global longitudinal strain (p = 0.066). The diet group showed significant improvements in the quality-of-life dimensions named "health change" and "general health" compared with the carvedilol group using the Short Form-36 Health Survey questionnaire. Conclusions: This study suggests that an evidence-based cardioprotective diet can contribute to the prevention of AIC. Although current treatments for AIC can be effective, further research is mandatory for more options. [ABSTRACT FROM AUTHOR]

ADCs have emerged as a promising class of therapeutics, combining the targeting specificity of monoclonal antibodies with the cytotoxic potency of small-molecule drugs. Although the majority of approved ADCs are still based on microtubule binder payloads, the recent success of topoisomerase I inhibitors has revitalized interest in the identification of novel agents overcoming present limitations in the field including narrow therapeutic window and chemoresistance. The success of DNA binders as payload for ADCs has been very limited, up to now, due, among other factors, to high hydrophobicity and planar chemical structures resulting in most cases in ADCs with a strong tendency to aggregate, poor plasma stability, and limited therapeutic index. Some of these molecules, however, continue to be of interest due to their favorable properties in terms of cytotoxic potency even in chemoresistant settings, bystander and immunogenic cell death effects, and known combinability with approved drugs. We critically evaluated several clinically tested ADCs containing DNA binders, focusing on payload physicochemical properties, cytotoxic potency, and obtained clinical results. Our analysis suggests that further exploration of certain chemical classes, specifically anthracyclines and duocarmycins, based on the optimization of physicochemical parameters, reduction of cytotoxic potency, and careful design of targeting molecules is warranted. This approach will possibly result in a novel generation of payloads overcoming the limitations of clinically validated ADCs. [ABSTRACT FROM AUTHOR]

Background: Hematologic cancers and solid tumors are frequently treated with anthracyclines. In approximately 9% of patients, they may cause cardiac dysfunction associated to cancer therapy (CTRD). Two-dimensional speckle tracking echocardiography (STE) with global longitudinal strain (GLS) and left atrial strain (LAS) have been developed as a significant and established tools for predicting subsequent CTRD during anthracycline therapy. CTRD is traditionally defined as a decreased left ventricular ejection fraction (LVEF) of less than 50% or ≥ 5% absolute reduction in symptomatic patients or ≥10% in asymptomatic patients. Methods: A cohort prospective study was carried out in the Cardiology department from February 2023 to May 2024. Prior to receiving chemotherapy, 143 patients had evaluations. Serial echocardiography was carried out at 0, 3, 6, and up to a year's follow-up, with 2D-STE conducted at 0 and 3 months. Results &Conclusion: This one-year cohort research comprised 143 patients receiving anthracycline chemotherapy (mean age of 56 years, 77.6% women). We evaluated the predictive relevance of LV GLS, LAs, brain natriuretic peptide (BNP), and troponin (TnT). Cardiotoxcity was consistently associated with proportionate reductions in LV GLS, LASct, and LASr, as well as 3-month increases in BNP levels. Multivariate Cox Regression Analysis showed that at 3 months after treatment, the development of cardiotoxicity was highly accurately and independently linked with Δ LV GLS ≥ 18.4%. [ABSTRACT FROM AUTHOR]

Data on the incidence, timing, and severity of myocardial damage after anthracycline-based chemotherapy (AC) in Japanese patients with breast cancer are limited. We evaluated cancer therapy-related cardiac dysfunction (CTRCD) in Japanese women with breast cancer (n = 51) after the first AC according to the definitions of the 2022 European Society of Cardiology onco-cardiology guideline, including assessment of high-sensitivity troponin I (TnI) and B-type natriuretic peptide (BNP) levels. CTRCD was detected in 67 % of the patients (3.9 %, 7.8 %, 9.8 %, 43 %, 37 %, 22 %, 20 %, and 9.8 % of patients at 1 week and 1, 2, 3, 6, 9, 12, and 15 months post-AC, respectively) without significant left ventricular ejection fraction reduction (<50 %) and heart failure. Elevated TnI levels (>26 pg/mL) were found in 43 % of patients, and elevated BNP levels (≥35 pg/mL) were observed in 22 % of patients during the follow-up period. Approximately two-thirds of the Japanese patients in this study experienced CTRCD, which was frequently observed at 3 or 6 months post-AC. However, all patients with CTRCD were diagnosed with mild asymptomatic CTRCD. Although, these patients were diagnosed with mild asymptomatic CTRCD, careful long-term follow-up will be required. [Display omitted] • Two-thirds of the Japanese patients experienced cancer therapy-related cardiac dysfunction (CTRCD). • CTRCD was frequently observed at 3 or 6 months post-anthracycline-based chemotherapy. • All patients with CTRCD were diagnosed with mild asymptomatic CTRCD. [ABSTRACT FROM AUTHOR]

Abstract Background Anthracyclines are essential in pediatric cancer treatment, but patients are at risk cancer therapy-related cardiac dysfunction (CTRCD). Standardized definitions by the International Cardio-Oncology Society (IC-OS) aim to enhance precision in risk assessment. Objectives Categorize distinct phenotypes among pediatric patients undergoing anthracycline chemotherapy using unsupervised machine learning. Methods Pediatric cancer patients undergoing anthracycline chemotherapy at our institution were retrospectively included. Clinical and echocardiographic data at baseline, along with follow-up data, were collected from patient records. Unsupervised machine learning was performed, involving dimensionality reduction using principal component analysis and K-means clustering to identify different phenotypic clusters. Identified phenogroups were analyzed for associations with CTRCD, defined following contemporary IC-OS definitions, and hypertensive response. Results A total of 187 patients (63.1% male, median age 15.5 years [10.4–18.7]) were included and received anthracycline chemotherapy with a median treatment duration of 0.66 years [0.35–1.92]. Median follow-up duration was 2.78 years [1.31–4.21]. Four phenogroups were identified with following distribution: Cluster 0 (32.6%, n = 61), Cluster 1 (13.9%, n = 26), Cluster 2 (24.6%, n = 46), and Cluster 3 (28.9%, n = 54). Cluster 0 showed the highest risk of moderate CTRCD (HR: 3.10 [95% CI: 1.18–8.16], P = 0.022) compared to other clusters. Cluster 3 demonstrated a protective effect against hypertensive response (HR: 0.30 [95% CI: 0.13– 0.67], P = 0.003) after excluding baseline hypertensive patients. Longitudinal assessments revealed differences in global longitudinal strain and systolic blood pressure among phenogroups. Conclusions Unsupervised machine learning identified distinct phenogroups among pediatric cancer patients undergoing anthracycline chemotherapy, offering potential for personalized risk assessment.

Abstract The combination of de novo hepatic dysfunction and AML in a medically fit patient presents an unusual predicament. Cases present with obstructive jaundice and imaging typically shows diffuse hepatosplenomegaly, with some cases visualizing myeloid sarcomas causing biliary ductal dilatation. Guidelines for use of anthracyclines in hepatic dysfunction recommend dose reduction based on bilirubin blood levels, either to 50% or even omitting anthracycline. Randomized data however has shown that reduction of anthracycline in AML induction decreases overall survival and lowers remission rate. This case suggests, along withthe literature reviewed, that some medically fit patients with hepatic dysfunction benefit from and tolerate intensive induction therapy well without toxicity.

Abstract Background The presence and burden of coronary artery calcium (CAC) is a strong predictor of cardiovascular events. Current guidelines of the European Society of Cardiology (ESC) for cardio-oncology do not recommend the use of the CAC score to determine the status of risk in cancer patients. The aim of this study is to evaluate the presence and burden of CAC on cardiac tomography and the distribution of the cardiovascular toxicity risk factors in patients with moderate and high baseline risk of cancer therapy-related cardiovascular toxicity. Methods The study prospectively included cancer patients, diagnosed and qualified for systemic treatment with anthracycline chemotherapy. Clinical data and blood samples were collected from all patients. Additionally, the echocardiography and coronary computed tomography (CCTA) with the calculation of the coronary artery calcium (CAC) score were performed. Results A total of 80 patients (mean age 60.5 years, 75 female) were included in the study. The majority of patients (62, 77.5%) had breast cancer, 11 (13.8%) were diagnosed with sarcoma, and 7 (8.8%) with lymphoma. There were 42 (52.5%) patients classified as having moderate (MR) and 38 (47.5%) as having high risk (HR) of cancer therapy-related cardiovascular toxicity according to current ESC guidelines. In comparison with moderate risk, high risk patients were older and more likely to have hypertension, hyperlipidaemia and chronic kidney disease. The mean coronary artery calcium score was significantly higher in the HR group (150.4 vs. 24.8; p = 0.000). Furthermore, cardiac biomarkers were also higher in high-risk patients (p = 0.000). In echocardiographic parameters global longitudinal strain (GLS) was lower (p = 0.012), and diastolic dysfunction was more common in the HR group. However, the left ventricle ejection fraction (LVEF) was similar in the MR and HR groups. Conclusions In patients at high and moderate risk for cancer therapy-related cardiovascular toxicity, cardiovascular toxicity risk factors were common and more prevalent in the high-risk group. The coronary artery calcium score was also significantly higher in the high-risk group. Assessing the presence and burden of coronary artery calcium is an attractive option to assess additional cardiovascular risk in cancer patients.

Background: Despite lower chemotherapy use in older triple-negative breast cancer (TNBC) patients, their outcomes match younger counterparts. We compared outcomes in early-stage TNBC patients by age receiving chemotherapy at a major cancer center with a national TNBC database. Methods: Retrospective study using institutional data on stage I-III TNBC (ER/PR < 10%) women with neoadjuvant/adjuvant chemotherapy. Based on their ages at diagnosis, patients were stratified into four categories: ≤40, 41–59, 60–69, and ≥ 70 years. Demographic and clinical characteristics recorded included race, disease stage, ER/PR positivity, treatment regimen, lymphatic or vascular invasion (LVI), histologic grade, Ki-67 level, body mass index (BMI), and pathologic complete response (pCR) following neoadjuvant treatment and are summarized using descriptive statistics. The primary endpoints were overall survival (OS), disease-free survival (DFS), and distant disease-free survival (DDFS); all were estimated using the Kaplan-Meier method. Both univariate and multivariate (MV) Cox regressions were applied to evaluate the impact of important covariates on these time-to-event endpoints. Results: Of the 2336 patients studied, 492 (21.1%) were ≤ 40 years old, 1239 (53.1%) were 41–59, 461 (19.7%) were 60–69, and 144 (6.2%) were ≥ 70. In the univariate regression model of OS/DFS/DDFS, age ≥ 70 was significantly associated with worse OS (p = 0.0217); other factors associated with worse OS were non-anthracycline-based chemotherapy, higher tumor stage, and neoadjuvant chemotherapy. The multivariate Cox regression model, adjusted for race and stage, showed no significant effects of age on OS; however, patients ≥ 70 years old who received non-anthracycline treatment combinations had worse DFS (hazard ratio = 0.349 vs. 1.049, p = 0.0293) and DDFS (hazard ratio = 0.317 vs. 1.016, p = 0.0251) than patients ≤ 40 years old. DFS from MV model after adjusting for age, race, and disease stage, the hazard ratio between anthracycline + taxane treatments and anthracycline + other treatments in patients ≥ 70 years old was statistically significantly lower than in patients ≤ 40 years old (hazard ratios [HRs] = 0.349 vs. 1.049, p = 0.0293). Conclusions: Our findings indicate that outcomes such as DFS are less favorable in older compared to younger patients with early-stage TNBC, primarily in those who did not receive an anthracycline based chemotherapy regimen. [ABSTRACT FROM AUTHOR]

Aclarubicin (aclacinomycin A) is one of the anthracycline antineoplastic antibiotics with a multifaceted mechanism of antitumor activity. As a second-generation drug, it offers several advantages compared to standard anthracycline drugs such as doxorubicin or daunorubicin, which could position it as a potential blockbuster drug in antitumor therapy. Key mechanisms of action for aclarubicin include the inhibition of both types of topoisomerases, suppression of tumor invasion processes, generation of reactive oxygen species, inhibition of chymotrypsin-like activity, influence on cisplatin degradation, and inhibition of angiogenesis. Therefore, aclarubicin appears to be an ideal candidate for antitumor therapy. However, despite initial interest in its clinical applications, only a limited number of high-quality trials have been conducted thus far. Aclarubicin has primarily been evaluated as an induction therapy in acute myeloid and lymphoblastic leukemia. Studies have indicated that aclarubicin may hold significant promise for combination therapies with other anticancer drugs, although further research is needed to confirm its potential. This paper provides an in-depth exploration of aclarubicin's diverse mechanisms of action, its pharmacokinetics, potential toxicity, and the clinical trials in which it has been investigated. [ABSTRACT FROM AUTHOR]

Purpose: Anthracycline-cyclophosphamide followed by docetaxel-containing chemotherapy is effective for perioperative breast cancer treatment. However, these treatments frequently induce oral mucositis (OM), with an incidence ranging from 20 to 50%. The association of OM development between different chemotherapeutic treatments remains unclear. Consequently, this study aimed to compare OM development during docetaxel-containing chemotherapy between patients with and without OM experience during previous anthracycline-cyclophosphamide treatments to assess the association between OM development and treatment regimens. Methods: Seventy-two patients with breast cancer receiving anthracycline-cyclophosphamide followed by docetaxel-containing chemotherapy as a perioperative treatment were categorized into the control (no prior OM experience with anthracycline-cyclophosphamide) and OM-experience (OM development during previous treatment) groups and retrospectively evaluated. The primary endpoint was the incidence of all-grade OM in the first docetaxel-containing chemotherapy cycle. Additionally, the incidences of OM and dysgeusia during all treatment cycles and factors associated with the incidence of OM were evaluated. Results: The incidence of all-grade OM in the first cycle was significantly higher in the OM-experience group (54.2%) than in the control group (10.4%; P < 0.0001). Furthermore, its incidence in all treatment cycles was higher in the OM-experience group (66.7%) than in the control group (12.5%, P < 0.0001). However, the incidence of dysgeusia did not differ between the groups. Multivariate logistic regression analysis revealed OM experience during previous anthracycline-cyclophosphamide treatment and concomitant pertuzumab use as independent risk factors for OM development in subsequent docetaxel-containing chemotherapy. Conclusion: Our study suggests that patients experiencing OM with anthracycline-cyclophosphamide during perioperative breast cancer treatment exhibit symptoms following subsequent docetaxel-containing chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To examine the differential effect of non- and anthracycline-based chemotherapy on fatigue over 12 months post-diagnosis among breast cancer survivors. Methods: This study is based on a prospective Wake Forest NCI Community Oncology Research Program (NCORP) multicenter cohort study (WF-97415) of women with stage I to III breast cancer and non-cancer controls. Analyses compared those: 1) receiving, or 2) not receiving anthracycline chemotherapy, 3) receiving aromatase inhibitors (AIs) without chemotherapy, with 4) a comparator group without a history of cancer. In-person clinic assessments were conducted at: baseline (prior to chemotherapy or start of AI therapy), and 3 and 12 months after baseline. The Functional Assessment of Chronic Illness Therapy-Fatigue scale was the primary outcome. Estimated least squares means by group using mixed models with a random subject effect, fixed effects of time and group, and the interaction between time and group was used to compare groups across time, controlling for age, comorbidities, and treatment variables. Results: Among 284 women (mean age = 53.4 years, sd 11.9 years), there was a significant (p < 0.0001) group by time interaction, with a sharp increase in fatigue at 3 months in the two chemotherapy groups in comparison to the non-chemotherapy and non-cancer controls. The two chemotherapy groups did not significantly differ in fatigue at any time point. Conclusion: Women with breast cancer who receive non- or anthracycline-based chemotherapy experience similar trends in and levels of fatigue within the first year of treatment and greater fatigue than women receiving AIs alone or women without breast cancer. [ABSTRACT FROM AUTHOR]

Left ventricular dysfunction in dogs after the administration of doxorubicin (DOX) has been extensively examined. However, the effects of DOX on right ventricular (RV) function remain unknown. Therefore, the present study investigated whether the chemotherapy treatment with DOX decreases RV function. Twelve dogs (five with multicentric lymphoma, four with hemangiosarcoma, two with thyroid cancer, and one with lung adenocarcinoma) that received at least two doses of DOX were prospectively enrolled. Echocardiography and the measurement of troponin I were performed prior to each administration of DOX and approximately one month after the last administration. Right ventricular function was assessed by the RV fractional area change and RV Tei index. Two (n=4), three (n=3), four (n=3), and five (n=2) doses of DOX were administered. While no significant differences were observed in the RV fractional area change, the RV Tei index was significantly impaired after two doses of DOX. Troponin I level significantly increased after four doses. Cumulative doses of DOX correlated with the RV Tei index (r=0.77, P<0.001). The present results demonstrated that the chemotherapy treatment with DOX decreased RV function in a dose-dependent manner in dogs. [ABSTRACT FROM AUTHOR]

Anthracycline chemotherapy-related cardiac dysfunction is believed to be refractory to conventional pharmacological therapy and is associated with a poor prognosis. Increased heart rate (HR) is a known marker of cardiovascular outcomes for various categories of heart failure (HF). However, little interest has been expressed regarding increased HR after anthracycline chemotherapy. Aim of this study was to investigate the effect of increased HR soon after completion of anthracycline chemotherapy on subsequent left ventricular (LV) ejection fraction (LVEF) in cancer patients. We studied 172 patients with breast cancer and malignant lymphoma with preserved LVEF (≥ 50 %) and sinus rhythm treated with anthracyclines. Electrocardiography was performed before and soon after completion of anthracycline chemotherapy (2.3 months), and echocardiography before and late after completion of anthracycline chemotherapy (10.5 months). HR significantly increased from 74.2 ± 14.2 bpm to 75.9 ± 13.2 bpm (P = 0.05) soon after completion of anthracycline chemotherapy, while LVEF subsequently significantly decreased from 65.3 ± 5.5 % to 62.4 ± 6.1 % (P < 0.01) late after completion of anthracycline chemotherapy. Patients whose HR increased ≥10 bpm subsequently showed a significantly greater decrease in LVEF than those whose HR increased <10 bpm [−4.9 % (−32.7 % - 10.8 %) vs. -2.2 % (−21.2 % - 12.9 %), p = 0.04]. Multivariable logistic regression analysis showed that an increase in HR soon after completion of anthracycline chemotherapy was independently associated with a subsequent decrease in LVEF (odds ratio: 1.022, 95 % confidential interval; 1.008–1.037, P = 0.002). Our findings may have a novel effect on the management of cancer patients scheduled for anthracycline chemotherapy. [Display omitted] • Heart rate (HR) increased soon after completion of anthracycline chemotherapy. • Left ventricular ejection fraction (LVEF) subsequently decreased late after completion of anthracycline chemotherapy. • Patients whose HR increased ≥10 bpm showed a greater decrease in LVEF. • Increased HR after anthracycline was associated with subsequent decrease in LVEF. [ABSTRACT FROM AUTHOR]

Opinion Statement: Anthracycline (ANT)-induced cardiotoxicity (AIC) is a particularly prominent form of cancer therapy-related cardiovascular toxicity leading to the limitations of ANTs in clinical practice. Even though AIC has drawn particular attention, the best way to treat it is remaining unclear. Updates to AIC therapy have been made possible by recent developments in research on the underlying processes of AIC. We review the current molecular pathways leading to AIC: 1) oxidative stress (OS) including enzymatic-induced and other mechanisms; 2) topoisomerase; 3) inflammatory response; 4) cardiac progenitor cell damage; 5) epigenetic changes; 6) renin-angiotensin-aldosterone system (RAAS) dysregulation. And we systematically discuss current prevention and treatment strategies and novel pathogenesis-based therapies for AIC: 1) dose reduction and change; 2) altering drug delivery methods; 3) antioxidants, dexrezosen, statina, RAAS inhibitors, and hypoglycemic drugs; 4) miRNA, natural phytochemicals, mesenchymal stem cells, and cardiac progenitor cells. We also offer a fresh perspective on the management of AIC by outlining the current dilemmas and challenges associated with its prevention and treatment. [ABSTRACT FROM AUTHOR]

Aim: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) lower anthracycline-induced cardiotoxicity. Methods: PubMed and Google Scholar were searched until September 2023 for studies regarding SGLT2i for treating anthracycline-induced cardiotoxicity. Overall mortality and cardiovascular events were considered. Using a random-effects model, data pooled RR and HR at a 95% confidence interval (CI). Results: 3 cohort studies were identified, analyzing 2817 patients. Results display a significant reduction in overall mortality [RR = 0.52 (0.33–0.82); p = 0.005; I2= 32%], HF hospitalization [RR = 0.20 (0.04–1.02); p = 0.05; I2= 0%] and no significant reduction in HF incidence [RR = 0.50 (0.20–1.16); p = 0.11, I2= 0%]. Conclusion: SGLT2i mitigates mortality and hospitalization due to heart failure, improving cancer patient's chances of survival by undergoing anthracycline treatment. Plain Language Summary What is this article about? This article explores the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) as a solution for reducing anthracycline-induced cardiotoxicity. Anthracycline is an established subclass of chemotherapeutic drugs which has been known to cause harm to the heart. The study, conducted a systematic search of PubMed and Google Scholar up until September 2023, assessing the effects of SGLT2i on overall mortality and cardiovascular events in cancer patients, regardless of the presence or absence of diabetes mellitus and the effectiveness of SGLT2i as a cardiotoxic therapy in cancer patients. What were the results? The analysis of studies involving 2817 patients showed findings indicating that giving SGLT2i could lower the chances of anthracycline-induced heart problems in cancer patients undergoing treatment. The findings showed a striking decrease in hospitalization due to heart failure and overall mortality whereas the findings for the effect of SGLT2i on incidence of heart failure were insignificant. The encouraging outcomes offer valuable insights that could help enhance the outlook and chances of survival for individuals with cancer. What do the results of the study mean? These findings indicate that SGLT2i notably reduces the risk of death and cardiovascular issues, like being hospitalized due to heart failure, in cancer patients undergoing anthracycline treatment. This has significant implications for how doctors might treat cancer patients in practice. Including SGLT2i in the treatment plan could improve the survival prospects of these patients, offering a promising advancement in handling anthracycline-induced heart issues with side effects that can be managed. Graphical Abstract Article highlights This meta-analysis assesses the cardio-protective effects of sodium-glucose transporter-2 inhibitor (SGLT2i) in cancer patients undergoing anthracycline therapy. The systematic review identified 3 cohort studies. Using a random-effects model, data for all outcomes of interest pooled risk ratio (RR) and hazard ratio (HR) at 95% confidence interval (CI) for this analysis. The pooled results showed a significant reduction in overall mortality and heart failure hospitalization in patients treated with SGLT2i compared with non-SGLT2i. [ABSTRACT FROM AUTHOR]

Purpose of Review: To provide an overview of (a) protective effects on mitochondria induced by remote ischemic conditioning (RIC) and (b) mitochondrial damage caused by anticancer therapy. We then discuss the available results of studies on mitochondrial protection via RIC in anticancer therapy-induced cardiotoxicity. Recent Findings: In three experimental studies in healthy mice and pigs, there was a RIC-mediated protection against anthracycline-induced cardiotoxicity and there was some evidence of improved mitochondrial function with RIC. The RIC-mediated protection was not confirmed in the two available studies in cancer patients. In adult cancer patients, RIC was associated with an adverse outcome. There are no data on mitochondrial function in cancer patients. Summary: Studies in tumor-bearing animals are needed to determine whether RIC does not interfere with the anticancer properties of the drugs and whether RIC actually improves mitochondrial function, ultimately resulting in improved cardiac function. [ABSTRACT FROM AUTHOR]

Anthracycline drugs mainly include doxorubicin, epirubicin, pirarubicin, and aclamycin, which are widely used to treat a variety of malignant tumors, such as breast cancer, gastrointestinal tumors, lymphoma, etc. With the accumulation of anthracycline drugs in the body, they can induce serious heart damage, limiting their clinical application. The mechanism by which anthracycline drugs cause cardiotoxicity is not yet clear. This review provides an overview of the different types of cardiac damage induced by anthracycline-class drugs and delves into the molecular mechanisms behind these injuries. Cardiac damage primarily involves alterations in myocardial cell function and pathological cell death, encompassing mitochondrial dysfunction, topoisomerase inhibition, disruptions in iron ion metabolism, myofibril degradation, and oxidative stress. Mechanisms of uptake and transport in anthracycline-induced cardiotoxicity are emphasized, as well as the role and breakthroughs of iPSC in cardiotoxicity studies. Selected novel cardioprotective therapies and mechanisms are updated. Mechanisms and protective strategies associated with anthracycline cardiotoxicity in animal experiments are examined, and the definition of drug damage in humans and animal models is discussed. Understanding these molecular mechanisms is of paramount importance in mitigating anthracycline-induced cardiac toxicity and guiding the development of safer approaches in cancer treatment. [ABSTRACT FROM AUTHOR]

• The effect of sex on chemotherapy-associated heart failure has not been clearly established. • In this retrospective cohort study, female sex was not associated with heart failure after anthracycline treatment in multivariable analyses, including in a Cox proportional hazards model and in a competing risk model accounting for all-cause death. • Age, coronary artery disease and hematopoietic stem cell transplant were associated with an increased risk of incident heart failure within 5 years after anthracycline treatment in a multivariable Cox proportional hazards model. • Age and body mass index were associated with an increased risk of incident heart failure within 5 years after anthracycline treatment in a multivariable competing risk model. Female sex is frequently cited as a risk factor for anthracycline cardiotoxicity based on pediatric data, but the role of sex in the development of cardiotoxicity has not been clearly established in adults. To assess the effect of female sex on the development of incident heart failure (HF) in adult patients treated with anthracyclines. This was a retrospective cohort study of 1525 adult patients with no prior history of HF or cardiomyopathy who were treated with anthracyclines between 1992 and 2019. The primary outcome was new HF within 5 years of the first dose of anthracyclines. The effect of sex was assessed using Cox proportional hazards and competing risk models. Over a median (IQR) follow-up of 1.02 (0.30–3.01) years, 4.78% of patients developed HF (44 men and 29 women). Female sex was not associated with the primary outcome in a multivariable Cox proportional hazards model (HR 0.87; 95% CI 0.53–1.43; P = 0.58). Similar results were observed in a multivariable model accounting for the competing risk of death (HR 0.94; 95% CI 0.39–2.25; P = 0.88). Age, coronary artery disease and hematopoietic stem cell transplant were associated with the primary outcome in a multivariable Cox proportional hazards model. Age and body mass index were associated with the primary outcome in a multivariable competing risk model. In this large, single-center, retrospective cohort study, female sex was not associated with incident HF in adult patients treated with anthracyclines. Female sex is frequently cited as a risk factor for anthracycline cardiotoxicity based on pediatric data, but the role of sex in the development of cardiotoxicity has not been clearly established in adults. In this retrospective cohort study, we assessed the effect of female sex on the development of incident heart failure in adult patients treated with anthracyclines. Using Cox proportional hazards and competing risk regression models, we found that there was no association between female sex and heart failure after treatment with anthracyclines. [ABSTRACT FROM AUTHOR]

Objectives: Currently, there are no biomarkers for early detection of anthracycline-induced cardiotoxicity. This study explores whether plasma levels of microRNA34a (miR34a) could serve as predictive markers for cardiotoxicity in breast cancer patients undergoing anthracycline-based chemotherapy. Methods: Forty-four breast cancer patients receiving anthracycline-based chemotherapy for the first time were enrolled. Plasma samples were collected before and after chemotherapy to assess cardiac troponin-I (cTn-I), miR34a, premiR34a levels, and echocardiographic strain. Results: We observed statistically significant increases in cTn-I, miR34a, and pre-miR34a levels post-treatment, with miR34a and pre-miR34a increasing by 2.5-fold and 2.3-fold, respectively. Echocardiographic analysis showed significant reductions in global longitudinal strain (GLS) from baseline after anthracycline treatment. Increases in plasma miR34a levels post-doxorubicin did not correlate with changes in cTn-I or GLS. Furthermore, while a higher miR34a/pre-miR34a ratio was noted in patients with myocardial deformation compared to those without, this did not reach statistical significance. Conclusion: Despite increases in miR34a levels following anthracycline-based chemotherapy, there is no clear statistical correlation with early myocardial damage. This suggests that miR34a is not a reliable biomarker for anthracyclineinduced cardiotoxicity, underscoring the need for further research to identify more definitive predictive markers for cardiotoxicity in breast cancer patients. [ABSTRACT FROM AUTHOR]

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Anthracyclines have significantly improved the survival of children with malignant tumors, but the associated cardiotoxicity, an effect now under the purview of pediatric cardio-oncology, due to its cumulative and irreversible effects on the heart, limits their clinical application. A systematic screening and risk stratification approach provides the opportunity for early identification and intervention to mitigate, reverse, or prevent myocardial injury, remodeling, and dysfunction associated with anthracyclines. This review summarizes the risk factors, surveillance indexes, and preventive strategies of anthracycline-related cardiotoxicity to improve the safety and efficacy of anthracyclines. [ABSTRACT FROM AUTHOR]

Background: Anthracycline- and taxane-based chemotherapy regimens are established treatments for human epidermal growth factor receptor (HER)2-negative early-stage breast cancer with high risk of recurrence. This study examined the prevalence of these chemotherapy regimens as perioperative therapy, the patterns of retreatment, and factors influencing prescription choices in Japan. Methods: This observational cohort study focused on high-risk early-stage breast cancer patients not undergoing anti-HER2 therapy, utilizing data from a hospital-based claims database in Japan spanning from April 2008 to September 2021. Results: Of 42,636 high-risk patients who underwent breast cancer surgery, 32,133 (75.4%) were categorized as having luminal-type (received endocrine therapy) and 10,503 (24.6%) as having triple-negative cancer (not receiving any endocrine therapies). Most patients (98.7%) with luminal-type breast cancer received perioperative therapy, and 40.3% of those received anthracycline/taxane. In the triple-negative group, 57.0% of all patients received perioperative therapy and of those, 93.4% received anthracycline/taxane. Being over 40 years old, having an early stage (clinical stage ≤ II), and receiving treatment in non-specialized facilities were associated with less use of anthracycline/taxane in the luminal-type group. For the triple-negative group, associated factors with less use of anthracycline/taxane included being over 60 years old, treatment in small hospital (capacity < 200 beds), and treatment in non-specialized facilities. Conclusions: Approximately half the patients in both the luminal-type and triple-negative groups were prescribed anthracycline and/or taxane for perioperative chemotherapy. The choice was associated with patient age, cancer stage, and the scale and specialization of the treatment facilities. This study sheds light on the current state of breast cancer treatment practices in Japan. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents; however, their use is hampered by subsequent cardiotoxicity risk. Our understanding of cardiomyocyte protective pathways activated following anthracycline-induced cardiotoxicity (AIC) remains incomplete. Insulin-like growth factor binding protein (IGFBP) 3 (Igfbp-3), the most abundant IGFBP family member in the circulation, is associated with effects on the metabolism, proliferation, and survival of various cells. Whereas Igfbp-3 is induced by Dox in the heart, its role in AIC is ill-defined. We investigated molecular mechanisms as well as systems-level transcriptomic consequences of manipulating Igfbp-3 in AIC using neonatal rat ventricular myocytes and human-induced pluripotent stem cell-derived cardiomyocytes. Our findings reveal that Dox induces the nuclear enrichment of Igfbp-3 in cardiomyocytes. Furthermore, Igfbp-3 reduces DNA damage, impedes topoisomerase IIβ expression (Top2β) which forms Top2β-Dox-DNA cleavage complex leading to DNA double-strand breaks (DSB), alleviates detyrosinated microtubule accumulation-a hallmark of increased cardiomyocyte stiffness and heart failure-and favorably affects contractility following Dox treatment. These results indicate that Igfbp-3 is induced by cardiomyocytes in an effort to mitigate AIC.

Raz Muhammed HamaSalih Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Slemani, Kurdistan Region, IraqCorrespondence: Raz Muhammed HamaSalih, College of Pharmacy, University of Sulaimani, Town Campus, Slemani, Kurdistan Region, 46001, Iraq, Tel +9647700591984, Email raz.hamasalih@univsul.edu.iqBackground: Doxorubicin (DOX) is used to treat various types of cancers. However, its use is restricted by cardiotoxicity, a leading cause of morbidity and mortality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) may be associated with cardioprotective properties.Purpose: This study aims to determine the protective effects of different semaglutide (SEM) doses on DOX-induced cardiotoxicity in a rat model.Methodology: Thirty-five female Wistar rats were divided into five groups. The first group received distilled water as a negative control (NC); the positive control (PC) group received distilled water plus DOX; the third group (SL) received a low dose of SEM (0.06 mg/kg) plus DOX; the fourth group (SM) received a moderate dose of SEM (0.12 mg/kg) plus DOX; and the fifth group (SH) received a high dose of SEM (0.24 mg/kg) plus DOX. Blood samples were collected on day 8 to assess serum troponin, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total lipid profile, and vascular cell adhesion molecule 1 (VCAM-1). Cardiac tissue was sent for histopathological analysis.Results: DOX increased the total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), LDH, and CKP levels. Moderate and high doses of semaglutide significantly reduced serum cholesterol levels (&ast;p = 0.0199), (&ast;&ast;p = 0.0077), respectively. A significant reduction (&ast;&ast;&ast;p = 0.0013) in total body weight after treatment with SEM was observed in the SL group and a highly significant reduction (&ast;&ast;&ast;&ast;p < 0.0001) was observed in the SM and SH groups. SEM at all doses reduced CPK levels. The SL group showed a significant reduction in troponin level (&ast;p=0.0344). Serum LDH levels were reduced by all three SEM doses. The histopathological findings support the biochemical results.Conclusion: Semaglutide may possess cardioprotective properties against DOX-induced cardiotoxicity in a rat model by decreasing serum biochemical markers of cardiotoxicity.Keywords: cardioprotection, GLP-1 receptor agonists, anthracycline, rodents

Abstract Background Previous studies have shown that the addition of platinum to neoadjuvant chemotherapy (NAC) improved outcomes for patients with triple-negative breast cancer (TNBC). However, no studies have assessed the efficacy and safety of the combination of taxane and lobaplatin. In this study, we conducted a randomized controlled phase II clinical study to compare the efficacy and safety of taxane combined with lobaplatin or anthracycline. Methods We randomly allocated patients with stage I–III TNBC into Arm A and Arm B. Arm A received six cycles of taxane combined with lobaplatin (TL). Arm B received six cycles of taxane combined with anthracycline and cyclophosphamide (TEC) or eight cycles of anthracycline combined with cyclophosphamide and sequential use of taxane (EC-T). Both Arms underwent surgery after NAC. The primary endpoint was the pathologic complete response (pCR). Secondary endpoints were event-free survival (EFS), overall survival (OS), and safety. Results A total of 103 patients (51 in Arm A and 52 in Arm B) were assessed. The pCR rate of Arm A was significantly higher than that of Arm B (41.2% vs. 21.2%, P = 0.028). Patients with positive lymph nodes and low neutrophil-to-lymphocyte ratio (NLR) benefited significantly more from Arm A than those with negative lymph nodes and high NLR (P interaction = 0.001, P interaction = 0.012, respectively). There was no significant difference in EFS (P = 0.895) or OS (P = 0.633) between the two arms. The prevalence of grade-3/4 anemia was higher in Arm A (P = 0.015), and the prevalence of grade-3/4 neutropenia was higher in Arm B (P = 0.044). Conclusions Neoadjuvant taxane plus lobaplatin has shown better efficacy than taxane plus anthracycline, and both regimens have similar toxicity profiles. This trial may provide a reference for a better combination strategy of immunotherapy in NAC for TNBC in the future.

Abstract Background Doxorubicin (DXR) is an effective chemotherapeutic agent. DOX-induced cardiomyopathy (DICM), a major limitation of DXR, is a complication with limited treatment options. We previously reported that Red Ginseng (steamed and dried the root of Panax Ginseng cultivated for over six years; RGin) is beneficial for the treatment of DICM. However, the mechanism underlying the action of RGin remains unclear. In this study, we investigated the mechanism of action underlying the efficacy of RGin in the treatment of DICM. Methods Four-week-old DBA/2 mice were divided into: vehicle, DXR, RGin, and DXR + RGin (n = 10/group). Mice were treated with DXR (4 mg/kg, once a week, accumulated 20 mg/kg, i.p.) or RGin (0.5 g/kg, three times a week, i.p.). To evaluate efficacy, the survival rate and left ventricular ejection fraction (LVEF) were measured as a measure of cardiac function, and cardiomyocytes were subjected to Masson trichrome staining. To investigate the mechanism of action, western blotting was performed to evaluate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1, transferrin receptor (TfR), and other related proteins. Data were analyzed using the Easy R software. Between-group comparisons were performed using one-way analysis of variance and analyzed using a post-hoc Tukey test. Survival rates were estimated using the Kaplan–Meier method and compared using the log-rank test. P

Abstract The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.

Abstract Background Long-term cardiovascular complications are common among pediatric cancer survivors, and anthracycline-induced hypertension has become an essential reason for concern. Compared to non-cancer controls, survivors have a higher prevalence of hypertension, and as they age, their incidence rises, offering significant dangers to cardiovascular health. Main body Research demonstrates that exposure to anthracyclines is a major factor in the development of hypertension in children who have survived cancer. Research emphasizes the frequency and risk factors of anthracycline-induced hypertension, highlighting the significance of routine measurement and management of blood pressure. Furthermore, cardiovascular toxicities, such as hypertension, after anthracycline-based therapy are a crucial be concerned, especially for young adults and adolescents. Childhood cancer survivors deal with a variety of cardiovascular diseases, such as coronary artery disease and cardiomyopathy, which are made worse by high blood pressure. In order to prevent long-term complications, it is essential to screen for and monitor for anthracycline-induced hypertension. Echocardiography and cardiac biomarkers serve as essential tools for early detection and treatment. In order to lower cardiovascular risks in pediatric cancer survivors, comprehensive management strategies must include lifestyle and medication interventions in addition to survivor-centered care programs. Short conclusion Proactive screening, monitoring, and management measures are necessary for juvenile cancer survivors due to the substantial issue of anthracycline-induced hypertension in their long-term care. To properly include these strategies into survivor-ship programs, oncologists, cardiologists, and primary care physicians need to collaborate together. The quality of life for pediatric cancer survivors can be enhanced by reducing the cardiovascular risks linked to anthracycline therapy and promoting survivor-centered care and research.

Objective: Anthracycline administration in children is associated with cardiac dysfunction. Speckle-tracking echocardiography (STE) can detect subclinical cardiac damage that may go undetected by conventional two-dimensional (2D) echocardiography. This study aims to investigate medium-term anthracycline cardiotoxicity using STE and determine a safer administrable level of anthracyclines (ACs). Methods: This observational case–control study enrolled 37 healthy controls and 78 pediatric cancer survivors who received chemotherapy. The patients were divided into two groups: cardiotoxic received (CR) and cardiotoxic free (CF). Data on segmental longitudinal strain (LS), global LS (GLS), and 2D echocardiographic parameters were collected after a drug-free period of at least one year. Results: A total of 115 children with a mean age of 108 ± 55 months, of whom 66% were males, were included in the study. Both the groups of cancer survivors exhibited significantly reduced GLS compared to healthy controls (CR vs. controls, P = 0.001; CF vs. controls, P = 0.013), but no significant difference in left ventricular ejection fraction (LVEF) was observed (P = 0.75). Overall, cancer survivors treated with ACs demonstrated a significant reduction in strain in 10 left ventricular segments, particularly in the basal segments (P < 0.05). Among CR patients, those with impaired GLS (n = 43, GLS worse than −21.9) had significantly higher mean age and cumulative anthracycline dose compared to CR patients with normal GLS (age, P = 0.024; anthracycline dosage, P = 0.036). Using an anthracycline cutoff of 223 mg/m2 resulted in a higher detection rate (49% vs. 25%) and fewer missed cases (51% vs. 74%) compared to the 360 mg/m2 anthracycline cutoff. Conclusion: Childhood cancer survivors demonstrate significantly reduced GLS while preserving a normal LVEF, which does not differ significantly from reference values of healthy children. The reduction in strain appears to be associated with higher anthracycline doses and older age. Lowering the anthracycline threshold to 223 mg/m2 may improve the predictability of a decline in cardiac function using strain imaging at medium-term follow-up.

Background: Previous studies have shown that the addition of platinum to neoadjuvant chemotherapy (NAC) improved outcomes for patients with triple-negative breast cancer (TNBC). However, no studies have assessed the efficacy and safety of the combination of taxane and lobaplatin. In this study, we conducted a randomized controlled phase II clinical study to compare the efficacy and safety of taxane combined with lobaplatin or anthracycline. Methods: We randomly allocated patients with stage I–III TNBC into Arm A and Arm B. Arm A received six cycles of taxane combined with lobaplatin (TL). Arm B received six cycles of taxane combined with anthracycline and cyclophosphamide (TEC) or eight cycles of anthracycline combined with cyclophosphamide and sequential use of taxane (EC-T). Both Arms underwent surgery after NAC. The primary endpoint was the pathologic complete response (pCR). Secondary endpoints were event-free survival (EFS), overall survival (OS), and safety. Results: A total of 103 patients (51 in Arm A and 52 in Arm B) were assessed. The pCR rate of Arm A was significantly higher than that of Arm B (41.2% vs. 21.2%, P = 0.028). Patients with positive lymph nodes and low neutrophil-to-lymphocyte ratio (NLR) benefited significantly more from Arm A than those with negative lymph nodes and high NLR (Pinteraction = 0.001, Pinteraction = 0.012, respectively). There was no significant difference in EFS (P = 0.895) or OS (P = 0.633) between the two arms. The prevalence of grade-3/4 anemia was higher in Arm A (P = 0.015), and the prevalence of grade-3/4 neutropenia was higher in Arm B (P = 0.044). Conclusions: Neoadjuvant taxane plus lobaplatin has shown better efficacy than taxane plus anthracycline, and both regimens have similar toxicity profiles. This trial may provide a reference for a better combination strategy of immunotherapy in NAC for TNBC in the future. [ABSTRACT FROM AUTHOR]

Background: Long-term cardiovascular complications are common among pediatric cancer survivors, and anthracycline-induced hypertension has become an essential reason for concern. Compared to non-cancer controls, survivors have a higher prevalence of hypertension, and as they age, their incidence rises, offering significant dangers to cardiovascular health. Main body: Research demonstrates that exposure to anthracyclines is a major factor in the development of hypertension in children who have survived cancer. Research emphasizes the frequency and risk factors of anthracycline-induced hypertension, highlighting the significance of routine measurement and management of blood pressure. Furthermore, cardiovascular toxicities, such as hypertension, after anthracycline-based therapy are a crucial be concerned, especially for young adults and adolescents. Childhood cancer survivors deal with a variety of cardiovascular diseases, such as coronary artery disease and cardiomyopathy, which are made worse by high blood pressure. In order to prevent long-term complications, it is essential to screen for and monitor for anthracycline-induced hypertension. Echocardiography and cardiac biomarkers serve as essential tools for early detection and treatment. In order to lower cardiovascular risks in pediatric cancer survivors, comprehensive management strategies must include lifestyle and medication interventions in addition to survivor-centered care programs. Short conclusion: Proactive screening, monitoring, and management measures are necessary for juvenile cancer survivors due to the substantial issue of anthracycline-induced hypertension in their long-term care. To properly include these strategies into survivor-ship programs, oncologists, cardiologists, and primary care physicians need to collaborate together. The quality of life for pediatric cancer survivors can be enhanced by reducing the cardiovascular risks linked to anthracycline therapy and promoting survivor-centered care and research. [ABSTRACT FROM AUTHOR]

The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients. [ABSTRACT FROM AUTHOR]

Background: During the physiological cardiac cycle, the helix orientation of the muscle fibres induces the rotation of the apex relative to the base of the left ventricular (LV). In heart failure, LV torsion is impaired, and rotation at basal and apical levels occurs in the same direction, a phenomenon called rigid body rotation (RBR). We aimed to evaluate whether the RBR pattern and GLS together could improve the diagnosis of cardiotoxicity in patients treated with anthracyclines and/or anti-HER2. Methods: With an observational, retrospective study involving 175 patients (mean age 55 ± 12 years, 94% females), we evaluated the development of cancer therapeutic–related cardiac dysfunction (CTRCD) defined according to ESC guidelines. We characterised LV dysfunction by echocardiographic standard and speckle-tracking (GLS and RBR pattern) measurements. Patients with a previous diagnosis of structural heart disease or atrial fibrillation were excluded. Results: At the time of enrolment, the chemotherapy regimen included trastuzumab (96%), pertuzumab (21%), and anthracyclines (13%). Twenty-two patients (12.5%) developed cardiotoxicity, and thirteen patients developed an RBR within 6 months of follow-up. In all cases, the RBR pattern was associated with cardiotoxicity (p < 0.001), reporting an optimal specificity but poor sensitivity at three and six months. However, the addition of the RBR pattern to the global longitudinal strain (GLS) ≥ −16% increased the odds ratio (OR) from 25.6 to 32.6 at three months and from 32.5 to 49.6 at six months rather than GLS alone. Conclusions: The RBR pattern improves the diagnostic accuracy of GLS for the detection of cardiotoxicity secondary to anthracyclines and anti-HER2-based treatments. [ABSTRACT FROM AUTHOR]

STOP-CA was a multicenter, double-blind, randomized, placebo-controlled trial comparing atorvastatin to placebo in treatment-naïve lymphoma patients receiving anthracycline-based chemotherapy. We performed a preplanned subgroup to analyze the impact of atorvastatin on efficacy in patients with diffuse large B-cell lymphoma (DLBCL). Patients received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at standard doses for six 21-day cycles and were randomly assigned to receive atorvastatin 40 mg daily (n = 55) or placebo (n = 47) for 12 months. The complete response (CR) rate was numerically higher in the atorvastatin arm (95% [52/55] vs. 85% [40/47], p =.18), but this was not statistically significant. Adverse event rates were similar between the atorvastatin and placebo arms. In summary, atorvastatin did not result in a statistically significant improvement in the CR rate or progression-free survival, but both were numerically improved in the atorvastatin arm. These data warrant further investigation into the potential therapeutic role of atorvastatin added to anthracycline-based chemotherapies. [ABSTRACT FROM AUTHOR]

Anthracycline antibiotic is one of the most effective anti-tumor drugs used to manage certain types of breast cancers, lymphomas, and leukemias. However, anthracyclines induce a dose-dependent cardiotoxicity that may progress to heart failure. Thus, using a sensitive predictor of early cardiac dysfunction in patients treated with anthracyclines can help detect subclinical cardiac dysfunction early and help initiate interventions to protect these patients. Among parameters of myocardial measure, cardiac magnetic resonance (CMR)-measured native myocardial T1 mapping is considered a sensitive and accurate quantitative measure of early subclinical cardiac changes, particularly cardiac inflammation and fibrosis. However, to understand the quality and the validity of the current evidence supporting the use of these measures in patients treated with anthracyclines, we aimed to conduct a systematic review of clinical studies of this measure to detect early myocardial changes in cancer patients treated with anthracyclines. The primary outcome was the level of native T1 mapping. We performed fixed-effects meta-analyses and assessed certainty in effect estimates. Of the 1780 publications reviewed (till 2022), 23 were retrieved, and 9 articles met the inclusion criteria. Our study showed that exposure to anthracycline was associated with a significant elevation of native myocardial T1 mapping from baseline (95% CI 0.1121 to 0.5802; p = 0.0037) as well as compared to healthy control patients (95% CI 0.2925 to 0.7448; p < 0.0001). No significant publication bias was noted on the assessment of the funnel plot and Egger's test. According to the Q test, there was no significant heterogeneity in the included studies (I2 = 0.0000% versus healthy controls and I2 = 14.0666% versus baseline). Overall, our study suggests that native myocardial T1 mapping is useful for detecting anthracycline-induced cardiotoxicity in patients with cancer. [ABSTRACT FROM AUTHOR]

With improved diagnosis and treatments, a greater percentage of breast cancer patients are achieving long-term survival. Consequently, long-term cardiotoxicity secondary to chemotherapy has become more prevalent, warranting improved cardiac surveillance. We evaluated changes in left atrial (LA) strain in breast cancer patients immediately post anthracycline (AC) therapy to assess its utility as a marker of diastolic dysfunction. This was a prospective cohort study of 128 consecutive human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients who underwent transthoracic echocardiography prior to and immediately post AC treatment. Traditional left ventricular (LV) systolic and diastolic parameters and LA volumes were evaluated; additionally, LV global longitudinal strain (LV GLS) and LA phasic strain were measured. All patients had normal LV ejection fraction (>53%) post AC, though LV GLS was significantly reduced. Peak E and é velocities were reduced post AC, with no change in LA volumes. LA reservoir strain (LAS RES 34.8% vs 31.5%, p<0.001) and conduit strain (LAS CD 17.2% vs 14.4%, p<0.001) were significantly lower post AC and correlated modestly with LV diastolic parameters. Reduction in LA strain post AC was evident even in patients with preserved LV systolic and diastolic function. More patients demonstrated alteration in diastolic function (≥15% reduction in LAS RES from baseline) (32%) compared to alteration in systolic function (≥15% reduction in LV GLS) (23%). LA strain is a promising marker of early diastolic dysfunction. We demonstrate its potential utility in surveillance of breast cancer patients treated with AC. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Left ventricular global longitudinal strain (LVGLS) has been recommended by current guidelines for diagnosing anthracycline-induced cardiotoxicity. However, little is known about the early changes in left atrial (LA) morphology and function in this population. Our study aimed to evaluate the potential usefulness of LA indices and their incremental value to LVGLS with three-dimensional echocardiography (3DE) in the early detection of subclinical cardiotoxicity in patients with lymphoma receiving anthracycline. Methods: A total of 80 patients with diffuse large B-cell lymphoma who received six cycles of anthracycline-based treatment were enrolled. Echocardiography was performed at baseline (T0), after four cycles (T1), and after the completion of six cycles of chemotherapy (T2). Left ventricular ejection fraction (LVEF), LVGLS, LA volumes, LA emptying fraction (LAEF), LA active emptying fraction (LAAEF), and LA reservoir longitudinal strain (LASr) were quantified with 3DE. Left atrioventricular global longitudinal strain (LAVGLS) was calculated as the sum of peak LASr and the absolute value of peak LVGLS (LAVGLS=LASr+|LVGLS|). LV cardiotoxicity was defined as a new LVEF reduction by ≥10 percentage points to an LVEF of ≤50%. Results: Fourteen (17.5%) patients developed LV cardiotoxicity at T2. LA volumes, LAEF, and LAAEF remained stable over time. Impairment of LASr (28.35 ± 5.03 vs. 25.04 ± 4.10, p < .001), LVGLS (-22.77 ± 2.45 vs. -20.44 ± 2.62, p < .001), and LAVGLS (51.12 ± 5.63 vs. 45.61 ± 5.22, p < .001) was observed by the end of the fourth cycle of chemotherapy (T1). Statistically significant declines in LVEF (61.30 ± 4.73 vs. 57.08±5.83, p<.001) were only observed at T2. The relative decrease in LASr (ΔLASr), LVGLS (ΔLVGLS), and LAVGLS (ΔLAVGLS) from T0 to T1 were predictors of LV cardiotoxicity. A ΔLASr of >19.75% (sensitivity, 71.4%; specificity, 87.9%; area under the curve (AUC), .842; p < .001), a ΔLVGLS of >13.19% (sensitivity, 78.6%; specificity, 74.2%; AUC, .763; p < .001), and a ΔLAVGLS of >16.80% (sensitivity, 78.6%; specificity, 93.9%; AUC, .905; p<.001) predicted subsequent LV cardiotoxicity at T2, with the AUC of ΔLAVGLS significantly larger than that of ΔLVGLS (.905 vs. .763, p = .027). Compared to ΔLVGLS, ΔLAVGLS showed improved specificity (93.9% vs. 74.2%, p = .002) and maintained sensitivity in predicting LV cardiotoxicity. Conclusions: LASr could predict anthracycline-induced LV cardiotoxicity with excellent diagnostic performance. Incorporating LASr into LVGLS (LAVGLS) led to a significantly improved specificity and maintained sensitivity in predicting LV cardiotoxicity. [ABSTRACT FROM AUTHOR]

Summary: Background: Anthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis. Methods: The ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS). Findings: Tumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI. Interpretation: The different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS. Funding: Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5 × 1000 Funds—2016, Italian Ministry of Health; AIRC Grant [ID#28546].

Background: Anthracyclines are associated with cardiac dysfunction. Little is known about the interplay of pre-existing hypertension and treatment response. We aimed to investigate the relationship between hypertension and the development of cancer therapy-related cardiac dysfunction (CTRCD) in pediatric patients treated with anthracycline chemotherapy. Methods: Pediatric patients with cancer who received anthracycline chemotherapy from 2013 to 2021 were retrospectively included. Serial cardiac assessments were conducted during and after chemotherapy. The primary outcome was the development of CTRCD, classified as mild, moderate, or severe according to contemporary definitions. Results: Among 190 patients undergoing anthracycline chemotherapy, 34 patients (17.9 %) had hypertension (24 patients Stage 1, and 10 patients Stage 2) at baseline evaluation. Patients underwent chemotherapy for a median of 234.4 days (interquartile range 127.8–690.3 days) and were subsequently followed up. Hypertension was frequent during follow-up 31.3 % (0–3 months), 15.8 % (3–6 months), 21.9 % (0.5–1 years), 24.7 % (1–2 years), 31.1 % (2–4 years) and 35.8 % (beyond 4 years) (P for trend

Objective: Shenmai injection is a classic herbal prescription, and is often recommended for the treatment of anthracycline-induced cardiotoxicity. However, the efficacy and safety of Shenmai injection for the treatment of anthracycline-induced cardiotoxicity have not been reported. Materials and methods: We conducted a comprehensive search of eight literature databases and two clinical trial registries, retrieving all randomized controlled trials (RCTs) related to the treatment of anthracycline-induced cardiotoxicity with Shenmai injection from the establishment of the databases to July 1, 2023. Data analysis was performed using the Meta package in RStudio and RevMan 5.4. The GRADE pro3.6.1 software was utilized for assessing the quality of evidence. Results: A total of 16 RCTs including 2140 patients were included in this study. Meta-analysis showed that Shenmai injection had an advantage in improving ST-T segment changes (RR = 0.28; 95 % CI, 0.20 to 0.39; P

In women with reproductive potential, ovarian dysfunction caused by chemotherapy for breast cancer has far-reaching effects. Ovarian insufficiency can manifest as amenorrhea, menstrual disorders, hot flashes and night sweats, impaired fertility in the short term, and increased cardiovascular risk, reduced bone density, cognitive impairment in the long term. The occurrence of ovarian insufficiency due to chemotherapy is closely related to the type of drug, the number of chemotherapy sessions, the dose of chemotherapy, and the age of the patient. There are many drugs for protecting ovarian function, but in clinical practice, gonadotropin-releasing hormone analogues (GnRHa) are still the mainstay. Other ovarian protection drugs generally lack clinical trial data, and their safety and impact on chemotherapy efficacy need further research.

ADCs have emerged as a promising class of therapeutics, combining the targeting specificity of monoclonal antibodies with the cytotoxic potency of small-molecule drugs. Although the majority of approved ADCs are still based on microtubule binder payloads, the recent success of topoisomerase I inhibitors has revitalized interest in the identification of novel agents overcoming present limitations in the field including narrow therapeutic window and chemoresistance. The success of DNA binders as payload for ADCs has been very limited, up to now, due, among other factors, to high hydrophobicity and planar chemical structures resulting in most cases in ADCs with a strong tendency to aggregate, poor plasma stability, and limited therapeutic index. Some of these molecules, however, continue to be of interest due to their favorable properties in terms of cytotoxic potency even in chemoresistant settings, bystander and immunogenic cell death effects, and known combinability with approved drugs. We critically evaluated several clinically tested ADCs containing DNA binders, focusing on payload physicochemical properties, cytotoxic potency, and obtained clinical results. Our analysis suggests that further exploration of certain chemical classes, specifically anthracyclines and duocarmycins, based on the optimization of physicochemical parameters, reduction of cytotoxic potency, and careful design of targeting molecules is warranted. This approach will possibly result in a novel generation of payloads overcoming the limitations of clinically validated ADCs.