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2/19/26

 


ABSTRACT


Cardiotoxicity is a severe side effect of the chemotherapeutic agent doxorubicin (DOX). We recently showed that DOX-induced cardiomyocyte apoptosis and death were attenuated through autophagy pre-induction. Herein, we assessed how the autophagy/mitophagy-inducing antitumor drug everolimus (EVL) affected DOX-induced cytotoxicity in the rat cardiomyocyte cell line H9c2 and human breast cancer cell line MCF-7. Apoptosis was assessed using annexin V assay. Autophagy and mitophagy were assessed using fluorescence assays. Cellular protein levels were determined using western blotting. Pretreatment with EVL (1 nM) before DOX exposure inhibited mammalian target of rapamycin (mTOR) activity, induced autophagy and mitophagy, and activated protein kinase B (AKT) in H9c2 cells. In mitochondria, DOX (1 μM) induced structural damage (decreased membrane potential and release of cytochrome c), increased superoxide levels, decreased apoptosis inhibitor Bcl-2, and increased apoptosis inducer Bax, leading to apoptosis and reduced viability in H9c2 cells. EVL pretreatment suppressed DOX-induced changes. EVL anti-apoptotic effects were inhibited by treatment with MK-2206, a selective AKT inhibitor. Furthermore, EVL suppressed DOX-induced cardiotoxicity through autophagy/mitophagy and AKT activation but did not attenuate DOX-induced apoptosis or reduction in viability in MCF-7 cells. Altogether, EVL can protect cardiomyocytes from DOX-induced apoptosis and toxicity without reducing DOX antitumor effects, allowing safer chemotherapy.


PMID:37739323 | DOI:10.1016/j.tiv.2023.105698

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PubMed articles on: Cardio-Oncology

The Value of Neoadjuvant Anthracycline-Based Regimens for HER2-Positive Breast Cancer: A Systematic Review and Meta-analysis Including 1366 Patients


Clin Med Insights Oncol. 2023 Sep 21;17:11795549231195293. doi: 10.1177/11795549231195293. eCollection 2023.


ABSTRACT


BACKGROUND: The standard recommendation for neoadjuvant therapy for human epidermal growth factor receptor-2 (HER2)-positive breast cancer patients is trastuzumab in combination with chemotherapy, but there is no current standard recommendation for appropriate chemotherapy regimens. This meta-analysis evaluated the efficacy and cardiac safety of the concurrent use of anti-HER2 targeted drugs and anthracycline-based neoadjuvant chemotherapy (NAC) for HER2-positive breast cancers.


METHODS: The pooled odds ratio (OR) rate for pathologic complete response (pCR), the pooled hazard ratio (HR) of overall survival (OS), and the left ventricular ejection fraction (LVEF) decline events were all calculated. Differences in efficacy, prognosis, and cardiac safety were compared between patients receiving an anthracycline-containing regimen (AB) and those treated with non-anthracycline-based (nAB) NAC.


RESULTS: A total of 1366 patients in 4 prospective and 3 retrospective studies were included in the meta-analysis. The pooled OR for pCR rate was 0.73 with a 95% confidence interval (CI) of 0.43 to 1.24 (P = .246). Subgroup analysis of low tumor burden cases showed no improvement in pCR rate for patients in the AB group compared with nAB, with the pooled OR rate being 0.73 with a 95% CI of 0.37 to 1.44 (P= .357). The 3-year OS rate was 95.63% and 95.54% in the AB and nAB groups, respectively, with no statistical difference (P= .157). There was a significant increase in the rate of LVEF decline of 19.07% in the AB group compared with 13.33% for the nAB group, with an HR of 1.62 and a 95% CI of 1.11 to 2.36 (P = .013).


CONCLUSIONS: The addition of anthracyclines did not improve pCR rates and survival after neoadjuvant and the increased cardiotoxicity of anthracyclines further limited their application. This study showed that it was feasible to use anti-HER2 drugs without anthracyclines in neoadjuvant therapy for HER2-positive breast cancer patients.


PMID:37744425 | PMC:PMC10515528 | DOI:10.1177/11795549231195293

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PubMed articles on: Cardio-Oncology

Clonal Hematopoiesis as a Molecular Risk Factor for Doxorubicin-Induced Cardiotoxicity: A Proof-of-Concept Study


JCO Precis Oncol. 2023 Sep;7:e2300208. doi: 10.1200/PO.23.00208.


ABSTRACT


PURPOSE: The main dose-limiting toxicity of anthracyclines is cardiotoxicity. Clonal hematopoiesis (CH), somatic mutations in hematopoietic stem or progenitor cells in patients without hematologic malignancy, is also associated with risk for adverse cardiovascular events and worse outcomes overall. We hypothesize that CH increases risk for doxorubicin-induced cardiotoxicity (DIC).


METHODS: We conducted a retrospective cohort study in patients treated with doxorubicin for cancer (N = 100). Patients (n = 25) had incident symptomatic heart failure, decline in left ventricular ejection fraction, or arrhythmia. CH was identified using paired peripheral blood and tumor DNA.


RESULTS: After adjusting for age at doxorubicin initiation, diabetes, dyslipidemia, and chest radiation, high cumulative dose of doxorubicin (>240 mg/m2; odds ratio [OR], 7.00; 95% CI, 1.77 to 27.74; P = .0056), CH (OR, 8.58; 95% CI, 2.05 to 35.99; P = .0033), and history of smoking (OR, 3.15; 95% CI, 1.00 to 9.93; P = .0495) were associated with DIC.


CONCLUSION: This study provides preliminary evidence for CH as a predictive risk factor for DIC, which, with further investigation, could serve as an important precision medicine biomarker for the large number of patients with cancer who have CH.


PMID:37738545 | DOI:10.1200/PO.23.00208

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PubMed articles on: Cardio-Oncology

Reply to Comment on: Cardiotoxicity in children with cancer treated with anthracyclines: A position statement on dexrazoxane


Pediatr Blood Cancer. 2023 Sep 22:e30690. doi: 10.1002/pbc.30690. Online ahead of print.


NO ABSTRACT


PMID:37737681 | DOI:10.1002/pbc.30690

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PubMed articles on: Cardio-Oncology

Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications


Front Cardiovasc Med. 2023 Sep 8;10:1150569. doi: 10.3389/fcvm.2023.1150569. eCollection 2023.


ABSTRACT


Cardio-oncology is an emerging field that seeks to enhance quality of life and longevity of cancer survivors. It is pertinent for clinicians to understand the cellular mechanisms of prescribed therapies, as this contributes to robust understanding of complex treatments and off-target effects, improved communication with patients, and guides long term care with the goal to minimise or prevent cardiovascular complications. Our aim is to review the cellular mechanisms of cardiotoxicity involved in commonly used anti-cancer treatments and identify gaps in literature and strategies to mitigate cardiotoxicity effects and guide future research endeavours.


PMID:37745115 | PMC:PMC10516301 | DOI:10.3389/fcvm.2023.1150569

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PubMed articles on: Cardio-Oncology

Galectin-3 contributes to acute cardiac dysfunction and toxicity by increasing oxidative stress and fibrosis in doxorubicin-treated mice


Int J Cardiol. 2023 Sep 21:131386. doi: 10.1016/j.ijcard.2023.131386. Online ahead of print.


ABSTRACT


BACKGROUND: Doxorubicin (DOX) leads to cardiovascular toxicity through direct cardiomyocyte injury and inflammation. We aimed to study the role of Galectin-3 (Gal-3), a β-galactosidase binding lectin associated with inflammation and fibrosis in DOX-induced acute cardiotoxicity in mice.


METHODS: Male C57 and Gal-3 knockout (KO) mice were given a single dose of DOX (15 mg/kg, i.p) or placebo. Serum creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and cardiac thiobarbituric acid-reactive substance (TBARS) were measured at 3 days to assess cardiac injury and oxidative stress. Cardiac remodeling and function were studied by echocardiography and catheterization at 7 days. Myocardial fibrosis was quantified in picrosirius red stained slices.


RESULTS: Absence of Gal-3 tended to reduce the mortality after DOX. DOX significantly increased CPK, LDH, AST and TBARS while treated Gal-3 KO mice showed reduced injury and oxidative stress. After 7 days, adverse remodeling, fibrosis and dysfunction in treated-C57 mice were severely affected while those effects were prevented by absence of Gal-3.


CONCLUSION: In summary, genetic deletion of Gal-3 prevented cardiac damage, adverse remodeling and dysfunction, associated with reduced cardiac oxidative stress and fibrosis. Understanding the contribution of GAL-3 to doxorubicin-induced cardiac toxicity reinforces its potential use as a therapeutic target in patients with several cancer types.


PMID:37741348 | DOI:10.1016/j.ijcard.2023.131386

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PubMed articles on: Cardio-Oncology

A Rapid Cardiovascular Magnetic Resonance Assessment for Cancer Therapy-Related Cardiac Dysfunction Supports the Routine Incorporation of Cardiovascular Magnetic Resonance into Cardio-Oncology Care


Am J Cardiol. 2023 Sep 22:S0002-9149(23)00985-2. doi: 10.1016/j.amjcard.2023.09.015. Online ahead of print.


NO ABSTRACT


PMID:37743145 | DOI:10.1016/j.amjcard.2023.09.015

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PubMed articles on: Cardio-Oncology

Effectiveness and Safety of Remdesivir in Treating Hospitalised Patients with COVID-19: A Propensity Score Analysis of Real-Life Data from a Monocentric Observational Study in Times of Health Emergency


Clin Drug Investig. 2023 Sep 22. doi: 10.1007/s40261-023-01304-4. Online ahead of print.


ABSTRACT


BACKGROUND AND OBJECTIVES: Remdesivir is an antiviral agent, which was shown to be safe and effective in treating early COVID-19, but its favourable impact in hospitalised patients with non-critical disease is still under investigation. The present study aimed to assess the effectiveness and safety of remdesivir as a treatment for hospitalised patients with COVID-19 by a propensity score analysis of observational data.


METHODS: In this monocentric retrospective cohort study, the effectiveness and safety of a 5-day course of remdesivir (200 mg intravenously at Day 1, then 100 mg from Days 2-5) in association with the standard of care were assessed in comparison with the standard of care only. The primary endpoint was the proportion of recovery on Day 14.


RESULTS: Of 3662 eligible inpatients who tested positive for the severe acute respiratory syndrome coronavirus 2 genome by nasopharyngeal swab at admission, 861 (24%) non-critical patients were included in a propensity score analysis and 281 (33%) were exposed to remdesivir. In total, 242/281 (86.1%) and 435/580 (75.0%) patients recovered in exposed and non-exposed, respectively, with a relative improvement of 11.1% (95% CI + 5.8 to 16.5%; unadjusted odds ratio: 2.07, 95% CI 1.40-3.05, p = 0.0001; after adjustment by propensity score weighting, odds ratio: 1.92, 95% CI 1.30-2.83, p = 0.001). In treated patients, 1 (0.03%) anaphylactic reaction and 1 (0.03%) acute reaction during drug injection were reported, and 24 (8.5%) patients stopped the treatment due to adverse reactions. No significant differences were found with respect to the secondary efficacy endpoints (in-hospital all-cause death, need for intensive care treatments, clinical improvement score at Day 28) and safety endpoints (any and serious adverse reactions).


CONCLUSION: A 5-day course of remdesivir in association with the standard of care effectively promoted recovery from COVID-19 among non-critical in-hospital patients and had an acceptable safety profile.


PMID:37740148 | DOI:10.1007/s40261-023-01304-4

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PubMed articles on: Cardio-Oncology

Hormone therapy, cardio-metabolic profile, and cardiotoxicity. Still a dark side of cardio-oncology - Part 2: Prostate cancer


G Ital Cardiol (Rome). 2023 Oct;24(10):781-791. doi: 10.1714/4100.40978.


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Cancer chemotherapy with doxorubicin (DOX) may have multiorgan toxicities including cardiotoxicity, and this is one of the major limitations of its clinical use. The present study aimed to evaluate the cardioprotective role of α-Bisabolol (BSB) in DOX-induced acute cardiotoxicity in rats and the underlying pharmacological and molecular mechanisms. DOX (12.5 mg/kg, single dose) was injected intraperitoneally into the rats for induction of acute cardiotoxicity. BSB was given orally to rats (25 mg/kg, p.o. twice daily) for a duration of five days. DOX administration induced cardiac dysfunction as evidenced by altered body weight, hemodynamics, and release of cardio-specific diagnostic markers. The occurrence of oxidative stress was evidenced by a significant decline in antioxidant defense along with a rise in lipid peroxidation and hyperlipidemia. Additionally, DOX also increased the levels and expression of proinflammatory cytokines and inflammatory mediators, as well as activated NF-κB/MAPK signaling in the heart, following alterations in the Nrf2/Keap-1/HO-1 and Akt/mTOR/GSK-3β signaling. DOX also perturbed NLRP3 inflammasome activation-mediated pyroptosis in the myocardium of rats. Furthermore, histopathological studies revealed cellular alterations in the myocardium. On the contrary, treatment with BSB has been observed to preserve the myocardium and restore all the cellular, molecular, and structural perturbations in the heart tissues of DOX-induced cardiotoxicity in rats. Results of the present study clearly demonstrate the protective role of BSB against DOX-induced cardiotoxicity, which is attributed to its potent antioxidant, anti-inflammatory, and antihyperlipidemic effects resulting from favorable modulation of numerous cellular signaling regulatory pathways, viz., Nrf2/Keap-1/HO-1, Akt/mTOR/GSK-3β, NF-κB/p38/MAPK, and NLRP3 inflammasomes, in countering the cascades of oxidative stress and inflammation. The observations suggest that BSB can be a promising agent or an adjuvant to limit the cardiac injury caused by DOX. Further studies including the role in tumor-bearing animals as well as regulatory toxicology are suggested.


PMID:37762315 | DOI:10.3390/ijms241814013

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PubMed articles on: Cardio-Oncology

Droplet Digital PCR Is a Novel Screening Method Identifying Potential Cardiac G-Protein-Coupled Receptors as Candidate Pharmacological Targets in a Rat Model of Pressure-Overload-Induced Cardiac Dysfunction


Int J Mol Sci. 2023 Sep 7;24(18):13826. doi: 10.3390/ijms241813826.


ABSTRACT


The identification of novel drug targets is needed to improve the outcomes of heart failure (HF). G-protein-coupled receptors (GPCRs) represent the largest family of targets for already approved drugs, thus providing an opportunity for drug repurposing. Here, we aimed (i) to investigate the differential expressions of 288 cardiac GPCRs via droplet digital PCR (ddPCR) and bulk RNA sequencing (RNAseq) in a rat model of left ventricular pressure-overload; (ii) to compare RNAseq findings with those of ddPCR; and (iii) to screen and test for novel, translatable GPCR drug targets in HF. Male Wistar rats subjected to transverse aortic constriction (TAC, n = 5) showed significant systolic dysfunction vs. sham operated animals (SHAM, n = 5) via echocardiography. In TAC vs. SHAM hearts, RNAseq identified 69, and ddPCR identified 27 significantly differentially expressed GPCR mRNAs, 8 of which were identified using both methods, thus showing a correlation between the two methods. Of these, Prostaglandin-F2α-receptor (Ptgfr) was further investigated and localized on cardiomyocytes and fibroblasts in murine hearts via RNA-Scope. Antagonizing Ptgfr via AL-8810 reverted angiotensin-II-induced cardiomyocyte hypertrophy in vitro. In conclusion, using ddPCR as a novel screening method, we were able to identify GPCR targets in HF. We also show that the antagonism of Ptgfr could be a novel target in HF by alleviating cardiomyocyte hypertrophy.


PMID:37762130 | DOI:10.3390/ijms241813826

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PubMed articles on: Cardio-Oncology

Social Determinants of Health Data Improve the Prediction of Cardiac Outcomes in Females with Breast Cancer


Cancers (Basel). 2023 Sep 19;15(18):4630. doi: 10.3390/cancers15184630.


ABSTRACT


Cardiovascular disease is the leading cause of mortality among breast cancer (BC) patients aged 50 and above. Machine Learning (ML) models are increasingly utilized as prediction tools, and recent evidence suggests that incorporating social determinants of health (SDOH) data can enhance its performance. This study included females ≥ 18 years diagnosed with BC at any stage. The outcomes were the diagnosis and time-to-event of major adverse cardiovascular events (MACEs) within two years following a cancer diagnosis. Covariates encompassed demographics, risk factors, individual and neighborhood-level SDOH, tumor characteristics, and BC treatment. Race-specific and race-agnostic Extreme Gradient Boosting ML models with and without SDOH data were developed and compared based on their C-index. Among 4309 patients, 11.4% experienced a 2-year MACE. The race-agnostic models exhibited a C-index of 0.78 (95% CI 0.76-0.79) and 0.81 (95% CI 0.80-0.82) without and with SDOH data, respectively. In non-Hispanic Black women (NHB; n = 765), models without and with SDOH data achieved a C-index of 0.74 (95% CI 0.72-0.76) and 0.75 (95% CI 0.73-0.78), respectively. Among non-Hispanic White women (n = 3321), models without and with SDOH data yielded a C-index of 0.79 (95% CI 0.77-0.80) and 0.79 (95% CI 0.77-0.80), respectively. In summary, including SDOH data improves the predictive performance of ML models in forecasting 2-year MACE among BC females, particularly within NHB.


PMID:37760599 | DOI:10.3390/cancers15184630

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PubMed articles on: Cardio-Oncology

The Impact of Drug-Drug Interactions on the Toxicity Profile of Combined Treatment with BRAF and MEK Inhibitors in Patients with BRAF-Mutated Metastatic Melanoma


Cancers (Basel). 2023 Sep 15;15(18):4587. doi: 10.3390/cancers15184587.


ABSTRACT


BACKGROUND: BRAF and MEK inhibition is a successful strategy in managing BRAF-mutant melanoma, even if the treatment-related toxicity is substantial. We analyzed the role of drug-drug interactions (DDI) on the toxicity profile of anti-BRAF/anti-MEK therapy.


METHODS: In this multicenter, observational, and retrospective study, DDIs were assessed using Drug-PIN software (V 2/23). The association between the Drug-PIN continuous score or the Drug-PIN traffic light and the occurrence of treatment-related toxicities and oncological outcomes was evaluated.


RESULTS: In total, 177 patients with advanced BRAF-mutated melanoma undergoing BRAF/MEK targeted therapy were included. All grade toxicity was registered in 79% of patients. Cardiovascular toxicities occurred in 31 patients (17.5%). Further, 94 (55.9%) patients had comorbidities requiring specific pharmacological treatments. The median Drug-PIN score significantly increased when the target combination was added to the patient's home therapy (p-value < 0.0001). Cardiovascular toxicity was significantly associated with the Drug-PIN score (p-value = 0.048). The Drug-PIN traffic light (p = 0.00821) and the Drug-PIN score (p = 0.0291) were seen to be significant predictors of cardiotoxicity. Patients with low-grade vs. high-grade interactions showed a better prognosis regarding overall survival (OS) (p = 0.0045) and progression-free survival (PFS) (p = 0.012). The survival analysis of the subgroup of patients with cardiological toxicity demonstrated that patients with low-grade vs. high-grade DDIs had better outcomes in terms of OS (p = 0.0012) and a trend toward significance in PFS (p = 0.068).


CONCLUSIONS: DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Our findings support the utility of DDI assessment in melanoma patients treated with BRAF/MEK inhibitors.


PMID:37760556 | DOI:10.3390/cancers15184587

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PubMed articles on: Cardio-Oncology

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PubMed articles on: Cardio-Oncology

Evaluation of Expression Level of miR-3135b-5p in Blood Samples of Breast Cancer Patients Experiencing Chemotherapy-Induced Cardiotoxicity


Indian J Clin Biochem. 2023 Oct;38(4):536-540. doi: 10.1007/s12291-022-01075-3. Epub 2022 Sep 6.


ABSTRACT


The efficacy of chemotherapeutics in the treatment of breast cancer is limited by cardiotoxicity, which could lead to irreversible heart failure. The evaluation of miRNA levels as a vital biomarker could predict cardiotoxicity induced by chemotherapy. According to our previous meta-analysis study on patients with heart failure, we found that miR-3135b had a significant increase in patients with heart failure. Therefore, the present study aimed to evaluate the expression level of miR-3135b in the blood sample of patients experiencing chemotherapy-induced cardiotoxicity. Blood samples were collected from breast cancer patients or breast cancer patients who had received chemotherapy and had not experienced any chemotherapy-induced cardiotoxicity (N = 37, control group) and breast cancer patients experiencing chemotherapy-induced cardiotoxicity after chemotherapy (N = 33). The expression level of miR-3135b was evaluated using real-time polymerase chain reaction (RT-PCR). The 2-ΔCt values of miR-3135b were compared between two groups. We observed a significant increase in the expression level of miR-3135b between patients experiencing chemotherapy-induced cardiotoxicity and the control group (P = 0.0001). Besides, the ejection fraction parameter was correlated with the expression level of miR-3135b (r = 0.5 and P = 0.0001). To sum up, miR-3135b might be useful as a promising circulating biomarker in predicting cardiotoxicity induced by chemotherapy. However, more studies are needed to validate miR-3135b as a biomarker for the diagnosis of chemotherapy-induced cardiotoxicity.


SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12291-022-01075-3.


PMID:37746544 | PMC:PMC10516830 | DOI:10.1007/s12291-022-01075-3

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PubMed articles on: Cardio-Oncology

Everolimus prevents doxorubicin-induced apoptosis in H9c2 cardiomyocytes but not in MCF-7 cancer cells: Cardioprotective roles of autophagy, mitophagy, and AKT


Toxicol In Vitro. 2023 Sep 20:105698. doi: 10.1016/j.tiv.2023.105698. Online ahead of print.


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ABSTRACT


Longitudinal strain (LS) measured by echocardiography has been reported to be useful not only for the diagnosis and risk stratification of various cardiac diseases, but also in cardio-oncology. Most previous studies have been conducted on patients undergoing treatment with anthracyclines and human epidermal growth factor receptor 2-targeted therapies. Existing guidelines recommend that global LS (GLS) should be measured before and after the administration of cancer drugs. This recommendation is based on many reports showing that a decline in GLS is indicative of early or mild cancer therapy-related cardiac dysfunction. The main purpose of this article is to provide insight into the importance of LS in patients undergoing cancer treatment and highlight the role of LS evaluation in patients undergoing immune checkpoint inhibitor (ICI) treatment, which is being used with increasing frequency. Among cancer drug therapies, immune checkpoint inhibitors (ICIs) have an important place in cancer treatment and are used for the treatment of many types of cancer. Although the efficacy of ICIs in cancer treatment has been reported, immune-related adverse events (irAEs) have also been reported. Among these irAEs, cardiovascular complications, although rare, are recognized as important adverse events that may result in ICI treatment discontinuation. Myocarditis is one severe adverse event associated with ICIs, and it is important to standardize diagnostic and therapeutic approaches to it. Several studies have reported a relationship between LS and cardiac complications associated with ICIs which may contribute to the early diagnosis of ICI-induced cardiac complications.


PMID:37765105 | DOI:10.3390/ph16091297

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PubMed articles on: Cardio-Oncology

Creatine and Resistance Training: A Combined Approach to Attenuate Doxorubicin-Induced Cardiotoxicity


Nutrients. 2023 Sep 19;15(18):4048. doi: 10.3390/nu15184048.


ABSTRACT


Doxorubicin (DOX), a potent chemotherapy agent, useful in the treatment of solid tumors, lymphomas, and leukemias, is limited by its potentially lethal cardiotoxicity. However, exercise has been consistently shown to mitigate the side effects of DOX, including cardiotoxicity. To date, most studies examining the relationship between exercise and DOX-induced cardiotoxicity have focused on aerobic exercise, with very few examining the role of anerobic activity. Therefore, this investigation explored the potential of creatine (CR) and resistance training (RT) in preserving cardiac health during DOX therapy. Male Sprague-Dawley rats were grouped into RT, RT + CR, sedentary (SED), and SED + CR, with each division further branching into saline (SAL) or DOX-treated subsets post-10 weeks of RT or SED activity. RT comprised progressive training utilizing specialized cages for bipedal stance feeding. CR-treated groups ingested water mixed with 1% CR monohydrate and 5% dextrose, while control animals received 5% dextrose. At week 10, DOX was administered (2 mg/kg/week) over 4-weeks to an 8 mg/kg cumulative dose. Cardiac function post-DOX treatment was assessed via transthoracic echocardiography. Left ventricular diameter during diastole was lower in DOX + CR, RT + DOX, and RT + CR + DOX compared to SED + DOX (p < 0.05). Additionally, cardiac mass was significantly greater in RT + CR + DOX SED + DOX animals (p < 0.05). These results suggest RT and CR supplementation, separately and in combination, could attenuate some measures of DOX-induced cardiotoxicity and may offer a cost-effective way to complement cancer treatments and enhance patient outcomes. More investigations are essential to better understand CR's prolonged effects during DOX therapy and its clinical implications.


PMID:37764831 | DOI:10.3390/nu15184048

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PubMed articles on: Cardio-Oncology

Aortic Valve Stenosis and Cancer: Problems of Management


J Clin Med. 2023 Sep 6;12(18):5804. doi: 10.3390/jcm12185804.


ABSTRACT


Aortic valve stenosis and malignancy frequently coexist and share the same risk factors as atherosclerotic disease. Data reporting the prognosis of patients with severe aortic stenosis and cancer are limited. Tailoring the correct and optimal care for cancer patients with severe aortic stenosis is complex. Cancer patients may be further disadvantaged by aortic stenosis if it interferes with their treatment by increasing the risk associated with oncologic surgery and compounding the risks associated with cardiotoxicity and heart failure (HF). Surgical valve replacement, transcatheter valve implantation, balloon valvuloplasty, and medical therapy are possible treatments for aortic valve stenosis, but when malignancy is present, the choice between these options must take into account the stage of cancer and associated treatment, expected outcome, and comorbidities. Physical examination and Doppler echocardiography are critical in the diagnosis and evaluation of aortic stenosis. The current review considers the available data on the association between aortic stenosis and cancer and the therapeutic options.


PMID:37762745 | DOI:10.3390/jcm12185804

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PubMed articles on: Cardio-Oncology

α-Bisabolol, a Dietary Sesquiterpene, Attenuates Doxorubicin-Induced Acute Cardiotoxicity in Rats by Inhibiting Cellular Signaling Pathways, Nrf2/Keap-1/HO-1, Akt/mTOR/GSK-3β, NF-κB/p38/MAPK, and NLRP3 Inflammasomes Regulating Oxidative Stress and Inflammatory Cascades


Int J Mol Sci. 2023 Sep 13;24(18):14013. doi: 10.3390/ijms241814013.


ABSTRACT

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ABSTRACT


Hormone therapies (HTs) with anti-androgenic properties are a cornerstone for the treatment of prostate cancer (PC) and have significantly improved the survival of patients, though exposing them to a higher risk of cardiovascular diseases (CVDs), which represent a major cause of morbidity and mortality. This occurs due to the high average age of patients undergoing HT for PC, an age group in which CVDs have a high prevalence and incidence, and due to the type and duration of HTs that are increasingly effective but at the same time more aggressive towards cardiovascular health. Recent evidence from the real world suggests, however, that the cardiometabolic risk is widely underestimated and undertreated with significant impact also on the oncological prognosis. In the light of the results of the PRONOUNCE study, in this review it is emphasized the need for a multidisciplinary management of patients with PC who are candidate for or treated with HT by implementing a personalized treatment program in accordance with the current European guidelines on CVD prevention.


PMID:37767830 | DOI:10.1714/4100.40978

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PubMed articles on: Cardio-Oncology

Cardiac safety assessment of a novel recombinant bispecific antibody targeting the ether-à-go-go related gene 1 (hERG1)-β1 integrin macromolecular complex


Front Pharmacol. 2023 Sep 12;14:1237431. doi: 10.3389/fphar.2023.1237431. eCollection 2023.


ABSTRACT


Introduction: In the last decades, mounting evidence has pointed out the human ether-á-go-go-related gene (hERG1) potassium channel as a novel biomarker in human cancers. However, hERG1 sustains the cardiac repolarizing current IKr and its blockade can induce a prolonged QT interval at the ECG, which increases the risk of life-threatening arrhythmias. This represents a major hindrance for targeting hERG1 for antineoplastic therapeutic purposes. Based on our discovery that hERG1 resides in a macromolecular complex with the β1 subunit of integrin adhesion receptors only in tumors, and not in the heart, we generated (and patented WO2019/015936) a novel engineered, single chain, bispecific antibody in the format of a diabody (scDb-hERG1-β1). This antibody has been proven to target with high affinity the hERG1/β1 integrin complex and to exert a good antineoplastic activity in preclinical mouse models. Methods: In the present study, we evaluated the cardiac safety of the scDb-hERG1-β1, determining the action potential duration (APD) of human cardiomyocytes, either atrial (from valve-disease patients) or ventricular (from aortic stenosis patients). Cardiac cells were incubated in vitro with i) the scDb-hERG1-β1, ii) the full length anti-hERG1 monoclonal antibody (mAb-hERG1) and iii) its single chain Fragment variable derivative (scFv-hERG1), from which the scDb-hERG1-β1 was assembled. All the tests were performed before and after treatment with the specific hERG1 blocker E4031. In addition, we have performed preliminary experiments, analyzing the effects of the scDb-hERG1/β1 in vivo measuring the QT interval length of the surface ECG after its injection intravenously in farm-pigs. Results: The scDb-hERG1-β1 did not produce any lengthening of APD compared to control (vehicle) conditions, either in atrial or ventricular cardiomyocytes, whereas both the hERG1-mAb and the scFv-hERG1 produced a significant APD prolongation. The addition of E4031 further prolonged APD. The scDb-hERG1-β1 did not produce any alterations of the QT (and QTc) interval values, once injected intravenously in farm pigs. Discussion: Overall, the above evidences plead for the cardiac safety of the scDb-hERG1-β1, suggesting that an application of this antibody for anti-cancer therapy will be untainted by cardiotoxicity.


PMID:37767396 | PMC:PMC10520717 | DOI:10.3389/fphar.2023.1237431

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PubMed articles on: Cardio-Oncology

Hyperhomocysteinaemia Promotes Doxorubicin-Induced Cardiotoxicity in Mice


Pharmaceuticals (Basel). 2023 Aug 28;16(9):1212. doi: 10.3390/ph16091212.


ABSTRACT


Doxorubicin, a widely used chemotherapeutic drug in clinical oncology, causes a series of cardiac side effects referred to as doxorubicin-induced cardiotoxicity. Hyperhomocysteinaemia is an independent risk factor for multiple cardiovascular diseases. However, whether hyperhomocysteinaemia contributes to doxorubicin-induced cardiotoxicity is currently unknown. In this study, we explored the pathogenic effects of hyperhomocysteinaemia induced by dietary methionine supplementation (2% wt/wt in rodent chow) in a mouse model of doxorubicin-induced cardiotoxicity. Our data showed that methionine supplementation doubled serum homocysteine levels, inducing mild hyperhomocysteinaemia. Doxorubicin at a cumulative dosage of 25 mg/kg body weight led to significant weight loss and severe cardiac dysfunction, which were further exacerbated by methionine-induced mild hyperhomocysteinaemia. Doxorubicin-induced cardiac atrophy, cytoplasmic vacuolisation, myofibrillar disarray and loss, as well as cardiac fibrosis, were also exacerbated by methionine-induced mild hyperhomocysteinaemia. Additional folic acid supplementation (0.006% wt/wt) prevented methionine-induced hyperhomocysteinaemia and inhibited hyperhomocysteinaemia-aggravated cardiac dysfunction and cardiomyopathy. In particular, hyperhomocysteinaemia increased both serum and cardiac oxidative stress, which could all be inhibited by folic acid supplementation. Therefore, we demonstrated for the first time that hyperhomocysteinaemia could exacerbate doxorubicin-induced cardiotoxicity in mice, and the pathogenic effects of hyperhomocysteinaemia might at least partially correlate with increased oxidative stress and could be prevented by folic acid supplementation. Our study provides preliminary experimental evidence for the assessment of hyperhomocysteinaemia as a potential risk factor for chemotherapy-induced cardiotoxicity in cancer patients.


PMID:37765020 | DOI:10.3390/ph16091212

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PubMed articles on: Cardio-Oncology

Usefulness of Longitudinal Strain to Assess Cancer Therapy-Related Cardiac Dysfunction and Immune Checkpoint Inhibitor-Induced Myocarditis


Pharmaceuticals (Basel). 2023 Sep 14;16(9):1297. doi: 10.3390/ph16091297.

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ABSTRACT


AIMS: Recently, interventional techniques and material to treat chronic total occlusion (CTO) with percutaneous coronary intervention (PCI) have evolved significantly. Nevertheless, it is still unknown whether this progress improved treatment success and patients' outcome. In a nationwide sample, we sought to analyze trends of patients' characteristics, complications and in-hospital case-fatality of patients undergoing CTO revascularization in Germany.


METHODS AND RESULTS: We analyzed data on characteristics, treatments, and in-hospital outcomes for all coronary artery disease (CAD) patients (ICD-code I25) undergoing dual-injection CTO recanalization (OPS procedural code: 8-839.9) in Germany from 2009 to 2020. Overall, 4,998,457 inpatients aged ≥ 18 years with diagnosis of CAD were treated in German hospitals in this period. Among these, 52,879 patients (1.1%) underwent CTO recanalization. Annual number of CTO PCIs increased from 1263 in 2009 to 6435 in 2020 (β 3.48 [95% CI 3.44-3.52]; p < 0.001) in parallel with a significant decrease of case-fatality (2.2% in 2009 to 1.4% in 2020; β - 0.60 [95% CI - 0.82 to - 0.39]; p < 0.001). Overall, 754 (1.4%) patients with CTO recanalization died during the in-hospital stay and in-hospital case-fatality grew exponentially with age (β 0.82 [95% CI 0.73-0.90]; p < 0.001). Significant predictors of in-hospital case fatality with an OR > 3 were cancer, stroke, hemopericardium, acute renal failure, pulmonary embolism and shock.


CONCLUSION: Annual number of CTO procedures performed in Germany increased from 2009 to 2020 with a concomitant anti-proportional decrease in the case-fatality. Our findings may help to draw more attention to predictors of in-hospital case fatality in patients hospitalized for CTO recanalization.


PMID:37695528 | DOI:10.1007/s00392-023-02298-x

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PubMed articles on: Cancer & VTE/PE

Prevalence of Thromboembolic Events in Patients With Non-Small Cell Lung Cancer and RET Fusions


JAMA Oncol. 2023 Sep 14:e233625. doi: 10.1001/jamaoncol.2023.3625. Online ahead of print.


NO ABSTRACT


PMID:37707807 | PMC:PMC10502692 | DOI:10.1001/jamaoncol.2023.3625

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PubMed articles on: Cancer & VTE/PE

Use of Thromboprophylaxis after Autologous Breast Reconstruction: A Cost-Effective Break-Even Analysis


Plast Reconstr Surg. 2023 Sep 12. doi: 10.1097/PRS.0000000000011055. Online ahead of print.


ABSTRACT


PURPOSE: Post-operative venous thromboembolism (VTE) is a major source of morbidity and mortality. The use of thromboprophylaxis amongst surgeons is not well studied in autologous breast reconstruction. The purpose of this study was to determine the rate of VTE in breast cancer patients undergoing autologous breast reconstruction and to compare the cost-effectiveness of postoperative chemoprophylactic agents.


METHODS: The TriNetX LLC. National Health Research Network database was used to identify patients with breast cancer who underwent autologous breast reconstruction surgery between 2002-2022. The incidence of occurrence of VTE within the first 30 days of surgery was calculated. Then a break-even analysis was performed to determine the break-even rate of VTE at which the chemoprophylactic agent would be cost effective.


RESULTS: A cohort of 8,221 patients was identified in this study. The rate of VTE was significantly higher in those without anticoagulation (4.0%) compared to those who received anticoagulation (2.6%) (*p=0.0008). The break-even analysis for heparin and enoxaparin's cost-effectiveness yielded ARRs of 0.73% and 1.63% for high risk patients requiring 30 days of therapy and 0.20% and 0.43% for moderate risk patients requiring 7 days of therapy, respectively.


CONCLUSION: The use of thromboprophylaxis significantly lowered the risk of VTE within 30 days after autologous breast reconstruction. Heparin appeared to be more cost-effective at preventing VTE compared to enoxaparin for both high and moderate risk patients. The presented model holds potential for other institution-specific variables that can be easily applied by plastic surgeons to determine the cost-effectiveness of any therapy of their choice.


PMID:37699552 | DOI:10.1097/PRS.0000000000011055

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PubMed articles on: Cancer & VTE/PE

Thromboembolic disease and cancer: Attitude and practice of general practitioners. A qualitative study


Bull Cancer. 2023 Sep 8:S0007-4551(23)00347-8. doi: 10.1016/j.bulcan.2023.08.001. Online ahead of print.


ABSTRACT


INTRODUCTION: Cancer is a major public health problem in France. Idiopathic venous thromboembolic disease may be one of the modes of discovery. Few studies have been performed on this subject in primary care. The general practitioner plays a key role in the diagnosis for which a more codified approach seems desirable. The aim was to study how general practitioners conceive the search for cancer in patients with idiopathic venous thromboembolic disease in primary care.


METHOD: A qualitative study, inspired by the grounded theory approach, was carried out using semi-structured interviews with 12 established general practitioners. It was conducted from May to July 2022. The interview guide was developed based on data from the literature.


RESULTS: Idiopathic venous thromboembolic disease as a mode of cancer discovery in primary care was a well-known topic among general practitioners but remained a difficult exercise in practice. Our study revealed similarities in their practices: a complete anamnesis, clinical examination, verification of screening tests, and finally a TAP scan. They emphasized the importance of collaboration with angiologists and asked for a more codified management.


DISCUSSION: The question of etiology of cancer remains unanswered. General practioners would like to be made aware of a common, codified attitude. This raises the question of the applicability of the recommendations. The aim is to avoid misdiagnosing a cancer or delaying a diagnosis, while at the same time, not unnecessarily exposing certain patients to excessive investigations when these are not needed. So, it is time to think about better dissemination of recommendations, tools to help GPs easily finding what they need among the multitude of existing recommendations and tools, to establish better collaboration between general practice and hospital medicine, and between general practice and specialist medicine in order to improve cancer diagnosis as early as possible.


PMID:37690878 | DOI:10.1016/j.bulcan.2023.08.001

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PubMed articles on: Cardio-Oncology

Hormone therapy, cardio-metabolic profile, and cardiotoxicity. Still a dark side of cardio-oncology - Part 2: Prostate cancer


G Ital Cardiol (Rome). 2023 Oct;24(10):781-791. doi: 10.1714/4100.40978.

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ABSTRACT


BACKGROUND: Acute arterial embolism due to tumor embolus is a rare complication in cancer patients, even rarer is lung tumor embolization leading to acute myocardial infarction. We report a patient who had a diagnosis of acute myocardial infarction(AMI)which was brought on by a coronary artery embolism by a metastatic lung cancer tumor. Clinicians need to be aware that tumor embolism can result in AMI.


CASE PRESENTATION: An 80-yeal-old male patient presented with persistent chest pain for 2 h and his electrocardiogram(ECG)showed anterior ST-segment elevation myocardial infarction. Instead of implanting a stent, thrombus aspiration was performed. Pathological examination of coronary artery thrombosis showed that a few sporadic atypical epithelial cells were scattered in the thrombus-like tissue. Combined with immune phenotype and clinical history, metastatic squamous cell carcinoma is more likely.


CONCLUSIONS: We report a rare case of a patient who was diagnosed of AMI due to a coronary artery embolism by a metastatic mass from lung cancer. Since there is no evidence-based protocol available for the treatment of isolated coronary thrombosis, we used thrombus aspiration to treat thrombosis rather than implanting a stent.


PMID:37710181 | PMC:PMC10503072 | DOI:10.1186/s12872-023-03505-3

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PubMed articles on: Cancer & VTE/PE

Estimating Venous Thromboembolism Risk in Metastatic Colorectal Cancer Inpatients: Validation of Existing Risk Scores and Development of New Risk Scores


Clin Appl Thromb Hemost. 2023 Jan-Dec;29:10760296231196859. doi: 10.1177/10760296231196859.


ABSTRACT


Metastatic colorectal cancer (mCRC) patients are predisposed to venous thromboembolism (VTE). This study aimed to (1) evaluate the efficacy of 4 existing cancer-specific VTE models in predicting VTE incidence among hospitalized mCRC patients, and (2) examine the influence of incorporating mCRC molecular subtypes into these models. We conducted an evaluation of 4 cancer-specific VTE models, including Khorana, Vienna CATS, Protecht, and CONKO in a dataset involving 1392 mCRC patients. To evaluate the predictive performance, we utilized receiver operating characteristic (ROC) curves for both the original models and the modified models that incorporated microsatellite instability status or KRAS/NRAS/BRAF mutations. Moreover, we computed the net reclassification improvement (NRI) to quantify the enhancements made to the modified VTE risk models. All models demonstrated a moderate area under the ROC curve (ROC-AUC) when predicting the occurrence of VTE: Khorana (0.550), Vienna CATS (0.671), Protecht (0.652), and CONKO (0.578). The incorporation of KRAS and BRAF mutations significantly improved the ROC-AUC of all 4 existing models (modified Khorana: 0.796, modified Vienna CATS: 0.832, modified Protecht: 0.834, and modified CONKO: 0.809). After dichotomizing the risk using a threshold of 3 points and comparing them with the original models, NRI values for the 4 modified models were 0.97, 0.95, 1.11, and 0.98, respectively. All 4 cancer-specific VTE models exhibit moderate performance when identifying mCRC patients at high risk of VTE. Incorporating KRAS and BRAF mutations may enhance the prediction of VTE in hospitalized mCRC patients.


PMID:37691565 | PMC:PMC10498692 | DOI:10.1177/10760296231196859

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PubMed articles on: Cancer & VTE/PE

Management of a Right Heart Intracavitary Thrombus in Transit in a Patient With Gastric Cancer in a Resource-Limited Setting: A Case Report


Cureus. 2023 Aug 8;15(8):e43133. doi: 10.7759/cureus.43133. eCollection 2023 Aug.


ABSTRACT


A right atrial thrombus is an unusual source of imminent massive saddle pulmonary embolism (PE) . A hypercoagulable state secondary to gastric cancer (GC) can result in deep vein thrombosis (DVT) with a resultant right-sided heart thrombus in transit. Here, we present a case of a young male patient from Honduras with DVT and multiple venous thrombi extending from the external iliac veins to the suprahepatic left vein, inferior vena cava, and right atrium of the heart, secondary to a hypercoagulable state from GC, adenocarcinoma type. We describe the approach of treating a right heart intracavitary thrombus with imminent risk for saddle PE and sudden cardiac death with thrombolysis through a central venous catheter (CVC) in a resource-limited setting.


PMID:37692570 | PMC:PMC10484470 | DOI:10.7759/cureus.43133

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PubMed articles on: Cancer & VTE/PE

Predicting Bleeding in Cancer-Associated Venous Thromboembolism: Another Milestone Achieved


Thromb Haemost. 2023 Sep 11. doi: 10.1055/s-0043-1775582. Online ahead of print.


NO ABSTRACT


PMID:37696302 | DOI:10.1055/s-0043-1775582

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PubMed articles on: Cancer & VTE/PE

Temporal trends of case-fatality in patients undergoing dual-injection coronary chronic total occlusion recanalization


Clin Res Cardiol. 2023 Sep 11. doi: 10.1007/s00392-023-02298-x. Online ahead of print.

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ABSTRACT


Cancer-associated thrombosis (CT), especially venous thromboembolism (VTE), is a common occurrence with several factors contributing to a wide diversity in thrombosis risk. The association between ABO blood groups and the risk for CT has been examined in various studies, with non-O blood type associated with an increased thrombosis risk; however, these studies have reported varying results with recognized limitations. ABO blood groups are known to be implicated in hemostasis, in an association mediated through von Willebrand factor (VWF). In this narrative review, we aim to summarize the current knowledge surrounding the role of ABO blood groups in VTE, with a particular focus on the role of VWF and other contributing risk factors on VTE occurrence. We found evidence from literature for the impact of ABO blood groups in determining the risk of VTE in healthy populations, with a limited number of studies examining this effect in cancer patients. Additionally, research on the impact of ABO on different cancer types lacks rigor, particularly in regard to other risk factors. Overall, most studies showed strong association of increased risk of VTE amongst cancer patients with non-O blood groups and increased VWF levels. This association was weaker in a few studies. Further research is needed before a solid conclusion can be made about the ABO or ABO-VWF-mediated hypercoagulability and VTE risk in various cancers. These studies will help determine if ABO typing can be an added biomarker to improve VTE risk assessment models in cancer patients.


PMID:37751774 | DOI:10.1055/s-0043-1775568

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PubMed articles on: Cancer & VTE/PE

Early identification of lung cancer patients with venous thromboembolism: development and validation of a risk prediction model


Thromb J. 2023 Sep 14;21(1):95. doi: 10.1186/s12959-023-00544-w.


ABSTRACT


INTRODUCTION: Venous thromboembolism(VTE) is a leading cause of death in patients with lung cancer. Furthermore, hospitalization of patients with advanced lung cancer for VTE treatment represents a major economic burden on the national public health resources. Therefore, we performed this prospective study to identify clinical biomarkers for the early identification of VTE in lung cancer patients.


METHODS: This prospective study enrolled 158 patients with confirmed lung cancer, including 27 who were diagnosed with VTE within six months of the follow-up after lung cancer diagnosis. Multivariate logistic regression analysis was used to evaluate the diagnostic performancese of all the relevant clinical features and laboratory indicators in identifying lung cancer patients with a higher risk of VTE. A novel risk prediction model was constructed consisting of five clinical variables with the best diagnostic performances and was validated using the receiver operation characteristic(ROC) curves. The diagnostic performances of the new risk prediction model was also compared with the Khorana risk score (KRS) and the Padua risk score (PRS).


RESULTS: The VTE group of lung cancer patients (n = 27) showed significantly higher serum levels of fibrin degradation products (FDP), D-dimer, thrombomodulin (TM), thrombin-antithrombin-complex (TAT), α2-plasmin inhibitor-plasmin Complex (PIC), and tissue plasminogen activator-plasminogen activator inhibitor complex (t-PAIC) compared to those in the non-VTE group (n = 131). ROC curve analyses showed that the diagnostic efficacy of the new VTE risk prediction model with TM ≥ 9.75 TU/ml, TAT ≥ 2.25ng/ml, t-PAIC ≥ 7.35ng/ml, history of VTE, and ECOG PS score ≥ 2 was superior than the KRS and the PRS in the early identification of lung cancer patients with a higher risk of VTE.


CONCLUSIONS: The new risk prediction model showed significantly high diagnostic efficacy in the early identification of lung cancer patients with a high risk of VTE. The diagnostic efficacy of the new risk prediction model was higher than the KRS and the PRS in this cohort of lung cancer patients.


PMID:37710256 | PMC:PMC10500728 | DOI:10.1186/s12959-023-00544-w

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PubMed articles on: Cancer & VTE/PE

Acute myocardial infarction due to coronary embolism caused by a metastatic mass from lung cancer


BMC Cardiovasc Disord. 2023 Sep 15;23(1):461. doi: 10.1186/s12872-023-03505-3.


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ABSTRACT


OBJECTIVE: This systematic review and meta-analysis compares the rate of venous thromboembolism (VTE) in surgical inpatients with pharmacological thromboprophylaxis and additional graduated compression stockings (GCS) versus pharmacological thromboprophylaxis alone.


SUMMARY BACKGROUND DATA: Surgical inpatients have elevated VTE risk; recent studies cast doubt whether GCS confer additional protection against VTE, compared to pharmacological thromboprophylaxis alone.


METHODS: The review followed PRISMA guidelines using a registered protocol (CRD42017062655). The MEDLINE and Embase databases were searched to November 2022. Randomised trials reporting VTE rate after surgical procedures, utilising pharmacological thromboprophylaxis, with or without GCS, were included. The rates of deep venous thrombosis (DVT), pulmonary embolism (PE), VTE-related mortality were pooled via fixed and random effects.


RESULTS: In head-to-head meta-analysis, the risk of DVT for GCS and pharmacological thromboprophylaxis was 0.85 (95% CI 0.54-1.36) versus for pharmacological thromboprophylaxis alone (2 studies, 70 events, 2653 participants). The risk of DVT in pooled trial arms for GCS and pharmacological thromboprophylaxis was 0.54 (95% CI 0.23-1.25) versus pharmacological thromboprophylaxis alone (33 trial arms, 1228 events, 14,108 participants). The risk of PE for GCS and pharmacological prophylaxis versus pharmacological prophylaxis alone was 0.71 (95% CI 0.0-30.0) (27 trial arms, 32 events, 11,472 participants). There were no between-group differences in VTE-related mortality (27 trial arms, 3 events, 12,982 participants).


CONCLUSIONS: Evidence from head-to-head meta-analysis and pooled trial arms demonstrates no additional benefit for GCS in preventing VTE and VTE-related mortality. GCS confer a risk of skin complications and an economic burden; current evidence does not support their use for surgical inpatients.


PMID:37753655 | DOI:10.1097/SLA.0000000000006096

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PubMed articles on: Cancer & VTE/PE

A case of metastatic breast cancer complicated by pulmonary tumor thrombotic microangiopathy


Zhonghua Jie He He Hu Xi Za Zhi. 2023 Oct 12;46(10):1014-1018. doi: 10.3760/cma.j.cn112147-20230521-00253.


ABSTRACT


Pulmonary tumor thrombotic microangiopathy is a malignancy-related complication with rapid progression and high mortality. To improve the understanding of the disease, early diagnosis and treatment are key to successful treatment. A 39-year-old patient with pulmonary hypertension transferred from another hospital was admitted to the First Affiliated Hospital of Guangzhou Medical University on September 26, 2021. The patient developed shortness of breath and progressive exacerbation over the past month. No pulmonary artery embolism was seen on computed tomography pulmonary angiography (CTPA) at the outside hospital where the breast cancer was diagnosed. Pulmonary tumor thrombotic microangiopathy was immediately considered on admission and oncological endocrine therapy was started. After treatment, the patient's dyspnoea improved, PET-CT showed significant tumor regression, and cardiac ultrasound showed a significant decrease in pulmonary artery pressure. The successful treatment experience of this case was summarized for reference.


PMID:37752045 | DOI:10.3760/cma.j.cn112147-20230521-00253

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PubMed articles on: Cancer & VTE/PE

Effect of factor XI inhibition on tumor cell-induced coagulation activation


J Thromb Haemost. 2023 Sep 24:S1538-7836(23)00717-1. doi: 10.1016/j.jtha.2023.09.015. Online ahead of print.


ABSTRACT


BACKGROUND: Cancer-associated thrombosis (CAT) is a frequent complication in patients with malignancies. While FXI/FXIa inhibition is efficacious in preventing postoperative venous thromboembolism, its role in tumor cell-induced coagulation is less defined.


OBJECTIVES: We thus aimed to provide mechanistic insights into FXI/FXIa inhibition in tumor cell-induced coagulation activation.


METHODS: Procoagulant activity (PCA) of four different tissue factor (TF) expressing tumor cell lines was analyzed by single-stage clotting and thrombin generation assay in the presence of a FXIa inhibitor, BMS-262084 (BMS), an inhibitory FXI antibody (anti-FXI), or peak and trough concentrations of rivaroxaban or tinzaparin. Further, tumor cell-induced platelet aggregation was recorded. Recombinant human TF (rhTF) served as positive control.


RESULTS: Although BMS and anti-FXI potently inhibited FXIa amidolytic activity, both inhibitors efficiently mitigated rhTF- and tumor cell-induced fibrin clot formation and platelet aggregation only in the presence of low TF PCA. The anticoagulant effects showed an inverse correlation with the magnitude of cellular TF PCA expression. Similarly, BMS markedly interfered with tumor cell-induced thrombin generation, with the most prominent effects on peak and total thrombin. In addition, anticoagulant effects of FXIa inhibition by 10 μM BMS were in a similar range to those obtained by 600 nM rivaroxaban and 1.6 μM tinzaparin at low TF PCA levels. However, rivaroxaban and tinzaparin also exerted marked anticoagulant activity at high TF PCA levels.


CONCLUSIONS: Our findings indicate that FXI/FXIa inhibition interferes with tumor cell-induced coagulation activation only at low TF PCA expression levels, a finding with potential implications for future in-vivo studies.


PMID:37751848 | DOI:10.1016/j.jtha.2023.09.015

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PubMed articles on: Cancer & VTE/PE

ABO Blood Group and the Risk of Thrombosis in Cancer Patients: A Mini-Review


Semin Thromb Hemost. 2023 Sep 26. doi: 10.1055/s-0043-1775568. Online ahead of print.

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ABSTRACT


Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists, mostly warfarin, for the main indications for oral anticoagulation, prevention and treatment of venous thromboembolism, and prevention of embolic stroke in atrial fibrillation. While DOACs offer practical, fixed-dose anticoagulation in many patients, specific restrictions or contraindications may apply. DOACs are not sufficiently effective in high-thrombotic risk conditions such as antiphospholipid syndrome and mechanical heart valves. Patients with cancer-associated thrombosis may benefit from DOACs, but the bleeding risk, particularly in those with gastrointestinal or urogenital tumors, must be carefully weighed. In patients with frailty, excess body weight, and/or moderate-to-severe chronic kidney disease, DOACs must be cautiously administered and may require laboratory monitoring. Reversal agents have been developed and approved for life-threatening bleeding. In addition, the clinical testing of potentially safer anticoagulants such as factor XI(a) inhibitors is important to further optimize anticoagulant therapy in an increasingly elderly and frail population worldwide. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.


PMID:37758192 | DOI:10.1146/annurev-pharmtox-032823-122811

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PubMed articles on: Cancer & VTE/PE

Venous thromboembolism prophylaxis practices for patients with sickle cell disease prior to and during the COVID-19 pandemic


Blood Coagul Fibrinolysis. 2023 Sep 21. doi: 10.1097/MBC.0000000000001250. Online ahead of print.


ABSTRACT


Patients with sickle cell disease (SCD) are predisposed to a hypercoagulable state due to alterations in the coagulation system. Despite concern for the development of venous thromboembolism (VTE) in this population, there are no standardized guidelines for routine thromboprophylaxis. The objective of this study was to assess thromboprophylaxis practices of adult and pediatric treaters of SCD before and during the coronavirus disease of 2019 (COVID-19) pandemic. A cross-sectional electronic survey was distributed to pediatric and adult hematology oncology practitioners through seven SCD-specific interest groups between May 29, 2020, and July 13, 2020. Of 93 total responses, 14% (N = 13) reported they only treat patients more than 21 years old; 38.7% (N = 36) only treat patients 0-21 years old and 47.3% (N = 44) reported they treat both. Our study showed that before the COVID-19 pandemic, 96% of adult practitioners would recommend pharmacologic thromboprophylaxis, mechanical thromboprophylaxis or both for hospitalized adults with thromboprophylaxis, but only 76% of pediatric treaters would recommend any thromboprophylaxis in hospitalized children (P < 0.0001), with 24% of pediatric treaters choosing no thromboprophylaxis at all. During the COVID-19 pandemic, pharmacologic thromboprophylaxis specifically was recommended for adults by 94% of treaters and for pediatric patients by 76% of treaters. These findings suggest that despite the lack of evidence-based thromboprophylaxis guidelines in adults and children with thromboprophylaxis, subspecialty treaters routinely provide pharmacologic thromboprophylaxis in their adult patients and will modify their practice in pediatric patients who are considered at a high risk for VTE.


PMID:37756203 | DOI:10.1097/MBC.0000000000001250

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PubMed articles on: Cardio-Oncology

Sexual dimorphism in doxorubicin cardiotoxicity: two sides of a complex coin


Am J Physiol Heart Circ Physiol. 2023 Nov 1;325(5):H949-H951. doi: 10.1152/ajpheart.00566.2023. Epub 2023 Sep 15.


NO ABSTRACT


PMID:37712921 | DOI:10.1152/ajpheart.00566.2023

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PubMed articles on: Cancer & VTE/PE

Correction to: Epidemiological Study Regarding the Incidence of Venous Thromboembolism in Patients After Cancer Remission


Cardiol Ther. 2023 Sep 27. doi: 10.1007/s40119-023-00330-9. Online ahead of print.


NO ABSTRACT


PMID:37755611 | DOI:10.1007/s40119-023-00330-9

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PubMed articles on: Cardio-Oncology

Exercise as Medicine in Cardio-Oncology: Reducing Health Disparities in Hispanic and Latina Breast Cancer Survivors


Curr Oncol Rep. 2023 Sep 16. doi: 10.1007/s11912-023-01446-w. Online ahead of print.


ABSTRACT


PURPOSE OF REVIEW: This review aims to access the current state of the evidence in exercise as medicine for cardio-oncology in Hispanic and Latina breast cancer survivors and to provide our preliminary data on the effects of supervised aerobic and resistance training on cardiovascular disease (CVD) risk in this population.


RECENT FINDINGS: Breast cancer survivors have a higher risk of CVD; particularly Hispanic and Latina breast cancer survivors have a higher burden than their White counterparts. Exercise has been shown to reduce CVD risk in breast cancer survivors; however, evidence in Hispanic and Latina breast cancer survivors is scarce. Our review highlights a clear need for exercise oncology clinical trials in Hispanic and Latina breast cancer survivors targeting CVD risk factors. Moreover, our exploratory results highlight that 16 weeks of aerobic and resistance training may reduce the 10-year risk of developing CVD by 15% in Hispanic and Latina breast cancer survivors.


PMID:37715884 | DOI:10.1007/s11912-023-01446-w

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PubMed articles on: Cardio-Oncology

Cardiotoxicity in breast cancer treatment: Causes and mitigation


Cancer Treat Res Commun. 2023 Sep 11;37:100760. doi: 10.1016/j.ctarc.2023.100760. Online ahead of print.


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ABSTRACT


The characterization of cardiac mechanical properties may contribute to better understanding of doxorubicin-induced cardiotoxicity. Our study aims to investigate the relationship between cardiac mechanical properties, T1 and T2 relaxation times and partition coefficient. Fifty childhood acute lymphoblastic leukemia survivors underwent a cardiac magnetic resonance (CMR) at rest on a 3T MRI system and included a standard ECG-gated 3(3)3(3)5 MOLLI sequence for T1 mapping and an ECG-gated T2-prepared TrueFISP sequence for T2 mapping. Partition coefficient, ejection fraction, end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated. CircAdapt model was used to study cardiac mechanical performance (left ventricle stiffness (LVS), contractility (LVC) and pressure (Pmin and Pmax), cardiac work efficiency (CWE) and ventricular arterial coupling). In the whole cohort, our results showed that LVC (R2 = 69.2%, r = 0.83), Pmin (R2 = 62.9%, r = 0.79) and Pmax can be predicted by significant CMR parameters, while T1 (R2 = 23.2%, r = 0.48) and partition coefficient (R2 = 13.8%, r = 0.37) can be predicted by significant cardiac mechanical properties. In SR group LVS (R2 = 94.8%, r = 0.97), LVC (R2 = 93.7%, r = 0.96) and Pmin (R2 = 90.6%, r = 0.95) can be predicted by significant cardiac mechanical properties, while in HR + DEX group CWE (R2 = 49.8%, r = 0.70) can be predicted by significant cardiac mechanical properties. Partition coefficient (R2 = 72.6%, r = 0.85) can be predicted by significant CMR parameters in SR group. Early characterization of cardiac mechanical properties from CMR parameters has the potential to early detect doxorubicin-induced cardiotoxicity.


PMID:37728802 | DOI:10.1007/s10554-023-02953-4

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PubMed articles on: Cardio-Oncology

Computational drug prediction in hepatoblastoma by integrating pan-cancer transcriptomics with pharmacological response


Hepatology. 2023 Sep 20. doi: 10.1097/HEP.0000000000000601. Online ahead of print.


ABSTRACT


Hepatoblastoma (HB) is the main paediatric liver cancer, but it is a very rare disease. Despite significant improvements in the treatment of children diagnosed with HB, limited treatment options exist for patients with advanced tumours. Besides, survivors generally have long-term adverse effects derived from treatment such as ototoxicity, cardiotoxicity, delayed growth, and secondary tumours. Accordingly, there is an urgent need to define new and efficient therapeutic strategies for patients with HB. Computational methods to predict drug sensitivity from a tumour's transcriptome have been successfully applied for some common adult malignancies, but specific efforts in paediatric cancers are lacking because of paucity of data. In this study, we computationally screened the efficacy of drugs in HB patients with the aggressive C2 subtype and poor clinical outcome starting from their transcriptome. Our method utilized publicly available collections of pan-cancer transcriptional profiles and drug responses across 36 tumour types and 495 compounds. The drugs predicted to be most effective were experimentally validated using patient-derived xenograft (PDX) models of HB grown in vitro and in vivo. We thus identified two CDK9 inhibitors, alvocidib and dinaciclib as potent HB growth inhibitors for the high-risk C2 molecular subtype. We also found that in a cohort of 46 patients with HB, high CDK9 tumour expression was significantly associated with poor prognosis. Our work proves the usefulness of computational methods trained on pan-cancer datasets to reposition drugs in rare paediatric cancers such as HB, and to help clinicians in choosing the best treatment options for their patients.


PMID:37729391 | DOI:10.1097/HEP.0000000000000601

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PubMed articles on: Cancer & VTE/PE

A New Risk Prediction Model for Venous Thromboembolism and Death in Ambulatory Lung Cancer Patients


Cancers (Basel). 2023 Sep 15;15(18):4588. doi: 10.3390/cancers15184588.


ABSTRACT


(1) Background: Venous thromboembolism (VTE) is a frequent complication in ambulatory lung cancer patients during chemotherapy and is associated with increased mortality. (2) Methods: We analyzed 568 newly diagnosed metastatic lung cancer patients prospectively enrolled in the HYPERCAN study. Blood samples collected before chemotherapy were tested for thrombin generation (TG) and a panel of hemostatic biomarkers. The Khorana risk score (KRS), new-Vienna CATS, PROTECHT, and CONKO risk assessment models (RAMs) were applied. (3) Results: Within 6 months, the cumulative incidences of VTE and mortality were 12% and 29%, respectively. Patients with VTE showed significantly increased levels of D-dimer, FVIII, prothrombin fragment 1 + 2, and TG. D-dimer and ECOG performance status were identified as independent risk factors for VTE and mortality by multivariable analysis and utilized to generate a risk score that provided a cumulative incidence of VTE of 6% vs. 25%, death of 19% vs. 55%, and in the low- vs. high-risk group, respectively (p < 0.001). While all published RAMs significantly stratified patients for risk of death, only the CATS and CONKO were able to stratify patients for VTE. (4) Conclusions: A new prediction model was generated to stratify lung cancer patients for VTE and mortality risk, where other published RAMs failed.


PMID:37760562 | DOI:10.3390/cancers15184588

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PubMed articles on: Cardio-Oncology

Narcissin induces developmental toxicity and cardiotoxicity in zebrafish embryos via Nrf2/HO-1 and calcium signaling pathways

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PubMed articles on: Cancer & VTE/PE

Oral Anticoagulants Beyond Warfarin


Annu Rev Pharmacol Toxicol. 2023 Sep 27. doi: 10.1146/annurev-pharmtox-032823-122811. Online ahead of print.


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ABSTRACT


BACKGROUND: Immune checkpoint inhibitor (ICI) myocarditis is associated with significant mortality risk. Electrocardiogram (ECG) changes in ICI myocarditis have strong prognostic value. However the impact of complete heart block (CHB) is not well defined. This study sought to evaluate the impact of CHB on mortality in ICI myocarditis, and to identify clinical predictors of mortality and CHB incidence.


METHODS: We conducted a retrospective cohort study of patients with ICI myocarditis at three Mayo Clinic sites from 1st January 2010 to 31st September 2022 to evaluate mortality rates at 180 days. Clinical, laboratory, ECG, echocardiographic, and cardiac magnetic resonance imaging (CMR) characteristics were assessed. Cox and logistic regression were performed for associations with mortality and CHB respectively.


RESULTS: Of 34 identified cases of ICI myocarditis, 7 (20.6%) had CHB. CHB was associated with higher mortality (HR 7.41, p = 0.03, attributable fraction 86.5%). Among those with CHB, troponin T (TnT) < 1000 ng/dL, low white blood cell count and high ventricular rate at admission were protective. There was trend towards increased survival among patients who underwent permanent pacemaker insertion (p = 0.051), although most experienced device lead complications. Factors associated with development of CHB included prolonged PR and QRS intervals and low Sokolow Lyon Index. Where these were normal and TnT was < 1000 ng/dL, no deaths occurred. Impaired myocardial longitudinal strain was sensitive for ICI myocarditis but was not prognostically significant.


CONCLUSION: There is a strong temporal association between CHB and early mortality in people with ICI myocarditis. Focusing on arrhythmogenic complications can be helpful in predicting outcomes for this group of critically ill individuals.


PMID:37730763 | PMC:PMC10510176 | DOI:10.1186/s40959-023-00185-y

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PubMed articles on: Cardio-Oncology

Disparities in cardio-oncology: Implication of angiogenesis, inflammation, and chemotherapy


Life Sci. 2023 Sep 18;332:122106. doi: 10.1016/j.lfs.2023.122106. Online ahead of print.


ABSTRACT


Cancers and cardiovascular diseases are the top two causes of death in the United States. Over the past decades, novel therapies have slowed the cancer mortality rate, yet cardiac failures have risen due to the toxicity of cancer treatments. The mechanisms behind this relationship are poorly understood and it is crucial that we properly treat patients at risk of developing cardiac failure in response to cancer treatments. Currently, we rely on early-stage biomarkers of inflammation and angiogenesis to detect cardiotoxicity before it becomes irreversible. Identification of such biomarkers allows healthcare professionals to decrease the adverse effects of cancer therapies. Angiogenesis and inflammation have a systemic influence on the heart and vasculature following cancer therapy. In the field of cardio-oncology, there has been a recent emphasis on gender and racial disparities in cardiotoxicity and the impact of these disparities on disease outcomes, but there is a scarcity of data on how cardiotoxicity varies across diverse populations. Here, we will discuss how current markers of angiogenesis and inflammation induced by cancer therapy are related to disparities in cardiovascular health.


PMID:37730108 | DOI:10.1016/j.lfs.2023.122106

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PubMed articles on: Cardio-Oncology

One-Lung Ventilation and Postoperative Pulmonary Complications After Major Lung Resection Surgery. A Multicenter Randomized Controlled Trial


J Cardiothorac Vasc Anesth. 2023 Apr 27:S1053-0770(23)00262-8. doi: 10.1053/j.jvca.2023.04.029. Online ahead of print.


ABSTRACT


OBJECTIVES: The effect of one-lung ventilation (OLV) strategy based on low tidal volume (TV), application of positive end-expiratory pressure (PEEP), and alveolar recruitment maneuvers (ARM) to reduce postoperative acute respiratory distress syndrome (ARDS) and pulmonary complications (PPCs) compared with higher TV without PEEP and ARM strategy in adult patients undergoing lobectomy or pneumonectomy has not been well established.


DESIGN: Multicenter, randomized, single-blind, controlled trial.


SETTING: Sixteen Italian hospitals.


PARTICIPANTS: A total of 880 patients undergoing elective major lung resection.


INTERVENTIONS: Patients were randomized to receive lower tidal volume (LTV group: 4 mL/kg predicted body weight, PEEP of 5 cmH2O, and ARMs) or higher tidal volume (HTL group: 6 mL/kg predicted body weight, no PEEP, and no ARMs). After OLV, until extubation, both groups were ventilated using a tidal volume of 8 mL/kg and a PEEP value of 5 cmH2O. The primary outcome was the incidence of in-hospital ARDS. Secondary outcomes were the in-hospital rate of PPCs, major cardiovascular events, unplanned intensive care unit (ICU) admission, in-hospital mortality, ICU length of stay, and in-hospital length of stay.


MEASUREMENTS AND MAIN RESULTS: ARDS occurred in 3 of 438 patients (0.7%, 95% CI 0.1-2.0) and in 1 of 442 patients (0.2%, 95% CI 0-1.4) in the LTV and HTV group, respectively (Risk ratio: 3.03 95% CI 0.32-29, p = 0.372). Pulmonary complications occurred in 125 of 438 patients (28.5%, 95% CI 24.5-32.9) and in 136 of 442 patients (30.8%, 95% CI 26.6-35.2) in the LTV and HTV group, respectively (risk ratio: 0.93, 95% CI 0.76-1.14, p = 0.507). The incidence of major complications, in-hospital mortality, and unplanned ICU admission, ICU and in-hospital length of stay were comparable in both groups.


CONCLUSIONS: In conclusion, among adult patients undergoing elective lung resection, an OLV with lower tidal volume, PEEP 5 cmH2O, and ARMs and a higher tidal volume strategy resulted in low ARDS incidence and comparable postoperative complications, in-hospital length of stay, and mortality.


PMID:37730455 | PMC:PMC10133024 | DOI:10.1053/j.jvca.2023.04.029

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PubMed articles on: Cardio-Oncology

Relationship between cardiac mechanical properties and cardiac magnetic resonance imaging at rest in childhood acute lymphoblastic leukemia survivors


Int J Cardiovasc Imaging. 2023 Sep 20. doi: 10.1007/s10554-023-02953-4. Online ahead of print.

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ABSTRACT


Photothermal therapy (PTT) is a highly clinical application promising cancer treatment strategy with safe, convenient surgical procedures and excellent therapeutic efficacy on superficial tumors. However, a single PTT is difficult to eliminate tumor cells completely, and tumor recurrence and metastasis are prone to occur in the later stage. Chemo-photothermal synergistic therapy can conquer the shortcomings by further killing residual tumor cells after PTT through systemic chemotherapy. Nevertheless, chemotherapy drugs' extreme toxicity is also a problematic issue to be solved, such as anthracycline-induced cardiotoxicity. Herein, we selected polydopamine nanoparticles (PDA) as the carrier of the chemotherapeutic drug doxorubicin (DOX) to construct a versatile PDA(DOX) nanoplatform for chemo-photothermal synergistic therapy against breast cancer and simultaneously attenuated DOX-induced cardiotoxicity (DIC). The excellent photothermal properties of PDA were used to achieve the thermal ablation of tumors. DOX carried out chemotherapy to kill residual and occult distant tumors. Furthermore, the PDA(DOX) nanoparticles significantly alleviate DIC, which benefits from PDA's excellent antioxidant enzyme activity. The experimental data of the chemotherapy groups showed that the results of the PDA(DOX) group were much better than the DOX group. This study not only effectively inhibits cancer but tactfully attenuates DIC, bringing a new perspective into synergistic therapy against breast cancer.


PMID:37735669 | PMC:PMC10512561 | DOI:10.1186/s12951-023-02072-1

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PubMed articles on: Cardio-Oncology

Inhibition of PRKAA/AMPK (Ser485/491) phosphorylation by crizotinib induces cardiotoxicity via perturbing autophagosome-lysosome fusion


Autophagy. 2023 Sep 21. doi: 10.1080/15548627.2023.2259216. Online ahead of print.


ABSTRACT


Crizotinib, a small-molecule tyrosine kinase inhibitor targeting ALK, MET and ROS1, is the first-line drug for ALK-positive metastatic non-small cell lung cancer and is associated with severe, sometimes fatal, cases of cardiac failure, which increases the risk of mortality. However, the underlying mechanism remains unclear, which causes the lack of therapeutic strategy. We established in vitro and in vivo models for crizotinib-induced cardiotoxicity and found that crizotinib caused left ventricular dysfunction, myocardial injury and pathological remodeling in mice and induced cardiomyocyte apoptosis and mitochondrial injury. In addition, we found that crizotinib prevented the degradation of MET protein by interrupting autophagosome-lysosome fusion and silence of MET or re-activating macroautophagy/autophagy flux rescued the cardiomyocytes death and mitochondrial injury caused by crizotinib, suggesting that impaired autophagy activity is the key reason for crizotinib-induced cardiotoxicity. We further confirmed that recovering the phosphorylation of PRKAA/AMPK (Ser485/491) by metformin re-activated autophagy flux in cardiomyocytes and metformin rescued crizotinib-induced cardiomyocyte injury and cardiac complications. In summary, we revealed a novel mechanism for crizotinib-induced cardiotoxicity, wherein the crizotinib-impaired autophagy process causes cardiomyocyte death and cardiac injury by inhibiting the degradation of MET protein, demonstrated a new function of impeded autophagosome-lysosome fusion in drugs-induced cardiotoxicity, pointed out the essential role of the phosphorylation of PRKAA (Ser485/491) in autophagosome-lysosome fusion and confirmed metformin as a potential therapeutic strategy for crizotinib-induced cardiotoxicity.


PMID:37733896 | DOI:10.1080/15548627.2023.2259216

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PubMed articles on: Cardio-Oncology

Ferritin nanoconjugates guide trastuzumab brain delivery to promote an antitumor response in murine HER2 + breast cancer brain metastasis


Pharmacol Res. 2023 Sep 19;196:106934. doi: 10.1016/j.phrs.2023.106934. Online ahead of print.


ABSTRACT


Brain metastasis (BM) represents a clinical challenge for patients with advanced HER2 + breast cancer (BC). The monoclonal anti-HER2 antibody trastuzumab (TZ) improves survival of BC patients, but it has low central nervous system penetrance, being ineffective in treating BM. Previous studies showed that ferritin nanoparticles (HFn) may cross the blood brain barrier (BBB) through binding to the transferrin receptor 1 (TfR1). However, whether this has efficacy in promoting the trans-BBB delivery of TZ and combating BC BM was not studied yet. Here, we investigated the potential of HFn to drive TZ brain delivery and promote a targeted antitumor response in a murine model of BC BM established by stereotaxic injection of engineered BC cells overexpressing human HER2. HFn were covalently conjugated with TZ to obtain a nanoconjugate endowed with HER2 and TfR1 targeting specificity (H-TZ). H-TZ efficiently achieved TZ brain delivery upon intraperitoneal injection and triggered stable targeting of cancer cells. Treatment with H-TZ plus docetaxel significantly reduced tumor growth and shaped a protective brain microenvironment by engaging macrophage activation toward cancer cells. H-TZ-based treatment also avoided TZ-associated cardiotoxicity by preventing drug accumulation in the heart and did not induce any other major side effects when combined with docetaxel. These results provided in vivo demonstration of the pharmacological potential of H-TZ, able to tackle BC BM in combination with docetaxel. Indeed, upon systemic administration, the nanoconjugate guides TZ brain accumulation, reduces BM growth and limits side effects in off-target organs, thus showing promise for the management of HER2 + BC metastatic to the brain.


PMID:37734460 | DOI:10.1016/j.phrs.2023.106934

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PubMed articles on: Cardio-Oncology

Assessment of short-term effects of thoracic radiotherapy on the cardiovascular parasympathetic and sympathetic nervous systems


Front Neurosci. 2023 Sep 4;17:1256067. doi: 10.3389/fnins.2023.1256067. eCollection 2023.

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 Cardiotoxicity News

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PubMed articles on: Cardio-Oncology

Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial


Circulation. 2023 Sep 25. doi: 10.1161/CIRCULATIONAHA.123.064274. Online ahead of print.


ABSTRACT


BACKGROUND: Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy.


METHODS: In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%.


RESULTS: Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; P=0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; P=0.92, not equivalent).


CONCLUSIONS: Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline.


REGISTRATION: URL: https://doi.org/10.1186/ISRCTN24439460; Unique identifier, ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2017-000896-99; Unique identifier: EudraCT 2017-000896-99.


PMID:37746692 | DOI:10.1161/CIRCULATIONAHA.123.064274

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PubMed articles on: Cardio-Oncology

Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications


Front Cardiovasc Med. 2023 Sep 8;10:1150569. doi: 10.3389/fcvm.2023.1150569. eCollection 2023.


ABSTRACT


Cardio-oncology is an emerging field that seeks to enhance quality of life and longevity of cancer survivors. It is pertinent for clinicians to understand the cellular mechanisms of prescribed therapies, as this contributes to robust understanding of complex treatments and off-target effects, improved communication with patients, and guides long term care with the goal to minimise or prevent cardiovascular complications. Our aim is to review the cellular mechanisms of cardiotoxicity involved in commonly used anti-cancer treatments and identify gaps in literature and strategies to mitigate cardiotoxicity effects and guide future research endeavours.


PMID:37745115 | PMC:PMC10516301 | DOI:10.3389/fcvm.2023.1150569

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PubMed articles on: Cardio-Oncology

A Rapid Cardiovascular Magnetic Resonance Assessment for Cancer Therapy-Related Cardiac Dysfunction Supports the Routine Incorporation of Cardiovascular Magnetic Resonance into Cardio-Oncology Care


Am J Cardiol. 2023 Sep 22:S0002-9149(23)00985-2. doi: 10.1016/j.amjcard.2023.09.015. Online ahead of print.


NO ABSTRACT


PMID:37743145 | DOI:10.1016/j.amjcard.2023.09.015

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PubMed articles on: Cardio-Oncology

The Value of Neoadjuvant Anthracycline-Based Regimens for HER2-Positive Breast Cancer: A Systematic Review and Meta-analysis Including 1366 Patients


Clin Med Insights Oncol. 2023 Sep 21;17:11795549231195293. doi: 10.1177/11795549231195293. eCollection 2023.


ABSTRACT


BACKGROUND: The standard recommendation for neoadjuvant therapy for human epidermal growth factor receptor-2 (HER2)-positive breast cancer patients is trastuzumab in combination with chemotherapy, but there is no current standard recommendation for appropriate chemotherapy regimens. This meta-analysis evaluated the efficacy and cardiac safety of the concurrent use of anti-HER2 targeted drugs and anthracycline-based neoadjuvant chemotherapy (NAC) for HER2-positive breast cancers.


METHODS: The pooled odds ratio (OR) rate for pathologic complete response (pCR), the pooled hazard ratio (HR) of overall survival (OS), and the left ventricular ejection fraction (LVEF) decline events were all calculated. Differences in efficacy, prognosis, and cardiac safety were compared between patients receiving an anthracycline-containing regimen (AB) and those treated with non-anthracycline-based (nAB) NAC.


RESULTS: A total of 1366 patients in 4 prospective and 3 retrospective studies were included in the meta-analysis. The pooled OR for pCR rate was 0.73 with a 95% confidence interval (CI) of 0.43 to 1.24 (P = .246). Subgroup analysis of low tumor burden cases showed no improvement in pCR rate for patients in the AB group compared with nAB, with the pooled OR rate being 0.73 with a 95% CI of 0.37 to 1.44 (P= .357). The 3-year OS rate was 95.63% and 95.54% in the AB and nAB groups, respectively, with no statistical difference (P= .157). There was a significant increase in the rate of LVEF decline of 19.07% in the AB group compared with 13.33% for the nAB group, with an HR of 1.62 and a 95% CI of 1.11 to 2.36 (P = .013).


CONCLUSIONS: The addition of anthracyclines did not improve pCR rates and survival after neoadjuvant and the increased cardiotoxicity of anthracyclines further limited their application. This study showed that it was feasible to use anti-HER2 drugs without anthracyclines in neoadjuvant therapy for HER2-positive breast cancer patients.


PMID:37744425 | PMC:PMC10515528 | DOI:10.1177/11795549231195293

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PubMed articles on: Cardio-Oncology

Galectin-3 contributes to acute cardiac dysfunction and toxicity by increasing oxidative stress and fibrosis in doxorubicin-treated mice


Int J Cardiol. 2023 Sep 21:131386. doi: 10.1016/j.ijcard.2023.131386. Online ahead of print.


ABSTRACT


BACKGROUND: Doxorubicin (DOX) leads to cardiovascular toxicity through direct cardiomyocyte injury and inflammation. We aimed to study the role of Galectin-3 (Gal-3), a β-galactosidase binding lectin associated with inflammation and fibrosis in DOX-induced acute cardiotoxicity in mice.


METHODS: Male C57 and Gal-3 knockout (KO) mice were given a single dose of DOX (15 mg/kg, i.p) or placebo. Serum creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and cardiac thiobarbituric acid-reactive substance (TBARS) were measured at 3 days to assess cardiac injury and oxidative stress. Cardiac remodeling and function were studied by echocardiography and catheterization at 7 days. Myocardial fibrosis was quantified in picrosirius red stained slices.


RESULTS: Absence of Gal-3 tended to reduce the mortality after DOX. DOX significantly increased CPK, LDH, AST and TBARS while treated Gal-3 KO mice showed reduced injury and oxidative stress. After 7 days, adverse remodeling, fibrosis and dysfunction in treated-C57 mice were severely affected while those effects were prevented by absence of Gal-3.


CONCLUSION: In summary, genetic deletion of Gal-3 prevented cardiac damage, adverse remodeling and dysfunction, associated with reduced cardiac oxidative stress and fibrosis. Understanding the contribution of GAL-3 to doxorubicin-induced cardiac toxicity reinforces its potential use as a therapeutic target in patients with several cancer types.


PMID:37741348 | DOI:10.1016/j.ijcard.2023.131386

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PubMed articles on: Cardio-Oncology

A Versatile PDA(DOX) Nanoplatform for Chemo-Photothermal Synergistic Therapy against Breast Cancer and Attenuated Doxorubicin-Induced Cardiotoxicity


J Nanobiotechnology. 2023 Sep 21;21(1):338. doi: 10.1186/s12951-023-02072-1.


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