[Prevention of radiotherapy-related cardiotoxicity : benefits of a specialized cardio-oncologic assessment and follow-up]. / Prévention de la cardio-toxicité de la radiothérapie : apport de la prise en charge cardio-oncologique.

To accept the toxic side effects of any treatment, whether medical, surgical or radiotherapeutic, cannot be avoided but implies to evaluate them taking into account the severity and prognosis of the disease that is concerned. Screening, preventing and treatment of these side effects are an integral aspect of the treatment of cancers. We will here review the contribution of the cardio-oncology, a recently emerged medical specialty. Cardiac irradiation cannot be avoided when treating several cancers, most frequently left sided breast cancer. As soon as radiotherapy is considered, it is of prime importance to evaluate each patient's risk factors and to handle them. If technical progresses have led to the complete disappearance of acute side effects of radiotherapy, this is not true for the delayed ones that may occur many years after the irradiation. Hence the need for «red flags¼ and for a systematic follow-up. Cardiac complications of left breast irradiation concern all aspects of cardiology: diseases of cardiac rhythm, valvulopathies, heart failure, coronary and pericardial disorders.

Admettre les effets secondaires d'un traitement, qu'il soit médical, chirurgical ou radiothérapique, est inévitable, mais impose de les évaluer en intégrant la gravité de l'affection pour laquelle ils sont prescrits. Leur dépistage, leur prévention et leur prise en charge font partie intégrante du traitement d'un cancer. Dans cette revue, nous ferons la synthèse de l'apport à cette démarche d'une discipline récente, la cardio-oncologie. L'irradiation cardiaque est incontournable lors du traitement de plusieurs cancers au premier rang desquels le cancer du sein gauche. Dès qu'elle est envisagée, il est essentiel d'évaluer les facteurs de risque de chaque patient et d'organiser leur prise en charge éventuelle. En effet, si les progrès techniques ont permis la disparition des complications cardiaques aiguës de la radiothérapie, ce n'est encore pas le cas des complications différées qui peuvent survenir de nombreuses années après l'irradiation. D'où la nécessité de «drapeaux rouges¼ et d'un suivi régulier systématique. Ces complications, rarement isolées, concernent tous les aspects de la cardiologie : troubles du rythme, valvulopathies, insuffisance cardiaque, maladies coronaires et atteintes péricardiques.

A multimodality assessment of the protective capacity of statin therapy in a mouse model of radiation cardiotoxicity.

PURPOSE: Despite technological advances in radiotherapy (RT), cardiotoxicity remains a common complication in patients with lung, oesophageal and breast cancers. Statin therapy has been shown to have pleiotropic properties beyond its lipid-lowering effects. Previous murine models have shown statin therapy can reduce short-term functional effects of whole-heart irradiation. In this study, we assessed the efficacy of atorvastatin in protecting against the late effects of radiation exposure on systolic function, cardiac conduction, and atrial natriuretic peptide (ANP) following a clinically relevant partial-heart radiation exposure. MATERIALS AND METHODS: Female, 12-week old, C57BL/6j mice received an image-guided 16 Gy X-ray field to the base of the heart using a small animal radiotherapy research platform (SARRP), with or without atorvastatin from 1 week prior to irradiation until the end of the experiment. The animals were followed for 50 weeks with longitudinal transthoracic echocardiography (TTE) and electrocardiography (ECG) every 10 weeks, and plasma ANP every 20 weeks. RESULTS: At 30-50 weeks, mild left ventricular systolic function impairment observed in the RT control group was less apparent in animals receiving atorvastatin. ECG analysis demonstrated prolongation of components of cardiac conduction related to the heart base at 10 and 30 weeks in the RT control group but not in animals treated with atorvastatin. In contrast to systolic function, conduction disturbances resolved at later time-points with radiation alone. ANP reductions were lower in irradiated animals receiving atorvastatin at 30 and 50 weeks. CONCLUSIONS: Atorvastatin prevents left ventricular systolic dysfunction, and the perturbation of cardiac conduction following partial heart irradiation. If confirmed in clinical studies, these data would support the use of statin therapy for cardioprotection during thoracic radiotherapy.

Use of Deep-Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin-Induced Cardiotoxicity.

Doxorubicin-induced cardiomyopathy (DIC) brings tough clinical challenges as well as continued demand in developing agents for adjuvant cardioprotective therapies. Here, a zebrafish phenotypic screening with deep-learning assisted multiplex cardiac functional analysis using motion videos of larval hearts is established. Through training the model on a dataset of 2125 labeled ventricular images, ZVSegNet and HRNet exhibit superior performance over previous methods. As a result of high-content phenotypic screening, cyanidin chloride (CyCl) is identified as a potent suppressor of DIC. CyCl effectively rescues cardiac cell death and improves heart function in both in vitro and in vivo models of Doxorubicin (Dox) exposure. CyCl shows strong inhibitory effects on lipid peroxidation and mitochondrial damage and prevents ferroptosis and apoptosis-related cell death. Molecular docking and thermal shift assay further suggest a direct binding between CyCl and Keap1, which may compete for the Keap1-Nrf2 interaction, promote nuclear accumulation of Nrf2, and subsequentially transactivate Gpx4 and other antioxidant factors. Site-specific mutation of R415A in Keap1 significantly attenuates the protective effects of CyCl against Dox-induced cardiotoxicity. Taken together, the capability of deep-learning-assisted phenotypic screening in identifying promising lead compounds against DIC is exhibited, and new perspectives into drug discovery in the era of artificial intelligence are provided.

ASSESSMENT OF CARDIOPROTECTIVE EFFECT OF NECROSTATIN-1 STABLE IN A MICE MODEL OF ACUTE DOXORUBICIN-INDUCED CARDIOTOXICITY.

OBJECTIVE: The aim: To evaluate the effect of Necrostatin-1s (Nec-1s), an inhibitor of necroptosis, on acute Dox-induced cardiotoxicity in a mice model. PATIENTS AND METHODS: Materials and methods: Fifteen male mice were used. The animals were allocated into three groups. On the third day of the experiment, a single intraper¬itoneal dose of 20 mg/kg Dox was used to induce cardiotoxicity. Mice in the control group were given vehicle (DMSO) intraperitoneally, whereas mice in the third group were given 5 mg/kg Nec-1s two days before Dox treatment and continued for a total of five days. Animals were euthanized at the conclusion of the research. ELISA was used to assess the following parameters: cTnI, TNF-α, IL-1ß, GPX-4, and Hmox-1. The expression of TNF-R1 and phosphorylated NF-κß p65 was measured using immunohistochemistry. In addition, a histopathologic evaluation of the cardiac lesions was conducted. RESULTS: Results: Our results showed that Dox treatment substantially elevated serum cTnI levels, increased tissue inflammatory biomarkers (TNF-α, IL-1ß, phospho NF-κß p65 and TNF-R1), and reduced tissue antioxidant enzymes (GPX-4, Hmox-1). A histopathological analysis showed pronounced necrosis and vacuolization. These results were drastically changed by pretreatment with Nec-1s, with serum cTnI levels in this group being much lower than in the Dox group. In addition to a significant decrease in inflammatory markers, antioxidant enzymes were partially recovered. Moreover, there was preservation of the cardiac morphology to a level that was roughly normal. CONCLUSION: Conclusions: Our findings demonstrate that pretreatment with Nec-1s protected against acute Dox-induced cardiotoxicity. This cardioprotective effect was mainly due to amelioration of inflammation that reflected by inhibition of NF-κß/TNF-α/TNF-R1 pathway, with partial restoration of antioxidant enzymes, GPX-4 and Hmox1.

In vitro to clinical translational pharmacokinetic/pharmacodynamic modeling of doxorubicin (DOX) and dexrazoxane (DEX) interactions: Safety assessment and optimization.

Despite high anticancer activity, doxorubicin (DOX)-induced cardiotoxicity (DIC) limits the extensive utility of DOX in a clinical setting. Amongst various strategies explored, dexrazoxane (DEX) remains the only cardioprotective agent to be approved for DIC. In addition, altering the dosing regimen of DOX has also proved to be somewhat beneficial in decreasing the risk of DIC. However, both approaches have limitations and further studies are required to better optimize them for maximal beneficial effects. In the present work, we quantitatively characterized DIC as well as the protective effects of DEX in an in vitro model of human cardiomyocytes, by means of experimental data and mathematical modeling and simulation (M&S) approaches. We developed a cellular-level, mathematical toxicodynamic (TD) model to capture the dynamic in vitro drug-drug interaction, and relevant parameters associated with DIC and DEX cardio-protection were estimated. Subsequently, we executed in vitro-in vivo translation by simulating clinical PK profiles for different dosing regimens of DOX alone and in combinations with DEX and using the simulated PK profiles to drive the cell-based TD models to evaluate the effects of long-term, clinical dosing regimens of these drugs on the relative cell viability of AC16 and to determine optimal drug combinations with minimal cellular toxicity. Here, we identified that the Q3W (once every three weeks) DOX regimen with 10:1 DEX:DOX dose ratio over three cycles (nine weeks) may offer maximal cardio-protection. Overall, the cell-based TD model can be effectively used to better design subsequent preclinical in vivo studies aimed for further optimizing safe and effective DOX and DEX combinations to mitigate DIC.

Assessment of the cardioprotective effect of liraglutide on methotrexate induced cardiac dysfunction through suppression of inflammation and enhancement of angiogenesis in rats.

OBJECTIVE: Methotrexate (MTX) is one of the most commonly used anti-cancer drugs for various types of neoplasms. It is associated with multiple cytotoxic effects including nephrotoxicity, hepatotoxicity and cardiotoxicity. Liraglutide (LIR) is a potent anti-diabetic drug and also has antioxidant and anti-inflammatory properties. In this study, we tried to investigate the protective effect of LIR on MTX induced cardiotoxicity and to identify the molecular mechanisms for this protection. MATERIALS AND METHODS:  Rats were divided into 4 groups, including control group, LIR group, MTX group and LIR + MTX group. ECG was measured then blood samples were taken, and hearts were excised for biochemical and histological investigations. RESULTS: MTX group exhibited a mild non-significant irregular bradycardia, an increase of CK-MB besides a decrease of total antioxidant capacity. MTX administration also resulted in downregulation of vascular endothelial growth factor (VEGF), while caused upregulation of interleukin 1 beta (IL-1B) and interleukin 6 (IL-6) in comparison to the control group. Also, MTX group showed histological abnormalities besides negative VEGF and positive iNOS as detected by immunohistochemical staining compared to the control group. LIR administration could reverse these results. CONCLUSIONS: LIR prevented MTX induced cardiotoxicity through its antioxidant and anti-inflammatory properties.

Cost-effectiveness of cardio-oncology clinical assessment for prevention of chemotherapy-induced cardiotoxicity.

INTRODUCTION: Cancer chemotherapy increases the risk of heart failure. This cost-effectiveness study analyzes cardio-oncology imaging assessment of left ventricular ejection fraction (LVEF) using a Portuguese healthcare payer perspective and a five-year time horizon. METHODS: Two cardioprotective strategies were assessed: universal cardioprotection (UCP) for all patients and cardioprotection initiated on diagnosis of LVEF-defined cardiotoxicity (EF-CTX). A Markov model, informed by the retrospective clinical course of breast cancer patients followed in a Portuguese public hospital, was developed to assess the cost-effectiveness of LVEF cardio-oncology imaging assessment. Data on transition probabilities, costs and utilities were retrieved from both the retrospective data and published literature to assess the cost-effectiveness of LVEF echocardiographic assessment. Costs and utilities of the cardioprotective strategies were assessed over a five-year range, using probabilistic sensitivity analyses. RESULTS: In the reference case of a 63-year-old breast cancer patient treated with cardioprotection initiated on diagnosis of EF-CTX, the five-year time horizon (4.22 QALYs and €2594 cost over five years) dominated UCP (3.42 QALYS and €3758 cost over five years). Under a time horizon of five years at a willingness-to-pay threshold of €22 986, over 65.7% of simulations provided additional QALYs. Monte Carlo simulation of the Markov model had no effect on the model's conclusions. CONCLUSION: In the Portuguese public healthcare system and under specific hypotheses, from a healthcare payer perspective, EF-CTX-guided cardioprotection for patients at risk of chemotherapy-related cardiotoxicity provides more QALYs at lower cost than UCP.

A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues.

Cardiotoxicity of pharmaceutical drugs, industrial chemicals, and environmental toxicants can be severe, even life threatening, which necessitates a thorough evaluation of the human response to chemical compounds. Predicting risks for arrhythmia and sudden cardiac death accurately is critical for defining safety profiles. Currently available approaches have limitations including a focus on single select ion channels, the use of non-human species in vitro and in vivo, and limited direct physiological translation. We have advanced the robustness and reproducibility of in vitro platforms for assessing pro-arrhythmic cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes and human cardiac fibroblasts in 3-dimensional microtissues. Using automated algorithms and statistical analyses of eight comprehensive evaluation metrics of cardiac action potentials, we demonstrate that tissue-engineered human cardiac microtissues respond appropriately to physiological stimuli and effectively differentiate between high-risk and low-risk compounds exhibiting blockade of the hERG channel (E4031 and ranolazine, respectively). Further, we show that the environmental endocrine disrupting chemical bisphenol-A (BPA) causes acute and sensitive disruption of human action potentials in the nanomolar range. Thus, this novel human 3D in vitro pro-arrhythmic risk assessment platform addresses critical needs in cardiotoxicity testing for both environmental and pharmaceutical compounds and can be leveraged to establish safe human exposure levels.

Assessment and Management of Cardiotoxicity in Hematologic Malignancies.

With the increasing overall survival of cancer patients due to recent discoveries in oncology, the incidence of side effects is also rising, and along with secondary malignancies, cardiotoxicity is one of the most concerning side effects, affecting the quality of life of cancer survivors. There are two types of cardiotoxicity associated with chemotherapy; the first one is acute, life-threatening but, fortunately, in most of the cases, reversible; and the second one is with late onset and mostly irreversible. The most studied drugs associated with cardiotoxicity are anthracyclines, but many new agents have demonstrated unexpected cardiotoxic effect, including those currently used in multiple myeloma treatment (proteasome inhibitors and immunomodulatory agents), tyrosine kinase inhibitors used in the treatment of chronic myeloid leukemia and some forms of acute leukemia, and immune checkpoint inhibitors recently introduced in treatment of refractory lymphoma patients. To prevent irreversible myocardial damage, early recognition of cardiac toxicity is mandatory. Traditional methods like echocardiography and magnetic resonance imaging are capable of detecting structural and functional changings, but unable to detect early myocardial damage; therefore, more sensible biomarkers like troponins and natriuretic peptides have to be introduced into the current practice. Baseline assessment of patients allows the identification of those with high risk for cardiotoxicity, while monitoring during and after treatment is important for early detection of cardiotoxicity and prompt intervention.

Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam.

BACKGROUND AND PURPOSE: Resurgence in the use of chloroquine as a potential treatment for COVID-19 has seen recent cases of fatal toxicity due to unintentional overdoses. Protocols for the management of poisoning recommend diazepam, although there are uncertainties in its pharmacology and efficacy in this context. The aim was to assess the effects of diazepam in experimental models of chloroquine cardiotoxicity. EXPERIMENTAL APPROACH: In vitro experiments involved cardiac tissues isolated from rats and incubated with chloroquine alone or in combination with diazepam. In vivo models of toxicity involved chloroquine administered intravenously to pentobarbitone-anaesthetised rats and rabbits. Randomised, controlled treatment studies in rats assessed diazepam, clonazepam and Ro5-4864 administered: (i) prior, (ii) during and (iii) after chloroquine and the effects of diazepam: (iv) at high dose, (v) in urethane-anaesthetised rats and (vi) co-administered with adrenaline. KEY RESULTS: Chloroquine decreased the developed tension of left atria, prolonged the effective refractory period of atria, ventricular tissue and right papillary muscles, and caused dose-dependent impairment of haemodynamic and electrocardiographic parameters. Cardiac arrhythmias indicated impairment of atrioventricular conduction. Studies (i), (ii) and (v) showed no differences between treatments and control. Diazepam increased heart rate in study (iv) and as with clonazepam also prolonged the QTc interval in study (iii). Combined administration of diazepam and adrenaline in study (vi) improved cardiac contractility but caused hypokalaemia. CONCLUSION AND IMPLICATIONS: Neither diazepam nor other ligands for benzodiazepine binding sites protect against or attenuate chloroquine cardiotoxicity. However, diazepam may augment the effects of positive inotropes in reducing chloroquine cardiotoxicity. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

Optimizing Cardiovascular Health in Patients With Cancer: A Practical Review of Risk Assessment, Monitoring, and Prevention of Cancer Treatment-Related Cardiovascular Toxicity.

Advances in cancer screening and improved treatment approaches have led to an increase in survivorship and, consequently, recognition of an association between cancer treatments and the development of cardiovascular complications. In addition, as the population becomes proportionally older, comorbid cardiovascular risk factors are more prevalent in the population and compound the risk of developing cancer treatment-related cardiovascular toxicity. Cardio-oncology has emerged as a new subspecialty of medicine that provides a multidisciplinary approach, bringing together oncologists, cardiologists, and allied health care providers who are tasked with optimizing the cardiovascular health of patients exposed to potentially cardiotoxic cancer therapy. Using a case-based approach, practical advice on how to identify, monitor, and treat patients with cancer who are at risk for developing cancer treatment-related cardiovascular dysfunction is discussed. Cardiovascular risk factors (e.g., age, hypertension, diabetes) and cancer therapies (chemotherapy, targeted therapy, radiation) associated with cardiovascular toxicity are presented. Current cardiac monitoring strategies such as two- and three-dimensional echocardiography, cardiac MRI, and biomarkers (troponin and brain natriuretic peptide [BNP]) are discussed. Last, the current literature on pharmacologic (e.g., angiotensin-converting enzyme inhibitors, ß-blockers, statins) and lifestyle (diet and exercise) strategies to mitigate cardiovascular toxicity during and following completion of cancer therapy are reviewed.

Longitudinal and quantitative assessment platform for concurrent analysis of anti-tumor efficacy and cardiotoxicity of nano-formulated medication in vivo.

Increasing nanomedicinal approaches have been developed to effectively inhibit tumor growth; however, critical questions such as whether a nanomedicinal approach can mitigate latent side effects are barely addressed. To this end, we established a zebrafish xenograft tumor model, combining pseudodynamic three-dimensional cardiac imaging and image analysis to enable simultaneous and quantitative determination of the change of tumor volume and cardiac function of zebrafish upon specific nanoformulation treatment. Doxorubicin (DOX), a well-known chemotherapeutic agent with cardiotoxicity, and a recently developed DOX-loaded nanocomposite were employed as two model drugs to demonstrate the effectiveness to utilize the proposed evaluation platform for rapid validation. The nanoformulation significantly mitigated DOX-associated cardiotoxicity, while retaining the efficacy of DOX in inhibiting tumor growth compared to administration of carrier-free DOX at the same dose. We anticipate that this platform possesses the potential as an efficient assessment system for nanoformulated cancer therapeutics with suspected toxicity and side effects to vital organs such as the heart.

Workshop Report: FDA Workshop on Improving Cardiotoxicity Assessment With Human-Relevant Platforms.

Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development. The main conclusion is that to reduce cardiovascular safety liabilities of new therapeutic agents, there is an urgent need to integrate human-relevant platforms/approaches into drug development. Potential regulatory applications of human-derived cardiomyocytes and future directions in employing human-relevant platforms to fill the gaps and overcome barriers and challenges in preclinical cardiovascular safety assessment were discussed. This paper is intended to serve as an initial step in a public-private collaborative development program for human-relevant cardiotoxicity tools, particularly for cardiotoxicities characterized by contractile dysfunction or structural injury.

[Economic assessment of dexrazoxane in prophylaxis of cardiotoxicity in children undergoing chemotherapy with anthracyclines]. / Avaliação econômica do uso de dexrazoxano na profilaxia de cardiotoxicidade em crianças em tratamento quimioterápico com antraciclinas.

Cancer in individuals 0 to 19 years of age is considered rare when compared to incidence in older age brackets, and is estimated at 2% to 3% of all malignant tumors recorded in Brazil. The use of anthracyclines is frequently associated with cardiotoxicity, and these drugs are part of approximately 60% of treatment protocols in pediatric oncology. Among the existing strategies for the prevention of cardiotoxicity, dexrazoxane obtained favorable results based on intermediate outcomes (biochemical markers and echocardiographic parameters). This study was based on a cost-effectiveness assessment comparing the use of dexrazoxane in different populations, besides an assessment of the budget impact from the technology's potential incorporation. The patient's lifetime was used as the timeline, and the analysis was performed from the perspective of the Brazilian Unified National Health System (SUS). A budget impact analysis was also performed for each technology. After a literature search, a Markov model was developed, capable of comparing the use of dexrazoxane in six profiles of patients at risk of developing cardiotoxicity. Use of the drug in children under 5 years of age proved to be the most cost-effective alternative (incremental cost effectiveness ratio - ICER of BRL 6,156.96), followed by use in all patients (ICER of BRL 58,968.70). If the price decreased to less than BRL 250.00 per vial, the alternative of using the drug in all children would become the most cost-effective. The budget impact at 5 years was BRL 30,622,404.81 for use only in children under 5 years of age. Using the technology in all the children could produce an incremental impact of BRL 94,352,898.77.

O câncer em indivíduos de 0 a 19 anos é considerado raro, quando comparado à incidência em faixas etárias maiores, sendo estimado entre 2% e 3% de todos os tumores malignos registrados no Brasil. O uso de antraciclinas está frequentemente associado ao aparecimento de cardiotoxicidade e faz parte de aproximadamente 60% dos protocolos terapêuticos em oncologia pediátrica. Dentre as estratégias existentes para a prevenção de cardiotoxicidade, o dexrazoxano obteve resultados favoráveis pautados em desfechos intermediários (marcadores bioquímicos e medidas ecocardiográficas). Foi desenvolvida, neste trabalho, uma avaliação de custo-efetividade que compare o uso do dexrazoxano em diferentes populações, além de uma avaliação do impacto orçamentário causado pela possível incorporação da tecnologia. Foi utilizado o horizonte temporal de toda a vida do paciente e a perspectiva de análise do Sistema Único de Saúde. Uma análise de impacto orçamentário para cada tecnologia também foi construída. Após uma busca na literatura, foi desenvolvido um modelo de Markov capaz de comparar o uso do dexrazoxano em seis perfis de pacientes com risco de desenvolver cardiotoxicidade. Usar o medicamento nas crianças menores de cinco anos de idade se mostrou a alternativa mais custo-efetiva (razão de custo-efetividade incremental - RCEI de R$ 6.156,96), seguida de usar em todos os pacientes (RCEI de R$ 58.968,70). Caso o preço diminua a um valor menor que R$ 250,00 por frasco, a alternativa de usar em todas as crianças se torna a mais custo-efetiva. O impacto orçamentário ao final de cinco anos foi de R$ 30.622.404,81 para uso apenas nas crianças menores de cinco anos. Usar a tecnologia em todas as crianças produziria um impacto incremental de R$ 94.352.898,77.

El cáncer en individuos de 0 a 19 años está considerado raro, cuando se compara la incidencia en franjas etarias mayores, estimándose entre 2% y 3% de todos los tumores malignos registrados en Brasil. El uso antraciclinas está frecuentemente asociado a la aparición de cardiotoxicidad y forma parte de aproximadamente un 60% de los protocolos terapéuticos en oncología pediátrica. Entre las estrategias existentes para la prevención de cardiotoxicidad, el dexrazoxano obtuvo resultados favorables pautados en desenlaces intermedios (marcadores bioquímicos y medidas ecocardiográficas). Se desarrolló en este trabajo, una evaluación de costo efectividad que compare el uso del dexrazoxano en diferentes poblaciones, además de una evaluación del impacto presupuestario causado por la posible incorporación de la tecnología. Se utilizó el horizonte temporal de toda la vida del paciente y la perspectiva de análisis del SUS. También se realizó un análisis del impacto presupuestario para cada tecnología. Tras una búsqueda en la literatura, se desarrolló un modelo de Markov capaz de comparar el uso del dexrazoxano en 6 perfiles de pacientes con riesgo de desarrollar cardiotoxicidad. Usar el medicamento en los niños menores de 5 años de edad se mostró la alternativa más costo-efectiva (relación costo-efectividad incremental - RCEI de BRL 6.156,96), seguido de usarlo en todos los pacientes (RCEI de BRL 58.968,7). En caso de que el precio disminuya a un valor inferior a BRL 250,00 por frasco, la alternativa de usarlo en todos los niños se convierte en la más costo-efectiva. El impacto presupuestario tras 5 años fue de BRL 30.622.404,81 para su uso exclusivo en niños menores de 5 años. Usar esta tecnología en todos los niños, tendría un impacto presupuestario incrementándolo hasta los BRL 94.352.898,77.

Curcumin loaded mesoporous silica nanoparticles: assessment of bioavailability and cardioprotective effect.

Rhizomes of the plant Curcuma longa has been traditionally used in medicine and culinary practices in India. It possesses various pharmacological effect, namely, antioxidant, hepatoprotective, anti-inflammatory, anti-thrombosis, and anti-apoptotic. The study was undertaken to assess the effect of curcumin and curcumin loaded mesoporous silica nanoparticles (MSNs) against doxorubicin (DOX)-induced myocardial toxicity in rats. Furthermore, the study also included the bioavailability estimation of curcumin delivered alone and delivered via mesoporous technology. Cardiotoxicity was produced by cumulative administration of DOX (2.5 mg/kg for two weeks). Curcumin and curcumin loaded mesoporous nanoparticles (MSNs) each 200 mg/kg, po was administered as pretreatment for two weeks and then for two alternate weeks with DOX. The repeated administration of DOX induced cardiomyopathy associated with an antioxidant deficit and increased level of cardiotoxic biomarkers. Pretreatment with curcumin (alone and via MSNs) significantly protected myocardium from the toxic effects of DOX by significantly decreased the elevated level of malondialdehyde and increased the reduced level of reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in cardiac tissue. MSNs based delivery was found superior compared to curcumin delivered alone. Moreover, the results of bioavailability assessment in rats clearly indicated higher Cmax and AUC values in rats when curcumin was administered via MSNs indicating superior bioavailability. The bioavailability of curcumin loaded MSNs, biochemical and histopathology reports support the good cardioprotective effect of curcumin which could be attributed to its increased bioavaibility lead to good antioxidant and anti-inflammatory activity.

Cardiovascular Complications Associated with Multiple Myeloma Therapies: Incidence, Pathophysiology, and Management.

PURPOSE OF REVIEW: Multiple myeloma is a common hematologic malignancy characterized by recurrent relapsing disease course requiring use of various therapies. Over the past few decades, significant advancements in the treatment of myeloma have occurred including routine use of proteasome inhibitors and immunomodulatory drugs. These have effectively improved survival; however, some also have increased risk of cardiovascular toxicity. Here, we will review the incidence, pathophysiology, and management of cardiovascular complications associated with antimyeloma agents. RECENT FINDINGS: Cardiovascular complications associated with myeloma treatment are common. These cardiovascular complications include accelerated hypertension, ischemic heart disease, congestive heart failure, arrhythmia, pulmonary hypertension, venous thromboembolism, and arterial thromboembolism. Thromboprophylactic strategies during treatment with immunomodulatory agents and screening strategies to detect changes in myocardial function prior to the development of overt heart failure have occurred. Cardiovascular complications associated with proteasome inhibitors and immunomodulatory drugs are an important component in supportive care of patients with myeloma. The incidence of cardiotoxicity is high, and, as such, early intervention and collaborative efforts between cardiologists and oncologists to mitigate and effectively manage these complications are imperative. Additional studies are needed to clarify the underlying pathophysiology and evaluate effective strategies for prevention and treatment.

Avaliação econômica do uso de dexrazoxano na profilaxia de cardiotoxicidade em crianças em tratamento quimioterápico com antraciclinas / Economic assessment of dexrazoxane in prophylaxis of cardiotoxicity in children undergoing chemotherapy with anthracyclines / Evaluación económica del uso del dexrazoxano en la profilaxia de cardiotoxicidad en niños en tratamiento quimioterápico con antraciclinas

Resumo: O câncer em indivíduos de 0 a 19 anos é considerado raro, quando comparado à incidência em faixas etárias maiores, sendo estimado entre 2% e 3% de todos os tumores malignos registrados no Brasil. O uso de antraciclinas está frequentemente associado ao aparecimento de cardiotoxicidade e faz parte de aproximadamente 60% dos protocolos terapêuticos em oncologia pediátrica. Dentre as estratégias existentes para a prevenção de cardiotoxicidade, o dexrazoxano obteve resultados favoráveis pautados em desfechos intermediários (marcadores bioquímicos e medidas ecocardiográficas). Foi desenvolvida, neste trabalho, uma avaliação de custo-efetividade que compare o uso do dexrazoxano em diferentes populações, além de uma avaliação do impacto orçamentário causado pela possível incorporação da tecnologia. Foi utilizado o horizonte temporal de toda a vida do paciente e a perspectiva de análise do Sistema Único de Saúde. Uma análise de impacto orçamentário para cada tecnologia também foi construída. Após uma busca na literatura, foi desenvolvido um modelo de Markov capaz de comparar o uso do dexrazoxano em seis perfis de pacientes com risco de desenvolver cardiotoxicidade. Usar o medicamento nas crianças menores de cinco anos de idade se mostrou a alternativa mais custo-efetiva (razão de custo-efetividade incremental - RCEI de R$ 6.156,96), seguida de usar em todos os pacientes (RCEI de R$ 58.968,70). Caso o preço diminua a um valor menor que R$ 250,00 por frasco, a alternativa de usar em todas as crianças se torna a mais custo-efetiva. O impacto orçamentário ao final de cinco anos foi de R$ 30.622.404,81 para uso apenas nas crianças menores de cinco anos. Usar a tecnologia em todas as crianças produziria um impacto incremental de R$ 94.352.898,77.

Abstract: Cancer in individuals 0 to 19 years of age is considered rare when compared to incidence in older age brackets, and is estimated at 2% to 3% of all malignant tumors recorded in Brazil. The use of anthracyclines is frequently associated with cardiotoxicity, and these drugs are part of approximately 60% of treatment protocols in pediatric oncology. Among the existing strategies for the prevention of cardiotoxicity, dexrazoxane obtained favorable results based on intermediate outcomes (biochemical markers and echocardiographic parameters). This study was based on a cost-effectiveness assessment comparing the use of dexrazoxane in different populations, besides an assessment of the budget impact from the technology's potential incorporation. The patient's lifetime was used as the timeline, and the analysis was performed from the perspective of the Brazilian Unified National Health System (SUS). A budget impact analysis was also performed for each technology. After a literature search, a Markov model was developed, capable of comparing the use of dexrazoxane in six profiles of patients at risk of developing cardiotoxicity. Use of the drug in children under 5 years of age proved to be the most cost-effective alternative (incremental cost effectiveness ratio - ICER of BRL 6,156.96), followed by use in all patients (ICER of BRL 58,968.70). If the price decreased to less than BRL 250.00 per vial, the alternative of using the drug in all children would become the most cost-effective. The budget impact at 5 years was BRL 30,622,404.81 for use only in children under 5 years of age. Using the technology in all the children could produce an incremental impact of BRL 94,352,898.77.

Resumen: El cáncer en individuos de 0 a 19 años está considerado raro, cuando se compara la incidencia en franjas etarias mayores, estimándose entre 2% y 3% de todos los tumores malignos registrados en Brasil. El uso antraciclinas está frecuentemente asociado a la aparición de cardiotoxicidad y forma parte de aproximadamente un 60% de los protocolos terapéuticos en oncología pediátrica. Entre las estrategias existentes para la prevención de cardiotoxicidad, el dexrazoxano obtuvo resultados favorables pautados en desenlaces intermedios (marcadores bioquímicos y medidas ecocardiográficas). Se desarrolló en este trabajo, una evaluación de costo efectividad que compare el uso del dexrazoxano en diferentes poblaciones, además de una evaluación del impacto presupuestario causado por la posible incorporación de la tecnología. Se utilizó el horizonte temporal de toda la vida del paciente y la perspectiva de análisis del SUS. También se realizó un análisis del impacto presupuestario para cada tecnología. Tras una búsqueda en la literatura, se desarrolló un modelo de Markov capaz de comparar el uso del dexrazoxano en 6 perfiles de pacientes con riesgo de desarrollar cardiotoxicidad. Usar el medicamento en los niños menores de 5 años de edad se mostró la alternativa más costo-efectiva (relación costo-efectividad incremental - RCEI de BRL 6.156,96), seguido de usarlo en todos los pacientes (RCEI de BRL 58.968,7). En caso de que el precio disminuya a un valor inferior a BRL 250,00 por frasco, la alternativa de usarlo en todos los niños se convierte en la más costo-efectiva. El impacto presupuestario tras 5 años fue de BRL 30.622.404,81 para su uso exclusivo en niños menores de 5 años. Usar esta tecnología en todos los niños, tendría un impacto presupuestario incrementándolo hasta los BRL 94.352.898,77.

Cardio-oncology organization patterns in Italy: one size does not fit all.

AIMS: Cardio-oncology is imposing as the specialty deputed to the management of a large and rapidly increasing population of cancer patients receiving anticancer treatments with cardiovascular side effects or presenting with cardiac and oncological comorbidities. Organization patterns dramatically vary across Italy. METHODS: On the behalf of ANMCO, we have analyzed the characteristics of cardio-oncology services across different hospital types in Italy. A questionnaire was sent out to all ANMCO divisions inquiring about inner organization, workload, multidisciplinary team and inter-hospital connections. RESULTS: Ninety-eight centers sent back the questionnaire. We summarize different paths into four reference assistance models (sizes XL, L, M and S) according to hospital characteristics, cardio-oncology population size, specialists availability, local facilities and the hospital-surrounding network. We define sizes of the proposed pathways highlighting the need to tailor the model in each single situation. CONCLUSION: No single cardio-oncology organization model can be applied to all hospitals. Each center could select the size/model that best fits its organization. Multidisciplinarity and networking play a crucial role.

Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer. METHODS: Women with HER2-positive, stage I through III breast cancer who initiated (neo)adjuvant HER2-targeted therapy (trastuzumab with or without pertuzumab) from January 2005 to March 2015 at the authors' institution were eligible. We analyzed differences in the incidence of cardiotoxicity (a decline in the left ventricular ejection fraction to <50% AND an absolute drop in the left ventricular ejection fraction of ≥10% from baseline) and incomplete therapy (<52 weeks of HER2-targeted therapy) between black and white women in univariate and multivariable analyses. RESULTS: The authors identified 59 black patients and 157 white patients who had a median follow-up 5.2 years. The median patient age was 53 years and was similar for black and white patients. The 1-year cardiotoxicity incidence was 12% overall (95% confidence interval [CI], 7%-16%), 24% in black women (95% CI, 12%-34%), and 7% in white women (95% CI, 3%-11%). Black patients had a significantly greater probability of incomplete therapy compared with white patients (odds ratio, 4.61; 95% CI, 1.70-13.07; P = .002). High correlation was observed between a cardiotoxicity event and incomplete therapy (96% concordance). CONCLUSIONS: Black patients have a higher rate of cardiotoxicity and resultant incomplete adjuvant HER2-targeted therapy than white patients. This patient population may benefit from enhanced cardiac surveillance, cardioprotective strategies, and early referral to cardiology when appropriate. Cancer 2018;124:1904-11. © 2018 American Cancer Society.

Cancer treatment-related cardiac toxicity: prevention, assessment and management.

Cancer therapies, especially anthracyclines and monoclonal antibodies, have been linked with increased rates of cardiotoxicity. The development of some cardiac side effects happens over several months, and changes in ejection fraction can be detected long before permanent damage or disability occurs. Advanced heart failure could be averted with better and earlier detection. Methodologies for early detection of cardiac changes include stress echocardiograms, cardiac velocity measurements, radionuclide imaging, cardiac MRI and several potential biomarkers. Many agents have been described for prophylaxis of cardiac events precipitated by cancer therapy. Prophylactic use of beta-blockers and ACE inhibitors may be considered for use with trastuzumab in breast cancer as tolerated. Recovery of cardiac function is possible early after the injury from a cancer therapy. Late complications for coronary artery disease, hypertension and arrhythmia are underappreciated. Treatments for severe cancer therapy-related cardiac complications follow the existing paradigms for congestive heart failure and coronary artery disease, although outcomes for cancer patients differ from outcomes for non-cancer patients.