Heart transplantation in patients with anthracycline-induced cardiomyopathy / Trasplante cardiaco en pacientes con cardiotoxicidad inducida por antraciclinas

Abstract Objective: The objective of this study was to describe the clinical and imaging characteristics and the evolution of heart transplantation patients due to anthracycline-induced cardiomyopathy Methods: Patients with a diagnosis of ACM who received a heart transplantation in our institution in the period of November 2009-April 2021 were included. Clinical characteristics, pre-transplant studies, and clinical outcomes after transplantation were collected retrospectively from the electronic medical record. Results: A total of 11 patients were included in the study. The median age at the time of cancer diagnosis was 15 years (IQR 10-37 years), while the median age at the time of heart transplant was 56 years (IQR 39-62 years). Regarding post-transplant outcomes, three patients died in the post-operative period. One died 4 years after the intervention due to chronic rejection, while the other seven had a favorable evolution. No oncological relapse was observed with a median follow-up of 2.5 years (IQR 1.86-3.85 years). Conclusion: End-stage anthracycline-induced cardiomyopathy can occur many years after chemotherapy treatment, so close cardiovascular follow-up is extremely important. Heart transplantation is a treatment option after an exhaustive multidisciplinary evaluation, to minimize the risk of oncological relapse.

Resumen Objetivo: Describir las características clínicas, imagenológicas y la evolución de los pacientes trasplantados cardiacos por cardiotoxicidad inducida por antraciclinas. Métodos: Serie de casos descriptiva de pacientes consecutivos trasplantados cardiacos debido a cardiotoxicidad mediada por antraciclinas en el periodo de Noviembre de 2009 a Abril de 2021.Las características clínicas, los estudios complementarios pretrasplante y la información sobre la evolución posterior al trasplante fue recolectada de la historia clínica electrónica de forma retrospectiva. Resultados: Se incluyeron un total de 11 pacientes. La mediana de edad al diagnóstico de la patología oncológica fue de 15 años (RIC 10-37 años), mientras que la mediana de edad en la que recibieron el trasplante cardiaco fue de 56 años (RIC 39-62 años). Con respecto a la evolución posterior al trasplante, 3 pacientes murieron en el periodo del post operatorio inmediato. 1 paciente falleció a los 4 años del trasplante y los otros 7 pacientes tuvieron una evolución favorable. No se observó recaída oncológica en ningún paciente durante una mediana de seguimiento o de 2,5 años (RIC 1.86-3.85 años). Conclusión: La etapa final de la miocardiopatía inducida por antraciclinas puede ocurrir muchos años después del tratamiento con quimioterapia, por lo que es extremadamente importante un seguimiento cardiológico estricto. El trasplante cardiaco es una opción en este grupo de pacientes luego de una exhaustiva evaluación multidisciplinaria, con el fin de minimizar el riesgo de recaída oncológica.

Antagonistas do Sistema Renina-Angiotensina e Betabloqueadores na Prevenção da Cardiotoxicidade por Antraciclinas: Revisão Sistemática e Metanálise / Renin-angiotensin System Antagonists and Beta-blockers in Prevention of Anthracycline Cardiotoxicity: a Systematic Review and Meta-analysis

Resumo Fundamento As evidências que embasam o uso de inibidores do sistema-renina-angiotensina aldosterona (SRAA) e betabloqueadores para prevenção de cardiomiopatia induzida por antraciclinas são controversas. Objetivo Realizamos uma metanálise para avaliar a eficácia desses medicamentos na prevenção da cardiotoxicidade. Métodos A metanálise incluiu estudos prospectivos e randomizados com adultos submetidos à quimioterapia com antraciclina e comparou o uso de terapias SRAA ou betabloqueadores versus placebo com seguimento de 6 a 18 meses. O desfecho primário foi alteração da fração de ejeção do ventrículo esquerdo (FEVE) durante a quimioterapia. Os desfechos secundários foram: a incidência de insuficiência cardíaca, mortalidade por todas as causas e alterações na medida do diâmetro diastólico final. A avaliação da heterogeneidade foi realizada por estratificação e meta-regressão. O nível de significância adotado foi p < 0,05. Resultados A busca resultou em 17 estudos, totalizando 1.530 pacientes. A variação (delta) da FEVE foi avaliada em 14 estudos. A terapia neuro-hormonal foi associada a um menor delta na FEVE pré-terapia versus pós-terapia (diferença média ponderada 4,42 [intervalo de confiança de 95% 2,3 a 6,6]) e maior FEVE final (p < 0,001). O tratamento resultou em menor incidência de insuficiência cardíaca (risk ratio 0,45 [intervalo de confiança de 95% 0,3 a 0,7]). Não houve efeito na mortalidade (p = 0,3). Para a análise da FEVE, foi documentada heterogeneidade substancial, não explicada pelas variáveis exploradas no estudo. Conclusão O uso de inibidores do SRAA e betabloqueadores para prevenção da cardiotoxicidade induzida por antraciclinas foi associado a redução menos pronunciada da FEVE, maior FEVE final e menor incidência de insuficiência cardíaca. Não foram observadas alterações na mortalidade. (CRD PROSPERO 42019133615)

Abstract Background The evidence supporting the use of renin-angiotensin-aldosterone system (RAAS) inhibitors and beta-blockers for the prevention of anthracycline-induced cardiomyopathy is controversial. Objective We performed a meta-analysis to assess the effectiveness of these drugs in preventing cardiotoxicity. Methods The meta-analysis included prospective, randomized studies in adults receiving anthracycline chemotherapy and compared the use of RAAS inhibitors or beta-blockers versus placebo with a follow-up of 6 to 18 months. The primary outcome was change in left ventricular ejection fraction (LVEF) during chemotherapy. Secondary outcomes were the incidence of heart failure, all-cause mortality, and changes in end-diastolic measurement. Heterogeneity was assessed by stratification and meta-regression. A significance level of p < 0.05 was adopted. Results The search resulted in 17 studies, totaling 1,530 patients. The variation (delta) in LVEF was evaluated in 14 studies. Neurohormonal therapy was associated with a lower delta in pre- versus post-therapy LVEF (weighted mean difference 4.42 [95% confidence interval 2.3 to 6.6]) and higher final LVEF (p < 0.001). Treatment resulted in a lower incidence of heart failure (risk ratio 0.45 [95% confidence interval 0.3 to 0.7]). There was no effect on mortality (p = 0.3). For analysis of LVEF, substantial heterogeneity was documented, which was not explained by the variables explored in the study. Conclusion The use of RAAS inhibitors and beta-blockers to prevent anthracycline-induced cardiotoxicity was associated with less pronounced reduction in LVEF, higher final LVEF, and lower incidence of heart failure. No changes in mortality were observed. (CRD PROSPERO 42019133615)

Valor Diagnóstico de Parâmetros Tridimensionais de Strain de Imagem de Speckle Tracking para Detecção de Disfunção Cardíaca Relacionada à Quimioterapia do Câncer: Uma Metanálise / Diagnostic Value of Three-Dimensional Speckle Tracking Imaging Strain Parameters for Detection of Cancer Chemotherapy-Related Cardiac Dysfunction: A Meta-Analysis

Resumo Fundamento Agentes quimioterápicos (por exemplo, antraciclinas, trastuzumabe) comumente usados para o tratamento de tumores malignos demonstraram ter efeitos cardiotóxicos, que estão associados a um prognóstico ruim. A ecocardiografia tridimensional tem sido usada para prever a disfunção cardíaca induzida pela quimioterapia do câncer. Objetivos Avaliação do desempenho diagnóstico de parâmetros de strain, área global de strain (AGS), strain longitudinal (SLG), strain circunferencial (SCG) e strain radial (SRG) por metanálise. Métodos Estudos relevantes foram pesquisados nas bases de dados Embase, PubMed e Web of Science. A análise estatística foi realizada usando Stata 12. O resumo da curva característica operacional do receptor, sensibilidade, especificidade, razão de verossimilhança positiva (RVP), razão de verossimilhança negativa (RVN), e o correspondente intervalo de confiança de 95% para os quatro parâmetros de strain foram combinados. P<0,05 foi considerado estatisticamente significativo. Resultados Nove estudos envolvendo 650 participantes foram incluídos. AGS e SLG mostraram vantagens diagnósticas significativas sobre SCG e SRG. Para AGS, a sensibilidade foi de 0,85 (0,70, 0,93) e a especificidade foi de 0,82 (0,78, 0,86) com RVP de 4,76 (3,55, 6,39) e RVN de 0,18 (0,09, 0,39) e uma área sob a curva (AUC) de 0,85 (0,82, 0,88). Para SLG, a sensibilidade foi de 0,81 (0,74, 0,86) e a especificidade foi de 0,81 (0,68, 0,90) com RVP de 4,35 (2,42, 7,80) e RVN de 0,23 (0,17, 0,33) e uma AUC de 0,85 (0,82, 0,88).OGCS mostrou uma sensibilidade de 0,63 e uma especificidade de 0,79 com uma AUC de 0,77.O SRG mostrou uma sensibilidade de 0,74e uma especificidade de 0,66 com umAUC de 0,73. Conclusão Parâmetros 3D-STI de strain AGS e SLG mostraram bom desempenho na detecção precoce de disfunção cardíaca em pacientes com tumores recebendo quimioterapia.

Abstract Background Chemotherapeutic agents (e.g., anthracyclines, trastuzumab) commonly used for treating malignant tumors have been demonstrated to have cardiotoxic effects, which is associated with poor prognosis. Three-dimensional echocardiography has been used to predict cancer chemotherapy-induced cardiac dysfunction. Objectives Evaluation of the diagnostic performance of strain parameters, global area strain (GAS), longitudinal strain (GLS), circumferential strain (GCS), and radial strain (GRS) by meta-analysis. Methods Relevant studies were searched from the Embase, PubMed, and Web of Science databases. Statistical analysis was performed using Stata 12. The summary receiver operating characteristic curve, sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and corresponding 95% confidence interval for the four strain parameters were pooled. P<0.05 was considered statistically significant. Results Nine studies involving 650 participants were included. GAS and GLS showed significant diagnostic advantages over GCS and GRS. For GAS, the sensitivity was 0.85 (0.70, 0.93) and specificity was 0.82(0.78, 0.86) with PLR of 4.76 (3.55, 6.39) and NLR of 0.18 (0.09, 0.39) and an area under the curve (AUC) of 0.85 (0.82, 0.88). For GLS, the sensitivity was 0.81 (0.74, 0.86) and specificity was 0.81(0.68, 0.90) with PLR of 4.35(2.42, 7.80) and NLR of 0.23 (0.17, 0.33) and an AUC of 0.85 (0.82, 0.88). The GCS showed a sensitivity of 0.63 and a specificity of 0.79 with an AUC of 0.77. The GRS showed a sensitivity of 0.74 and a specificity of 0.66 with an AUC of 0.73. Conclusion 3D-STI strain parameters GAS and GLS showed good performance in detecting early cardiac dysfunction in patients with tumors receiving chemotherapy.

Treinamento muscular inspiratório na qualidade de vida e capacidade funcional na cardiotoxicidade: relato de caso / Entrenamiento muscular inspiratorio en la calidad de vida y capacidad funcional en la cardiotoxicidad: reporte de un caso / Inspiratory muscle training in quality of life and functional capacity in cardiotoxicity: case report

RESUMO Pacientes oncológicos desenvolvem problemas cardíacos frequentes devido à toxidade dos quimioterápicos, com consequente impacto na capacidade funcional (CF) e na qualidade de vida (QV). O treinamento muscular inspiratório (TMI) pode ser um recurso terapêutico viável, já que estudos de causa-efeito demonstraram melhora da CF e da QV em outras populações. Contudo, seu efeito ainda não foi avaliado em pacientes cardio-oncológicos. Assim, o objetivo deste estudo foi descrever o efeito de um programa de TMI sobre a CF e a QV de uma paciente com cardiotoxicidade: LDM, com 41 anos, mulher e sedentária, que desenvolveu insuficiência cardíaca após tratamento quimioterápico. A QV foi avaliada pelo teste de Minnesota. Foram avaliados também a força muscular inspiratória dinâmica (S-Index) e o limiar glicêmico (LG) dos músculos inspiratórios. O LG foi determinado pela glicemia capilar por meio do glicosímetro digital (Accu-Chek - Roche) no menor valor da glicemia da carga correspondente ao teste muscular inspiratório incremental (TMII). A progressão da carga foi realizada a cada duas semanas. Ao final de dois meses, todos os testes foram reaplicados. No teste de Minnesota, os valores relacionados à CF, antes e após o TMI, foram de 36 vs. 8 (melhora de 78%); aos aspectos clínicos e psicológicos foram de 32 vs. 7 (melhora de 78%), a S-Index foram de 41 vs. 51cmH2O (melhora de 24%). O TMI melhorou a CF e a QV de uma paciente cardio-oncológica, configurando-se como um recurso terapêutico viável para essa população.

RESUMEN Los pacientes con cáncer desarrollan problemas cardíacos frecuentes debido a la cardiotoxicidad de la quimioterapia, con el consiguiente impacto en la capacidad funcional (FC) y la calidad de vida (CV). El entrenamiento muscular inspiratorio (IMT) puede ser un recurso terapéutico viable, ya que los estudios de causa-efecto han demostrado una mejora en la FC y la CV en otras poblaciones. Sin embargo, su efecto aún no se ha evaluado en pacientes cardio-oncológicos. Por lo tanto, el objetivo de este estudio fue describir el efecto de un programa de IMT sobre la FC y la CV de un paciente con cardiotoxicidad: LDM, 41 años, mujer y sedentaria, que desarrolló insuficiencia cardíaca después del tratamiento de quimioterapia. La CV se evaluó mediante la prueba de Minnesota. También se evaluaron la fuerza muscular inspiratoria dinámica (índice S) y el umbral glucémico (LG) de los músculos inspiratorios. El LG se determinó por glucemia capilar mediante el glucómetro digital (Accu-Chek - Roche) al valor más bajo de la carga glucélica correspondiente a la prueba muscular inspiratoria incremental (IMI). La progresión de la carga se realizó cada dos semanas. Después de dos meses, todas las pruebas se volvieron a aplicar. En la prueba de Minnesota, los valores relacionados con la FC, antes y después de THE, fueron 36 vs. 8 (78% de mejora); los aspectos clínicos y psicológicos fueron 32 vs. 7 (mejora del 78%), el índice S fue de 41 vs. 51cmH2O (mejora del 24%). El IMT mejoró la FC y la CV de un paciente cardio-oncológico, constituyendo un recurso terapéutico viable para esta población.

ABSTRACT Cancer patients develop frequent cardiac problems due to chemotherapy toxicity, which impacts functional capacity (FC) and quality of life (QoL). Inspiratory Muscle Training (IMT) may be a viable therapeutic resource since cause-effect studies have shown improvement in FC and QoL in other populations. However, its effect was not evaluated in cardio-oncology patients. The study aimed to describe the effect of an IMT program on the FC and QoL of a patient with cardiotoxicity, LDM, aged 41 years, female and, sedentary that developed heart failure after chemotherapy. The QoL was evaluated by the Minnesota test. Dynamic Inspiratory Muscle Strength (S-Index) and Glycemic Threshold (GT) of the inspiratory muscles were also evaluated. The GT was determined by capillary glycemia with a digital glucometer (Accu-Chek - Roche), at the lowest value of glycemia of the load corresponding to the Incremental Inspiratory Muscle Test (IIMT). The load progression was performed every two weeks. After two months, all tests were reapplied. In the Minnesota test, the values related to FC, pre and post IMT, were 36 v. 8 (78% improvement); the clinical and psychological aspects 32 v. 7 (78% improvement); S-Index was 41 v. 51cmH2O (24% improvement). IMT improved the FC and QoL of a cardio-oncology patient, configuring itself as a possible and viable therapeutic resource for this population.

Early-onset Cardiotoxicity assessment related to anthracycline in children with leukemia. A Prospective Study / Evaluación de la cardiotoxicidad temprana asociada al tratamiento con antraciclinas en niños con Leucemia. Estudio prospectivo

Abstract Background: Acute leukemias are the most frequent malignancies in children. Advances in treatment have improved the overall survival to 80%. Almost 10% of children with cancer develop clinical cardiac toxicity. Total anthracycline cumulative dose is a risk factor for early-onset cardiotoxicity. Objective: To describe the incidence of early-onset cardiotoxicity in children with acute leukemia treated with chemotherapy. Methods: A prospective descriptive study of patients >1 y and <18 years diagnosed with acute leukemia. Assessed with electrocardiograma, echocardiography, and blood biomarkers at diagnosis and during the follow-up. Results: 94 patients with acute lymphoblastic leukemia and 18 with acute myeloid leukemia were included. 20 patients (17.9%) developed early-onset cardiotoxicity. Statistically significant data was seen after anthracycline dose >150 mg/m2, between the first echocardiographic evaluation and posterior analyses in the left ventricular fraction ejection with Teicholz p 0.05, Simpson p 0.018 and GLS p 0.004. In this study, there was no relation between blood biomarkers and cardiotoxicity. Conclusions: Cancer therapeutic-related cardiac dysfunction is related to anthracycline cumulative dose. In this study, echocardiographic follow-up was useful to predict risk factors for early cardiac dysfunction.

Resumen Antecedentes: Las leucemias son la principal causa de cáncer infantil. Los avances en el tratamiento han llevado a los pacientes a una supervivencia global hasta del 80%. Cerca del 10% de los niños con cáncer tienen toxicidad cardiovascular sintomática, la dosis acumulada de antraciclinas es un factor de riesgo para afección cardíaca. Objetivo: Describir la frecuencia de afectación cardíaca temprana en niños con leucemias agudas que recibieron tratamiento antineoplásico. Métodos: Estudio prospectivo observacional, de pacientes <18 años con diagnóstico confirmado de leucemia aguda. Fueron evaluados con electrocardiograma, ecocardiograma bidimensional y biomarcadores séricos en diferentes momentos durante el tratamiento. Resultados: Se evaluaron 94 pacientes con leucemia linfoide aguda y 18 con leucemia mieloide aguda. 20 pacientes (17.9%) tuvieron disfunción cardiaca de inicio temprano. Se observaron diferencias estadísticamente significativas, después de recibir 150 mg/m2 de antraciclinas, entre la evaluación del ecocardiograma basal y evaluaciones posteriores de la fracción de eyección ventricular izquierda por Teicholz p 0.05, fracción de eyección ventricular izquierda por Simpson p 0.018 y la deformación longitudinal global p 0.004. No se encontraron alteraciones en los niveles séricos de las troponinas y péptido natriurético cerebral. Conclusiones: La disfunción cardíaca relacionada con quimioterapia estuvo directamente relacionada con las dosis acumuladas de antraciclinas. En este estudio el uso del ecocardiograma como método de seguimiento permitió identificar factores predictores de riesgo para disfunción cardiaca temprana.

Cardiotoxicidad en una Cohorte de pacientes con Diagnóstico de Cáncer de Mama que Recibieron Quimioterapia con Antraciclinas. Seguimiento a 12 años / Cardiotoxicity in a Cohort of Patients Diagnosed with Breast Cancer Who Received Anthracycline Chemotherapy. 12-year follow-up

Introducción: Los esquemas de quimioterapia en el tratamiento de cáncer de mama incluyen Antraciclinas con una efectividad de respuesta alta, sin embargo en algunos casos el potencial efecto terapéutico se ve limitado por la Cardiomiopatía Inducida por Antraciclinas (CIPA).El objetivo del estudio fue establecer la prevalencia longitudinal de esta entidad. Métodos:Este estudiolongitudinalfue realizado en el Instituto Oncológico Nacional "Dr.Juan Tanca Marengo" -SOLCA-Guayaquil. El período de exposición fue abril a diciembredel 2008,laobservación terminó enjunio 2020.Seincluyó mujeres con cáncer de mama, en tratamiento con antraciclinas, clasificadas por riesgo Cardiovascular de Framingham Bajo (A), moderado (B) y alto (C).Se midió lasalteraciones electrocardiográficas (AEKG) basales, a las 6 y 24 horas.Desarrollo de CIPA en seguimiento a 12 años.La muestra fue no probabilística tipo censo. Se utiliza estadística descriptivacon Intervalo de confianza para proporciones. Resultados: Ingresaron al estudio 50 casos son AEKG. El desarrollo de AEKG a 6 horas en 18/50 casos (36% IC95% 34.1-37.9%), estas AEKG persistieron hasta las 24 horas. Las AEKG se presentaron en un 18.5% en mujeres con Riesgo A, 52.4% enRiesgo B y 100%en Riesgo C. El desarrollo de CIPA a12 años fue de 3.6% (2.3-4.9%) en CIPA-Subaguda y de 7.1% (5.3-9.0%)en CIPA crónica. CIPA Subaguda+ crónica 10.7% (8.6-12.9%). Conclusiones: los eventos de cardiotoxicidad aguda fueron detectados por AEKG,en el seguimiento a largo plazo laCIPAsedesarrollóen un porcentaje un poco mayor a la literatura reportada.

Introduction:Chemotherapy regimens in the treatment of breast cancer include Anthracyclines with a high response effectiveness, however in some cases the potential therapeutic effect is limited by Anthracycline Induced Cardiomyopathy (CIPA). The objective of the study was to establish the longitudinal prevalence of this entity. Methods: This longitudinal, observational study was conducted at the National Oncological Institute "Dr. Juan Tanca Marengo "-SOLCA-Guayaquil. The exposure period was April to December 2008. The observation period ended on June 30, 2020. It included women> 18 years with breast cancer, treated with anthracyclines, classified by Framingham Cardiovascular Risk as Low Risk (A) , moderate risk (B) and high risk (C). Electrocardiographic abnormalities (AEKG) were measured at baseline, at 6 hours and at 24 hours and development of CIPA at 12-yearfollow-up. The sample was non-probabilistic, census type. Descriptive statistics with confidence interval for proportions are used. Results: Fifty cases entered the study are AEKG. The development of AEKG at 6 hours in 18/50 cases (36% 95% CI 34.1-37.9%),these AEKG persisted until 24 hours. AEKG were presented in 18.52% in women with Risk A, 52.38% in Risk B and 100% in Risk C. The development of CIPA at 12 years was 3.57% (2.27-4.87%) in CIPA-Subacute and 7.14 % (5.34-8.95% in chronic CIPA. Subacute + chronic CIPA 10.71% (8.55-12.88%). Conclusions: In this study it is concluded that acute cardiotoxicity events were detected by electrocardiographic changes and that in the long-term follow-up they were evident in a slightly higher percentage than that reported in the international literature.

Factores predictivos de cardiotoxicidad inducida por antraciclinas en una cohorte retroprolectiva de niños supervivientes de cáncer / Predictors of anthracycline-induced cardiotoxicity in a retro-prolective cohort of children surviving cancer

Resumen Introducción: La cardiotoxicidad es una reacción adversa asociada al uso de antraciclinas. Objetivo: Estimar los factores asociados al desarrollo de cardiotoxicidad por antraciclinas en pacientes pediátricos supervivientes de cáncer. Método: Cohorte retroprolectiva de niños con diagnóstico de cáncer tratados con antraciclinas. Se realizó determinación ecocardiográfica basal de la fracción de expulsión (FEVi0) antes del inicio del tratamiento y a los 12 meses (FEVi1). Del expediente se obtuvieron las características demográficas y el tratamiento. Se realizó un modelo de regresión logística múltiple (RLM); la FEVi1 < 50 % fue la variable dependiente, que se ajustó por las principales variables confusoras. Resultados: Se incluyeron 65 pacientes, 36.9 % fue del sexo femenino y 56.8 % presentó un tumor sólido. La FEVi0 fue de 74.79 ± 7.3 % y la FEVi1, de 67.96 ± 6.7 % (p = 0.001); 60 % desarrolló cardiotoxicidad. En la RLM solo la dosis acumulada > 430 mg se asoció a cardiotoxicidad (p = 0.001). Conclusiones: En los niños mexicanos se debe evitar una dosis acumulada > 430 mg de antraciclinas para evitar la cardiotoxicidad.

Abstract Introduction Cardiotoxicity is an adverse reaction associated with the use of anthracyclines. Objective: To estimate the factors associated with the development of anthracycline cardiotoxicity in pediatric patients surviving cancer. Method: Retro-prolective cohort of children diagnosed with cancer and treated with anthracyclines. Baseline echocardiographic determination of ejection fraction (LVEF0) was carried out before the start of treatment and again at 12 months (LVEF1). Demographic characteristics and treatment were obtained from the medical record. A multiple logistic regression (MLR) model was constructed; LVEF1 < 50 % was the dependent variable, which was adjusted for the main confounding variables. Results: Sixty-five patients were included, out of which 36.9 % were females and 56.8 % had a solid tumor. LVEF0 was 74.79 ± 7.3 % and LVEF1, 67.96 ± 6.7 % (p = 0.001); 60 % developed cardiotoxicity. In the MLR, only a cumulative dose > 430 mg was associated with cardiotoxicity (p = 0.001). Conclusions: In Mexican children, an anthracycline cumulative dose > 430 mg should be avoided in order to prevent cardiotoxicity.

Disfunción cardiaca subclínica en pacientes oncológicos: reporte de un caso / Subclinical cardiac dysfunction in cancer patients: a case report

RESUMEN La cardiotoxicidad es una entidad clínica relativamente nueva que, en caso de insuficiencia cardiaca, es un marcador de mal pronóstico en sobrevivientes de cáncer que han recibido, con mayor frecuencia, tratamiento con antraciclinas o trastuzumab. En estos pacientes, la detección de la disfunción cardiaca en estadio subclínico permite descubrir precozmente el compromiso miocárdico y evitar un mayor daño al corazón. El incremento de troponina I y los avances tecnológicos en imágenes como el Strain Longitudinal Global permiten detectar esta condición. Presentamos el caso de una paciente de 17 años diagnosticada de osteosarcoma en la pierna izquierda y que recibió antraciclinas. En la evaluación cardiovascular fue asintomática, con función ventricular izquierda normal (60 %), strain disminuido (-15 %) y troponina I elevada (115 ng/mL). Se diagnosticó disfunción cardiaca asintomática, y se indicó carvedilol 6,25 mg/día. Luego de 3 meses de tratamiento el strain se normalizó (-20 %) y la troponina I (19 ng/mL). Este caso es un ejemplo de la utilidad de las nuevas unidades de cardio-oncología que permiten evaluar, diagnosticar y tratar precozmente a los pacientes oncológicos, para evitar la cardiotoxicidad y su respectiva mortalidad.

ABSTRACT Cardiotoxicity is a relatively new clinical entity which, in the case of heart failure, is a marker of poor prognosis in cancer survivors who have received more frequent treatments with anthracyclines or trastuzumab. In these patients, detecting a cardiac dysfunction in the subclinical stage allows revealing early myocardial involvement and avoiding further damage to the heart. The increase in troponin I and the technological advances in imaging, such as the global longitudinal strain, enable the detection of this condition. This case report involves a 17-year-old female patient who was diagnosed with osteosarcoma in her left leg and received anthracyclines. In the cardiovascular evaluation, she was asymptomatic, and showed normal left ventricular function (60 %), decreased strain rate (-15 %) and elevated troponin I levels (115 ng/mL). Asymptomatic cardiac dysfunction was diagnosed and carvedilol 6.25 mg/day was prescribed. After 3 months of treatment, the strain rate (-20 %) and troponin I levels (19 ng/mL) returned to normal. This is an example of the usefulness of new cardio-oncology units that allow cancer patients to be evaluated, diagnosed and treated early in order to avoid cardiotoxicity and the resulting mortality.

Leucemia cutis: presentación no habitual de una enfermedad conocida

RESUMEN La leucemia es una proliferación neoplásica de las células progenitoras del origen tejido hematopoyético y se conoce como leucemia cutis a toda la infiltración en de la piel por el proceso neoplásico. Se presenta el caso de una mujer de 60 años de edad con un cuadro de tres semanas de evolución de aparición de pápulas y placas eritemato-violáceas, inicialmente tratada como cuadro alérgico. Su diagnóstico final fue leucemia cutis secundaria a leucemia mieloide aguda, presentando evolución clínica tórpida.

ABSTRACT Leukemia is a neoplastic proliferation of progenitor cells of hematopoietic tissue origin and the infiltration of the neoplastic process into the skin is known as leukemia cutis. We present the case of a 60-year-old woman with a three-week history of the appearance of erythematous-violet papules and plaques, initially treated as an allergic condition. Her final diagnosis was leukemia cutis secondary to acute myeloid leukemia, presenting a torpid clinical course.

Cáncer de mama Triple Negativo / Triple Negative Breast Cancer

El cáncer de mama Triple Negativo ha sido estudiado a lo largo de los años principalmente por ser uno de los de peor pronóstico y, además, por carecer de terapia blanco. El debut de esta patología se puede dar de diversas formas, y es en función de esto que el especialista optará entre distintas medidas: ya sea instaurará tratamiento adyuvante o neoadyuvante o enfrentará directamente la enfermedad metastásica. Si bien muchas veces las terapias a utilizar no se encuentran bien establecidas, las drogas quimioterápicas no difieren de las de los otros subtipos. Pero, al ser tumores que se asocian con mayor frecuencia a mutaciones en el brca, se han investigado tratamientos que apuntan más hacia el defecto de reparación del adn mediante la recombinación homóloga, como son los platinos y los inhibidores del parp. Por otro lado, no se debe dejar de mencionar las terapias dirigidas hacia los distintos subtipos tumorales como, por ejemplo, los antagonistas androgénicos que aún se encuentran en estudio. Sabemos que el cáncer de mama Triple Negativo es una patología extremadamente difícil de tratar, pero todavía quedan en el tintero investigaciones para esclarecer y enfocar las terapias blanco según cada subtipo dentro de estos tumores

Over the years, Triple Negative breast cancers have been studied, mainly because of its poor prognosis but also because it lacks a target therapy. Its debut may occur in different ways, therefore specialists can choose between different measures for treatment. The choices lay between adjuvant or neoadjuvant therapies or to directly face metastatic disease. Although these therapies are not fully established, chemotherapeutic drugs do not differ from other breast cancer subtypes. The association between these tumors and brca mutations is so high, target treatments have been focusing in dna defect repair, through homologous recombination, such as platinum-based chemotherapy and parp inhibitors. Other target therapies should be taken into account, such as androgenic antagonists, which are still being studied. Considering the nature of such an heterogeneous disease, which is extremely difficult to treat, we should acknowledge research in this subject is yet to be clarified to be able to provide new target therapies for each subtype within the triple negative tumors

Incorporación de las altas dosis de antraciclina en el tratamiento de la leucemia mieloide aguda del adulto / Incorporation of the high dose of anthracycline in the treatment of adult acute myeloid leukemia

Introducción: La leucemia mieloide aguda representa el 80 por ciento de las leucemias agudas entre los adultos; el tratamiento de inducción a la remisión, para los pacientes menores de 60 años, está basado en la combinación de antraciclinas y arabinósido de citosina. Objetivo: incorporar las altas dosis de antraciclinas al tratamiento de inducción de la leucemia mieloide aguda no promielocítica en pacientes adultos menores de 60 años. Método: Se realizó un estudio cuasiexperimental en 41 pacientes con este diagnóstico, atendidos en el servicio de Adultos del Instituto de Hematología e Inmunología, desde septiembre del 2013 hasta diciembre del 2016. A todos los pacientes se les realizó estudios morfológicos, inmunológicos, citogenéticos y moleculares al inicio de la enfermedad y ecocardiografía para determinar la fracción de eyección y de acortamiento del ventrículo izquierdo al año de finalizado el tratamiento, para determinar la cardiotoxicidad por el uso de las altas dosis de antraciclinas. Resultados: La distribución por edad fue mayor en el grupo de 46 a 52 años representado por el 26,8 por ciento de los casos y predominó el sexo masculino 60,9 por ciento. En el 85 por ciento de los casos la enfermedad apareció de novo. Según los criterios morfológicos de la clasificación Franco Británico Americana el 31,7 por ciento correspondió a la variante M1, en estrecha relación con las determinaciones por citometría de flujo, para esta variedad. Los genes más comúnmente involucrados fueron el NPM1 y el AML/ETO, para el 24 por ciento y 22 por ciento, respectivamente. El 56,1 por ciento de los pacientes alcanzó la remisión hematológica con un solo ciclo de tratamiento y el 14,6 por ciento, necesitó realizar un segundo esquema de inducción. No se reportaron eventos de cardiotoxocidad por antraciclina durante el tratamiento, ni al año de culminado este. Conclusiones: Con el uso de las altas dosis de antraciclina se lograron remisiones hematológicas, sin toxicidad cardiovascular demostrada(AU)

Introduction: Acute myeloid leukemia represents 80 percent of acute leukemias among adults; the induction treatment to obtain remission in patients under 60 years old is based on the combination of anthracyclines and cytosine arabinoside. Objective: to incorporate the high doses of anthracyclines to the treatment of induction of non-promyelocytic acute myeloid leukemia in adult patients under 60 years of age. Method: We conducted a quasi-experimental study in 41 patients with this diagnosis, at the adult clinic service of the Institute of Hematology and Immunology, from september 2013 to december 2016. Morphological, immunological, cytogenetic and molecular studies were carried out at the beginning of the disease and also echocardiography was performed to determine the ejection fraction and shortening of the left ventricle a year after the end of treatment, to determine cardiotoxicity due to the use of high doses of anthracyclines. Results: The distribution by age was higher in the group of 46 to 52 years represented by 26.8 percent of the cases and the male sex predominated 60.9 percent. In 85 percent of the cases the disease appeared de novo. According to the morphological criteria of the French American British classification, 31.7 percent corresponded to the M1 variant, in close relation with the determinations by flow cytometry, for this variety. The genes most commonly involved were NPM1 and AML / ETO, for 24 percent and 22 percent respectively. 56.1 percent of patients achieved hematological remission with a single treatment cycle and 14.6 percent of patients needed a second induction scheme. No anthracycline cardiotoxicity events were reported during the treatment, nor a year after the treatment, in the patients evaluated. Conclusions: With the use of high doses of anthracycline, have been hematological remissions, without demonstrated cardiovascular toxicity(AU)

Left Ventricular Regional Wall Motion Abnormality is a Strong Predictor of Cardiotoxicity in Breast Cancer Patients Undergoing Chemotherapy / Alteração Contrátil Segmentar Ventricular Esquerda é Preditor Independente de Cardiotoxicidade em Pacientes com Câncer de Mama em Tratamento Quimioterápico

Abstract Background: Chemotherapeutic agents of anthracyclines class and humanized monoclonal antibodies are effective treatments for breast cancer, however, they present a potential risk of cardiotoxicity. Several predictors have been recognized as predictors in the development of cardiac toxicity, and the evaluation of left ventricular segmental wall motion abnormalities (LVSWMA) has not been studied. Objective: To analyze prospectively the role of LVSWMA among echocardiographic parameters in the prediction of development of cardiotoxicity in breast cancer patients undergoing treatment with chemotherapy. Methods: Prospective cohort of patients diagnosed with breast cancer and in chemotherapy treatment with potential cardiotoxicity medications including doxorubicin and trastuzumab. Transthoracic echocardiograms including speckle tracking strain echocardiography were performed at standard times before, during and after the treatment to assess the presence (or lack thereof) of cardiotoxicity. Cardiotoxicity was defined by a 10% decrease in the left ventricular ejection fraction, on at least one echocardiogram. Multivariate logistic regression models were used to verify the predictors related to the occurrence of cardiotoxicity over time. Results: Of the 112 patients selected (mean age 51,3 ± 12,9 years), 18 participants (16.1%) had cardiotoxicity. In the multivariate analysis using the logistic regression model, those with LVWMA (OR = 6.25 [CI 95%: 1.03; 37.95], p < 0,05), LV systolic dimension (1.34 [CI 95%: 1.01; 1.79], p < 0,05) and global longitudinal strain by speckle tracking (1.48 [CI 95%: 1.02; 2.12], p < 0,05) were strongly associated with cardiotoxicity. Conclusion: In the present study, we showed that LVWMA, in addition to global longitudinal strains, were strong predictors of cardiotoxicity and could be useful in the risk stratification of these patients.

Resumo Fundamento: Os agentes quimioterápicos da classe das antraciclinas e dos anticorpos monoclonais humanizados são tratamentos eficazes para o câncer de mama, entretanto, apresentam alto risco de cardiotoxicidade. Diversos parâmetros têm sido reconhecidos como preditores no desenvolvimento de toxicidade cardíaca, sendo que a avaliação da alteração contrátil segmentar ventricular esquerda (ACSVE) ainda não foi estudada. Objetivo: Analisar a associação entre o surgimento de ACSVE e o desenvolvimento de cardiotoxicidade em pacientes com câncer de mama em tratamento com quimioterapia. Métodos: Coorte prospectiva de pacientes diagnosticados com câncer de mama e em tratamento quimioterápico com doxorrubicina e/ou trastuzumab. Foram realizados ecocardiogramas transtorácicos antes, durante e depois do tratamento para avaliar a presença ou não de cardiotoxicidade. A cardiotoxicidade foi definida por um decréscimo de 10% na fração de ejeção do ventrículo esquerdo, em pelo menos um ecocardiograma. Modelos de regressão logística multivariada foram utilizados para verificar os fatores preditores na ocorrência de cardiotoxicidade ao longo do tempo. Resultados: Dos 112 pacientes selecionados (idade média = 51,3 ± 12,9 anos), 18 (16,1%) apresentaram cardiotoxicidade. Na análise multivariada os pacientes com ACSVE (OR = 6,25 [IC 95%: 1,03; 37,95], p < 0,05), diâmetro sistólico do VE (OR = 1,34 [IC 95%:1,01; 1,79], p < 0,05) e strain longitudinal global pela técnica de speckle tracking (OR = 1,48 [IC 95%: 1,02; 2,12], p < 0,05) foram preditores significativos e independentes na predição de cardiotoxidade. Conclusão: Mostramos que ACSVE, bem como a redução do strain longitudinal global foram preditores independentes para cardiotoxicidade, podendo ser úteis na estratificação de risco destes pacientes.

Cardiotoxicidad de los quimioterapéuticos tipo antraciclinas de la lista oficial de medicamentos de la Caja Costarricense del Seguro Social / Cardiotoxicity of anthracycline-type chemotherapeutics in the official list of medicines of the Caja Costarricense del Seguro Social

Resumen La cardiotoxicidad asociada al uso de quimioterapéuticos ha sido ampliamente corroborada a través de diversos estudios clínicos. En Costa Rica se han empezado a desarrollar Unidades Cardio-oncológicas en diversos centros médicos con el fin de detectar de manera precoz el efecto deletéreo cardiovascular asociado a los diferentes quimioterapéuticos. A con tinuación, se presenta un resumen de las manifestaciones clínicas cardiovasculares asociadas al uso de antraciclinas que tenemos a disposición en la Caja Costarricense del Seguro Social (CCSS)

Abstract Cardiotoxicity of anthracycline-type chemotherapeutics in the official list of medicines of the Caja Costarricense del Seguro Social Cardiotoxicity associated with the use of chemotherapy has been largely corroborated along multiple clinical trials. In Costa Rica, the development of Cardio-oncologic Units has begun recently in various medical centers with the purpose of achieving an early detection of the deleterious cardiovascular effect associated with different chemotherapeutics. This review consists of a summary of the clinical manifestations related to the use of anthracyclines available in the Costa Rican public health system.

Anthracycline-associated cardiotoxicity in adults: systematic review on the cardioprotective role of beta-blockers

SUMMARY OBJECTIVES This study aimed at assessing the role of beta-blockers on preventing anthracycline-induced cardiotoxicity in adults. METHODS A systematic review was performed on electronic databases, including relevant studies that analysed beta-blockers as cardioprotective agents before the use of anthracyclines by adult oncologic patients. RESULTS After application of eligibility and selection criteria, eight articles were considered as high quality, complying with the proposed theme; all eight clinical trials, four of them placebo-controlled, with a total number of 655 patients included. From this sample, 281 (42.9%) used beta-blocker as intervention, and carvedilol was the most frequent (167 patients - 25.5%). Six studies were considered positive regarding the cardioprotection role played by beta-blockers, although only four demonstrated significant difference on left ventricle ejection fraction after chemotherapy on groups that used beta-blockers compared to control groups. Carvedilol and nebivolol, but not metoprolol, had positive results regarding cardioprotection. Other beta-blockers were not analysed in the selected studies. CONCLUSIONS Despite the potential cardioprotective effect of beta-blockers, as demonstrated in small and unicentric clinical trials, its routine use on prevention of anthracycline-associated cardiotoxicity demands greater scientific evidence.

RESUMO OBJETIVO Este estudo teve como objetivo analisar o papel dos betabloqueadores na prevenção da cardiotoxicidade induzida pelas antraciclinas em adultos. MÉTODOS Foi realizada uma revisão sistemática em bases de dados eletrônicos, incluindo os estudos relevantes que analisaram fármacos betabloqueadores como agentes cardioprotetores antes do início do uso de antraciclinas por pacientes oncológicos adultos. RESULTADOS Após aplicação dos critérios de elegibilidade e seleção, foram obtidos oito artigos considerados de boa qualidade, que se adequavam à temática proposta, sendo todos ensaios clínicos, quatro placebo-controlados, totalizando 655 pacientes incluídos. Destes, 281 (42,9%) fizeram uso de algum betabloqueador como intervenção, sendo o carvedilol o mais utilizado (167 pacientes - 25,5%). Seis estudos foram considerados positivos quanto à cardioproteção exercida pelos betabloqueadores, porém apenas quatro demonstraram diferença na fração de ejeção do ventrículo esquerdo após a quimioterapia nos grupos que usaram betabloqueadores em relação aos grupos controle. O carvedilol e o nebivolol, mas não o metoprolol, tiveram resultados positivos quanto à cardioproteção. Outros betabloqueadores não foram avaliados nos estudos incluídos. CONCLUSÕES Apesar de haver um potencial efeito cardioprotetor dos betabloqueadores, conforme demonstrado em ensaios clínicos pequenos e unicêntricos, sua utilização rotineira na prevenção da cardiotoxicidade associada às antraciclinas requer maiores comprovações científicas.

Subclinical Anthracycline-Induced Cardiotoxicity in the Long - Term Follow-Up of Lymphoma Survivors: A Multi-Layer Speckle Tracking Analysis / Cardiotoxicidade Subclínica Induzida por Antraciclina no Seguimento a Longo Prazo de Sobreviventes de Linfoma: Uma Análise Speckle Tracking Multi-Layer

Abstract Background: Anthracycline generates progressive left ventricular dysfunction associated with a poor prognosis. Objectives: The purpose of this study was to evaluate whether layer-specific strain analysis could assess the subclinical left ventricular dysfunction after exposure to anthracycline. Methods: Forty-two anthracycline-treated survivors of large B-cell non-Hodgkin lymphoma, aged 55.83 ± 17.92 years (chemotherapy group) and 27 healthy volunteers, aged 51.39 ± 13.40 years (control group) were enrolled. The cumulative dose of epirubicin in chemotherapy group was 319.67 ± 71.71mg/m2. The time from last dose of epirubicin to the echocardiographic examination was 52.92 ± 22.32 months. Global longitudinal (GLS), circumferential (GCS) and radial strain (GRS), subendocardial, mid and subepicardial layer of longitudinal (LS-ENDO, LS-MID, LS-EPI) and circumferential strain (CS-ENDO, CS-MID, CS-EPI) values were analyzed. Transmural strain gradient was calculated as differences in peak systolic strain between the subendocardial and subepicardial layers. A value of p < 0.05 was considered significant. Results: Conventional parameters of systolic and diastolic function showed no significant difference between two groups. Compared with controls, patients had significantly lower GCS and GLS. Multi-layer speckle tracking analysis showed significant reduction of circumferential strain of subendocardial layer, transmural CS gradient and longitudinal strain of all three layers. In contrast, the two groups did not differ in transmural longitudinal strain gradient and radial strains. Conclusions: It proved the preferential impairment of subendocardial deformation in long-term survivors after exposure to anthracycline. Multi-layer speckle tracking echocardiography might facilitate the longitudinal follow-up of this at-risk patient cohort.

Resumo Fundamentos: A antraciclina gera uma disfunção ventricular esquerda progressiva associada a um prognóstico ruim. Objetivos: O propósito deste estudo foi avaliar se a análise layer específico de strain poderia avaliar disfunção ventricular esquerda subclínica após exposição a antraciclina. Métodos: Foram inscritos quarenta e dois sobreviventes tratados com antraciclina por linfoma não Hodgkin de células B grandes, de 55,83 ± 17,92 anos (grupo de quimioterapia) e 27 voluntários saudáveis, de 51,39 ± 13,40 anos (grupo controle). A dose cumulativa de epirrubicina no grupo de quimioterapia foi de 319,67 ± 71,71 mg/m2. O tempo desde a última dose de epirrubicina até o exame ecocardiográfico foi de 52,92 ± 22,32 meses. Analisaram-se o strain longitudinal global (GLS), o circunferencial (GCS) e o strain radial (GRS), os valores das camadas subendocárdica, média e subepicárdica so strain longitudinal (LS-ENDO, LS-MID, LS-EPI) e do strain circunferencial (CS-ENDO, CS-MID, CS-EPI). O gradiente de strain transmural foi calculado como a diferença no strain sistólico pico entre as camadas subendocárdicas e subepicárdicas. Um valor de p < 0,05 foi considerado significativo. Resultados: Os parâmetros convencionais da função sistólica e diastólica não mostraram diferenças significativas entre dois grupos. Comparados aos controles, os pacientes apresentaram GCS e GLS significativamente menores. A análise de speckle tracking multi-layer mostrou uma redução significativa no strain circunferencial da camada subendocárdica, o gradiente transmural CS e o strain longitudinal das três camadas. Em contraste, os dois grupos não diferiram no gradiente de strain longitudinal transmural e de strain radiais. Conclusões: Provou-se a deterioração preferencial do strain subendocárdico em sobreviventes de longa duração após exposição à antraciclina. O ecocardiograma de speckle tracking multi-layer pode facilitar o acompanhamento longitudinal dessa coorte de pacientes em risco. (Arq Bras Cardiol. 2018; 110(3):219-228)