Consensus document on anemia and iron deficiency in heart failure: Consejo Interamericano de Falla Cardiaca e Hipertensión Pulmonar (CIFACAH) of the Interamerican Society of Cardiology (IASC).

Heart failure is a pathology that affects 1% of the population and is accompanied by iron deficiency as a comorbidity in 50% of cases. Anemia, meanwhile, is present between 22-37%. This is a consensus document that seeks to synthesize the information available on anemia and iron deficiency and its behavior in patients with HF, which is divided into pathophysiology, classification, clinical scenarios and algorithms (clinical pathways), treatment, and follow-up. This article integrates international recommendations based on evidence and presents a synthesis of management strategies.

La insuficiencia cardíaca (IC) es una patología que afecta al 1% de la población y se encuentra acompañada de deficiencia de hierro como comorbilidad en el 50% de los casos. La anemia, por su parte, está presente en el 22-37% de los casos de IC. Este es un documento de consenso que busca sintetizar la información disponible sobre la anemia y la deficiencia de hierro, y su comportamiento en pacientes con IC, que se divide en fisiopatología, clasificación, escenarios clínicos y algoritmos (rutas de manejo), tratamiento y seguimiento. Este artículo integra las recomendaciones internacionales basadas en la evidencia y se presenta una síntesis de las estrategias de manejo.

Interamerican Society of Cardiology (CIFACAH - ELECTROSIAC)/Latin American Heart Rhythm Society (LAHRS): multidisciplinary review on the appropriate use of cardiac resynchronization therapy in heart failure.

Epidemiological studies suggest that approximately half of the patients with heart failure (HF) have reduced ejection fraction, while the other half have normal ejection fraction (EF). Currently, international guidelines consider QRS duration greater than 130 ms, in the presence of ventricular dysfunction (EF < 35%), as a criterion for selecting patients for cardiac resynchronization therapy (CRT). CRT helps restore intraventricular and auriculoventricular synchrony, improving left ventricular (LV) performance, reducing functional mitral regurgitation, and inducing reverse LV remodeling. This is evidenced by increased LV filling time and left ventricular ejection fraction, decreased LV end-diastolic and end-systolic volumes, mitral regurgitation, and septal dyskinesia. Because the mechanisms of dyssynchrony may be heterogeneous, no single measure may accurately predict response to CRT. Finally, CRT has been progressively shown to be safe and feasible, improves functional status and quality of life, reversely remodels the LV, decreases the number of hospitalizations, total mortality in patients with refractory HF, LV dysfunction, and intraventricular conduction disorders; is a pacemaker-based therapy for HF and thanks to current technology, safe remote monitoring of almost all types of cardiac devices is possible and provides useful alerts in clinical practice.

Los estudios epidemiológicos sugieren que aproximadamente la mitad de los pacientes con insuficiencia cardiaca (IC) tiene fracción de eyección reducida, mientras que la otra mitad, fracción de eyección (FE) normal. Actualmente, las guías internacionales consideran la duración de QRS mayor a 130 ms, en presencia de disfunción ventricular (FE < 35%), como criterio para selección de pacientes a terapia de resincronización cardiaca (TRC). La TRC ayuda a restaurar la sincronía intraventricular y auriculoventricular, mejorando el rendimiento del ventrículo izquierdo (VI), reduciendo la regurgitación mitral funcional e induciendo la remodelación inversa del VI. Esto se evidencia en el aumento del tiempo de llenado del VI y la fracción de eyección del VI, la disminución de los volúmenes telediastólico y telesistólico del VI, y la regurgitación mitral y discinesia septal. Como los mecanismos de la disincronía pueden ser heterogéneos, es posible que ninguna medida prediga con exactitud la respuesta a la TRC. Finalmente, la TRC cardiaca ha demostrado progresivamente ser segura y factible, mejora el estado funcional y la calidad de vida, remodela inversamente el VI, disminuye el número de hospitalizaciones, la mortalidad total en pacientes con IC refractaria, la disfunción ventricular izquierda y los trastornos de conducción intraventricular; es una terapia basada en marcapasos para la IC y gracias a la tecnología actual es posible realizar una supervisión remota y segura de casi todos los tipos de dispositivos cardiacos y obtener alertas útiles en la práctica clínica.

Relict duck-billed dinosaurs survived into the last age of the dinosaurs in subantarctic Chile.

In the dusk of the Mesozoic, advanced duck-billed dinosaurs (Hadrosauridae) were so successful that they likely outcompeted other herbivores, contributing to declines in dinosaur diversity. From Laurasia, hadrosaurids dispersed widely, colonizing Africa, South America, and, allegedly, Antarctica. Here, we present the first species of a duck-billed dinosaur from a subantarctic region, Gonkoken nanoi, of early Maastrichtian age in Magallanes, Chile. Unlike duckbills further north in Patagonia, Gonkoken descends from North American forms diverging shortly before the origin of Hadrosauridae. However, at the time, non-hadrosaurids in North America had become replaced by hadrosaurids. We propose that the ancestors of Gonkoken arrived earlier in South America and reached further south, into regions where hadrosaurids never arrived: All alleged subantarctic and Antarctic remains of hadrosaurids could belong to non-hadrosaurid duckbills like Gonkoken. Dinosaur faunas of the world underwent qualitatively different changes before the Cretaceous-Paleogene asteroid impact, which should be considered when discussing their possible vulnerability.

[Interamerican Society of Cardiology (CIFACAH - ELECTROSIAC)/Latin American Heart Rhythm Society (LAHRS): multidisciplinary review on the appropriate use of cardiac resynchronization therapy in heart failure]. / Sociedad Interamericana de Cardiología (CIFACAH-ELECTROSIAC)/Sociedad Latinoamericana de Ritmo Cardiaco (LAHRS): revisión multidisciplinaria sobre el uso apropiado de la terapia de resincronización cardiaca en la insuficiencia cardiaca.

Epidemiological studies suggest that approximately half of the patients with heart failure (HF) have reduced ejection fraction, while the other half have normal ejection fraction (EF). Currently, international guidelines consider QRS duration greater than 130 ms, in the presence of ventricular dysfunction (EF < 35%), as a criterion for selecting patients for cardiac resynchronization therapy (CRT). CRT helps restore intraventricular and auriculoventricular synchrony, improving left ventricular (LV) performance, reducing functional mitral regurgitation, and inducing reverse LV remodeling. This is evidenced by increased LV filling time and left ventricular ejection fraction, decreased LV end-diastolic and end-systolic volumes, mitral regurgitation, and septal dyskinesia. Because the mechanisms of dyssynchrony may be heterogeneous, no single measure may accurately predict response to CRT. Finally, CRT has been progressively shown to be safe and feasible, improves functional status and quality of life, reversely remodels the LV, decreases the number of hospitalizations, total mortality in patients with refractory HF, LV dysfunction, and intraventricular conduction disorders; is a pacemaker-based therapy for HF and thanks to current technology, safe remote monitoring of almost all types of cardiac devices is possible and provides useful alerts in clinical practice.

Los estudios epidemiológicos sugieren que aproximadamente la mitad de los pacientes con insuficiencia cardiaca (IC) tiene fracción de eyección reducida, mientras que la otra mitad, fracción de eyección (FE) normal. Actualmente, las guías internacionales consideran la duración de QRS mayor a 130 ms, en presencia de disfunción ventricular (FE < 35%), como criterio para selección de pacientes a terapia de resincronización cardiaca (TRC). La TRC ayuda a restaurar la sincronía intraventricular y auriculoventricular, mejorando el rendimiento del ventrículo izquierdo (VI), reduciendo la regurgitación mitral funcional e induciendo la remodelación inversa del VI. Esto se evidencia en el aumento del tiempo de llenado del VI y la fracción de eyección del VI, la disminución de los volúmenes telediastólico y telesistólico del VI, y la regurgitación mitral y discinesia septal. Como los mecanismos de la disincronía pueden ser heterogéneos, es posible que ninguna medida prediga con exactitud la respuesta a la TRC. Finalmente, la TRC cardiaca ha demostrado progresivamente ser segura y factible, mejora el estado funcional y la calidad de vida, remodela inversamente el VI, disminuye el número de hospitalizaciones, la mortalidad total en pacientes con IC refractaria, la disfunción ventricular izquierda y los trastornos de conducción intraventricular; es una terapia basada en marcapasos para la IC y gracias a la tecnología actual es posible realizar una supervisión remota y segura de casi todos los tipos de dispositivos cardiacos y obtener alertas útiles en la práctica clínica.

Sudden Cardiac Arrest in Basketball and Soccer Stadiums, the Role of Automated External Defibrillators: A Review. For the BELTRAN Study (BaskEtbaLl and soccer sTadiums: Registry on Automatic exterNal defibrillators).

Sudden cardiac arrest (SCA) during sports events has a dramatic impact on stadium-goers and the public and is often associated with poor outcomes unless treated with an automated external defibrillator (AED). Despite this, stadiums vary in AED use. This review aims to identify the risks and incidences of SCA, and the use of AEDs in soccer and basketball stadiums. A narrative review of all relevant papers was conducted. Athletes across all sports face an SCA risk of 1:50,000 athlete-years, with the greatest risk of SCA in young male athletes (1:35,000 person-years) and black male athletes (1:18,000 person-years). Africa and South America have the poorest soccer SCA outcomes at 3% and 4% survival. AED use on-site improves survival greater than defibrillation by emergency services. Many stadiums do not have AEDs implemented into medical plans and the AEDs are often unrecognisable or are obstructed. Therefore, AEDs should be used on-site, use clear signalling, have certified trained personnel, and be incorporated into stadiums' medical plans.

Lung Allograft Microbiome Association with Gastroesophageal Reflux, Inflammation, and Allograft Dysfunction.

Rationale: It remains unclear how gastroesophageal reflux disease (GERD) affects allograft microbial community composition in lung transplant recipients and its impact on lung allograft inflammation and function. Objectives: Our objective was to compare the allograft microbiota in lung transplant recipients with or without clinically diagnosed GERD in the first year after transplant and assess associations between GERD, allograft microbiota, inflammation, and acute and chronic lung allograft dysfunction (ALAD and CLAD). Methods: A total of 268 BAL samples were collected from 75 lung transplant recipients at a single transplant center every 3 months after transplant for 1 year. Ten transplant recipients from a separate transplant center provided samples before and after antireflux Nissen fundoplication surgery. Microbial community composition and density were measured using 16S ribosomal RNA gene sequencing and quantitative polymerase chain reaction, respectively, and inflammatory markers and bile acids were quantified. Measurements and Main Results: We observed a range of allograft community composition with three discernible types (labeled community state types [CSTs] 1-3). Transplant recipients with GERD were more likely to have CST1, characterized by high bacterial density and relative abundance of the oropharyngeal colonizing genera Prevotella and Veillonella. GERD was associated with more frequent transitions to CST1. CST1 was associated with lower inflammatory cytokine concentrations than pathogen-dominated CST3 across the range of microbial densities observed. Cox proportional hazard models revealed associations between CST3 and the development of ALAD/CLAD. Nissen fundoplication decreased bacterial load and proinflammatory cytokines. Conclusions: GERD was associated with a high bacterial density, Prevotella- and Veillonella-dominated CST1. CST3, but not CST1 or GERD, was associated with inflammation and early development of ALAD and CLAD. Nissen fundoplication was associated with a reduction in microbial density in BAL fluid samples, especially the CST1-specific genus, Prevotella.

Therapeutic interventions and mechanisms associated with gut microbiota-mediated modulation of immune checkpoint inhibitor responses.

The link between the gut microbiome and responsiveness to immune checkpoint inhibitor (ICI) therapy is now well established. New therapeutic opportunities exploiting this relationship are being developed with the goal of augmenting ICI efficacy. In this review, we summarize the foundational research establishing these interactions and discuss the mechanisms and novel therapeutic options associated with this gut microbiome-ICI connection.

Clinical impact of the correction of the value of left ventricular ejection fraction in patients with mitral valve regurgitation. / Efectos clínicos de la corrección del valor de la fracción de expulsión del ventrículo izquierdo en pacientes con insuficiencia valvular mitral.

Introducción y objetivos: La insuficiencia valvular mitral provoca el vaciado simultáneo hacia la aorta y la aurícula izquierda durante la sístole ventricular, lo que produce una disminución del volumen hacia la circulación sistémica. En este estudio se busca obtener un dato preciso del porcentaje de volumen expulsado en sentido anterógrado en pacientes con insuficiencia mitral. Métodos: Se aplica una fórmula ecocardiográfica de "corrección" de la fracción de expulsión del ventrículo izquierdo (FEVI) en 114 pacientes con insuficiencia mitral, con base en la medición de la fracción regurgitante. Resultados: La corrección de la FEVI demostró que el 44.7% de los casos (n = 51) debe reclasificarse en cuanto a la calidad de su función sistólica ventricular izquierda. De 79 sujetos con FEVI normal (≥ 50%) sólo se mantuvieron 32 en la misma categoría; en el grupo con FEVI moderadamente reducida (intervalo intermedio, 40-49.9%) se pasó de 6 a 23 casos y, en aquéllos con FEVI reducida (< 40%), el grupo aumentó de 29 a 59; el subgrupo de pacientes con FEVI < 30% se incrementó de 21 a 41 sujetos. Conclusiones: Puesto que en la mayoría de las guías de tratamiento la FEVI se usa para estratificar riesgos e indicaciones terapéuticas, los autores creen que la ponderación de la insuficiencia mitral puede incrementar la precisión del tratamiento y la posibilidad de incluir a pacientes que no están considerados en esos tratamientos en el momento actual. Introduction and objectives: Mitral valve regurgitation causes simultaneous emptying to the aorta and left atrium during ventricular systole, generating a decrease in volume supply to the systemic circulation. In this study we seek to obtain an accurate data on the percentage of volume expelled in the anterograde direction in patients with mitral regurgitation. Methods: An echocardiographic formula for "correction" of the left ventricular ejection fraction (LVEF) was applied in 114 patients with mitral regurgitation, based on the measurement of the regurgitant fraction. Results: Correction of the LVEF showed that 44.7% of cases (n = 51) should be reclassified in terms of the quality of their left ventricular systolic function. Of 79 subjects with normal LVEF (≥ 50%) only 32 remained in the same category; in the group with moderately reduced LVEF (medium range, 40-49.9%) it went from 6 to 23 cases and, in those with reduced LVEF (< 40%), the group increased from 29 to 59; the subgroup of patients with LVEF < 30% increased from 21 to 41 subjects. Conclusions: Given that in most treatment guidelines LVEF is used to stratify risks and therapeutic indications, the authors believe that the weighting of mitral regurgitation can increase the accuracy of treatment, and the possibility of including patients who, at this current moment, are not considered for these therapies.

Efectos clínicos de la corrección del valor de la fracción de expulsión del ventrículo izquierdo en pacientes con insuficiencia valvular mitral / Clinical impact of the correction of the value of left ventricular ejection fraction in patients with mitral valve regurgitation

Resumen Introducción y objetivos: La insuficiencia valvular mitral provoca el vaciado simultáneo hacia la aorta y la aurícula izquierda durante la sístole ventricular, lo que produce una disminución del volumen hacia la circulación sistémica. En este estudio se busca obtener un dato preciso del porcentaje de volumen expulsado en sentido anterógrado en pacientes con insuficiencia mitral. Métodos: Se aplica una fórmula ecocardiográfica de “corrección” de la fracción de expulsión del ventrículo izquierdo (FEVI) en 114 pacientes con insuficiencia mitral, con base en la medición de la fracción regurgitante. Resultados: La corrección de la FEVI demostró que el 44.7% de los casos (n = 51) debe reclasificarse en cuanto a la calidad de su función sistólica ventricular izquierda. De 79 sujetos con FEVI normal (≥ 50%) sólo se mantuvieron 32 en la misma categoría; en el grupo con FEVI moderadamente reducida (intervalo intermedio, 40-49.9%) se pasó de 6 a 23 casos y, en aquéllos con FEVI reducida (< 40%), el grupo aumentó de 29 a 59; el subgrupo de pacientes con FEVI < 30% se incrementó de 21 a 41 sujetos. Conclusiones: Puesto que en la mayoría de las guías de tratamiento la FEVI se usa para estratificar riesgos e indicaciones terapéuticas, los autores creen que la ponderación de la insuficiencia mitral puede incrementar la precisión del tratamiento y la posibilidad de incluir a pacientes que no están considerados en esos tratamientos en el momento actual.

Abstract Introduction and objectives: Mitral valve regurgitation causes simultaneous emptying to the aorta and left atrium during ventricular systole, generating a decrease in volume supply to the systemic circulation. In this study we seek to obtain an accurate data on the percentage of volume expelled in the anterograde direction in patients with mitral regurgitation. Methods: An echocardiographic formula for “correction” of the left ventricular ejection fraction (LVEF) was applied in 114 patients with mitral regurgitation, based on the measurement of the regurgitant fraction. Results: Correction of the LVEF showed that 44.7% of cases (n = 51) should be reclassified in terms of the quality of their left ventricular systolic function. Of 79 subjects with normal LVEF (≥ 50%) only 32 remained in the same category; in the group with moderately reduced LVEF (medium range, 40-49.9%) it went from 6 to 23 cases and, in those with reduced LVEF (< 40%), the group increased from 29 to 59; the subgroup of patients with LVEF < 30% increased from 21 to 41 subjects. Conclusions: Given that in most treatment guidelines LVEF is used to stratify risks and therapeutic indications, the authors believe that the weighting of mitral regurgitation can increase the accuracy of treatment, and the possibility of including patients who, at this current moment, are not considered for these therapies.

Hidroxicloroquina: Mensajes desde la cardiología en tiempos de pandemia por Coronavirus / Hydroxychloroquine. Cardiology's viewpoint in times of coronavirus pandemic

Ante la pandemia de COVID-19 (del inglés coronavirus disease 2019), uno de los fármacos propuesto para su tratamiento es la hidroxicloroquina. Se revisan aquí aspectos cardiológicos del uso de cloroquina e hidroxicloroquina. Se realizó una revisión no sistemática en la literatura médica orientada a la búsqueda de información acerca de su seguridad y eficacia como antimaláricos y antivirales, así como en el tratamiento prolongado de enfermedades reumatológicas. Se halló un efecto antiinflamatorio con reducción de eventos cardiovasculares a largo plazo, una cardiopatía muy infrecuente por un efecto lisosomal del fármaco, y a nivel hemodinámico hipotensión, taquicardia, y prolongación del intervalo QT, exacerbado si se combina con azitromicina. Sin embargo, la tasa de eventos adversos cardíacos de la hidroxicloroquina y la cloroquina fue baja.

Due to the coronavirus disease 2019 (COVID-19) pandemic, a wide number of compounds are under scrutiny regarding their antiviral activity, one of them being hydroxychloroquine. Cardiac aspects of the use of chloroquine and hydroxychloroquine are reviewed in this manuscript. A non-systematic review of the medical literature was performed. Information about their safety and efficacy as antimalarials, antivirals, as well as in the long-term treatment of rheumatic diseases was collected. We found an anti-inflammatory effect with reduction of long-term cardiovascular events, a very infrequent heart disease due to a lysosomal effect of the drug, and at the hemodynamic level hypotension, tachycardia, and QT interval prolongation, exacerbated when combined with azithromycin. However, the rate of adverse cardiac events of hydroxychloroquine (and chloroquine) was low.

[Hydroxychloroquine. Cardiology's viewpoint in times of coronavirus pandemic]. / Hidroxicloroquina. Mensajes desde la cardiología en tiempos de pandemia por coronavirus.

Due to the coronavirus disease 2019 (COVID-19) pandemic, a wide number of compounds are under scrutiny regarding their antiviral activity, one of them being hydroxychloroquine. Cardiac aspects of the use of chloroquine and hydroxychloroquine are reviewed in this manuscript. A non-systematic review of the medical literature was performed. Information about their safety and efficacy as antimalarials, antivirals, as well as in the long-term treatment of rheumatic diseases was collected. We found an anti-inflammatory effect with reduction of longterm cardiovascular events, a very infrequent heart disease due to a lysosomal effect of the drug, and at the hemodynamic level hypotension, tachycardia, and QT interval prolongation, exacerbated when combined with azithromycin. However, the rate of adverse cardiac events of hydroxychloroquine (and chloroquine) was low.

Ante la pandemia de COVID-19 (del inglés coronavirus disease 2019), uno de los fármacos propuesto para su tratamiento es la hidroxicloroquina. Se revisan aquí aspectos cardiológicos del uso de cloroquina e hidroxicloroquina. Se realizó una revisión no sistemática en la literatura médica orientada a la búsqueda de información acerca de su seguridad y eficacia como antimaláricos y antivirales, así como en el tratamiento prolongado de enfermedades reumatológicas. Se halló un efecto antiinflamatorio con reducción de eventos cardiovasculares a largo plazo, una cardiopatía muy infrecuente por un efecto lisosomal del fármaco, y a nivel hemodinámico hipotensión, taquicardia, y prolongación del intervalo QT, exacerbado si se combina con azitromicina. Sin embargo, la tasa de eventos adversos cardíacos de la hidroxicloroquina y la cloroquina fue baja.

Variable impact of three different antiangiogenic drugs alone or in combination with chemotherapy on multiple bone marrow-derived cell populations involved in angiogenesis and immunity.

In contrast to VEGF pathway-targeting antibodies, antiangiogenic tyrosine kinase inhibitors (TKIs) have failed to meet primary endpoints in almost all phase III clinical trials when combined with conventional chemotherapy. One exception is the combination of nintedanib and docetaxel as a second-line therapy for rapidly progressing advanced NSCLC. In addition to increased toxicity caused by this type of combination, thus necessitating drug dose reductions or treatment breaks, such phase III trial failures may also be related to the differential impact of host-mediated responses involving mobilization and tumor infiltration of bone marrow-derived cell populations (BMDCs), comprising both pro-angiogenic as well as immune effector cells. Herein, we evaluated two different antiangiogenic TKIs (sunitinib or nintedanib) and a VEGFR-2 antibody (DC101) either alone or combined with maximum tolerated dose paclitaxel for their differential impact on the BMDC host response, evaluating four different cell types. TKIs (in particular sunitinib) induced myelosuppression similar to paclitaxel, whereas DC101 had no such effect. Sunitinib also significantly decreased the number of tumor-infiltrating CD8 + T and B cells, MDSCs, and macrophages. In contrast, the effect of nintedanib on these BMDC populations was less marked, behaving closer to the VEGFR-2 antibody effects than sunitinib. The results raise the possibility that differences observed between antiangiogenic antibodies and TKIs in increasing chemotherapy efficacy could be related, at least in part, to differential effects on cells associated with local immunity within the tumor microenvironment.

Fórmula para corregir la fracción de expulsión del ventrículo izquierdo en pacientes con insuficiencia valvular mitral / Formula to Correct Left Ventricular Ejection Fraction in Patients with Mitral Valve Regurgitation

RESUMEN La fracción de expulsión del ventrículo izquierdo es una medición clave para la valoración de su función sistólica. En caso de insuficiencia valvular mitral, parte del volumen eyectado se regurgita hacia el atrio izquierdo, el volumen anterógrado es menor que el supuesto y la fracción de expulsión se mantiene en un valor que no representa adecuadamente el estado inotrópico. Esto no permite que ciertos pacientes con falla cardíaca puedan ser correctamente clasificados y tratados, en especial en cuanto se refiere a la indicación de dispositivos (terapia de resincronización, implante de desfibriladores). Tomando como base el cálculo de la fracción regurgitante se propone una sencilla fórmula para hacer una "corrección" de la fracción de expulsión en este tipo de casos y se puso a prueba en un grupo de pacientes ambulatorios citados consecutivamente. Se confirma que en un 54% de pacientes se ven modificados su pronóstico, su tratamiento o ambos al aplicarse la fórmula propuesta.

ABSTRACT Left ventricular ejection fraction is a key measurement for the assessment of systolic function. In case of mitral valve insufficiency, part of the ejected volume regurgitates to the left atrium, the anterograde volume is less than expected, and the ejection fraction maintains a value that does not adequately represent the inotropic state. This does not allow certain patients with heart failure to be correctly classified and treated, especially regarding the indication of devices (resynchronization therapy and defibrillator implant). Based on the calculation of the regurgitant fraction, we propose a simple formula to make a "correction" of the ejection fraction in this type of cases. The corrected ejection fraction was tested in a group of consecutive outpatients. The study confirmed that 54% of patients have their prognosis and/or treatment modified when applying the proposed formula.

Therapeutic impact of Nintedanib with paclitaxel and/or a PD-L1 antibody in preclinical models of orthotopic primary or metastatic triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis, in part because of the current lack of any approved molecularly targeted therapy. We evaluated various combinations of three different drugs: nintedanib, an antiangiogenic TKI targeting VEGF receptors, paclitaxel (PTX), or a PD-L1 antibody, using models of orthotopic primary or advanced metastatic TNBC involving a metastatic variant of the MDA-MB-231 human cell line (called LM2-4) in SCID mice and two mouse lines (EMT-6 and a drug-resistant variant, EMT-6/CDDP) in immunocompetent mice. These drugs were selected based on the following: PTX is approved for TNBC; nintedanib combined with docetaxel has shown phase III clinical trial success, albeit in NSCLC; VEGF can act as local immunosuppressive factor; and PD-L1 antibody plus taxane therapy was recently reported to have encouraging phase III trial benefit in TNBC. METHODS: Statistical analyses were performed with ANOVA followed by Tukey's Multiple Comparison Test or with Kruskal-Wallis test followed by Dunn's Multiple Comparison Test. Survival curves were analyzed using a Log-rank (Mantel Cox) test. Differences were considered statistically significant when p values were < 0.05. RESULTS: Toxicity analyses showed that nintedanib is well tolerated when administered 5-days ON 2-days OFF; PTX toxicity differed in mice, varied with cell lines used and may have influenced median survival in the metastatic EMT6/CDDP model; while toxicity of PD-L1 therapy depended on the cell lines and treatment settings tested. In the LM2-4 system, combining nintedanib with PTX enhanced overall antitumor efficacy in both primary and metastatic treatment settings. In immunocompetent mice, combining nintedanib or PTX with the PD-L1 antibody improved overall antitumor efficacy. Using the advanced metastatic EMT-6/CDDP model, optimal efficacy results were obtained using the triple combination. CONCLUSIONS: These results suggest circumstances where nintedanib plus PTX may be potentially effective in treating TNBC, and nintedanib with PTX may improve PD-L1 therapy of metastatic TNBC.

Terapia de resincronización cardíaca: un paciente con extrema disfunción ventricular y múltiples comorbilidades / Cardiac resynchronization therapy: a patient with extreme ventricular dysfunction and multiple comorbidities

Resumen Se presenta el caso de un varón de 56 años con cardiomiopatía no compactada y muy severa disfunción ventricular, con trastorno de conducción intraventricular y QRS ancho. Adolecía de comorbilidades incluyendo nefropatía diabética termi nal (en diálisis) y nunca pudo recibir terapia médica óptima por hipotensión e hiperkalemia. Con indicación IIa para terapia de resincronización cardíaca se le implantó resincronizador con desfibrilador, con respuesta aguda clínica y ecocardiográ fica excelente. Falleció a los tres meses del implante por asistolia que no pudo ser rescatada por el dispositivo. Es nuestra opinión que la presencia de comorbilidades graves y la imposibilidad de dar terapia médica óptima son una limitante para el éxito a mediano y largo plazo de la terapia de resincronización.

Abstract We present the case of a 56-year-old man with non-compaction cardiomyopathy and very severe ventricular dysfunction, with intraventricular conduction disorder and wide QRS. He suffered from comorbidities including terminal diabetic nephropathy (on dialysis) and was never able to receive optimal medical therapy for hypotension and hyperkalemia. With indication IIa for cardiac resynchronization therapy, a resynchronizer with a defibrillator was implanted, with an acute clinical and excellent echocardiographic response. He died three months after the implant due to asystole that could not be rescued by the device. It is our opinion that the presence of severe comorbidities and the impossibility of giving optimal medical therapy are a limitation for the medium and long-term success of the resynchronization therapy.

Preclinical impact of high dose intermittent antiangiogenic tyrosine kinase inhibitor pazopanib in intrinsically resistant tumor models.

Antiangiogenic tyrosine kinase inhibitors (TKIs) target vascular endothelial growth factor receptors and other receptor tyrosine kinases. As a result of toxicity, the clinical failures or the modest benefits associated with antiangiogenic TKI therapy may be related in some cases to suboptimal drug dosing and scheduling, thereby facilitating resistance. Most antiangiogenic TKIs, including pazopanib, are administered on a continuous daily basis. Here, instead, we evaluated the impact of increasing the dose and administering the drug intermittently. The rationale is that using such protocols, antitumor efficacy could be enhanced by direct tumor cell targeting effects in addition to inhibiting tumor angiogenesis. To test this, we employed two human tumor xenograft models, both of which manifest intrinsic resistance to pazopanib when it is administered continuously: the VHL-wildtype SN12-PM6-1 renal cell carcinoma (RCC) and the metastatic MDA-MB-231/LM2-4 variant breast cancer cell line, when treated as distant metastases. We evaluated four different doses and schedules of pazopanib in the context of primary tumors and advanced metastatic disease, in both models. The RCC model was not converted to drug sensitivity using the intermittent protocol. Using these protocols did not enhance the efficacy when treating primary LM2-4 tumors. However, one of the high-dose intermittent pazopanib protocols increased median survival when treating advanced metastatic disease. In conclusion, these results overall suggest that primary tumors showing sensitivity to continuous pazopanib treatment may predict response to this drug when given at high doses intermittently in the context of advanced metastatic disease, that are otherwise resistant to the conventional protocol.

Chronic total occlusion of an infarct-related artery: a new predictor of ventricular arrhythmias in primary prevention implantable cardioverter defibrillator patients.

Aims: The aim of this article is to evaluate the impact of a coronary chronic total occlusion in an infarct-related artery (IRA-CTO) on the occurrence of ventricular arrhythmias (VAs) in patients implanted with an implantable cardioverter defibrillator (ICD) for primary prevention. Methods and Results: The study includes a prospective cohort of 108 consecutive patients with ischaemic cardiomyopathy, in whom an ICD was implanted for primary prevention and a coronary angiography performed before ICD implantation. About 49 patients (45%) had a CTO and 34 (31%) had an IRA-CTO. Patients with IRA-CTO did not differ from the rest of the population in terms of basal characteristics and severity of cardiac disease. Median follow-up was 33 months (interquartile range 46). Infarct-related artery-CTO was associated with higher rates of any VA (53 vs. 26%, P = 0.006) and fast ventricular tachycardia (fast VT, cycle length <300 ms) or ventricular fibrillation (VF) (47 vs. 19%, P = 0.002). At multivariate Cox regression, IRA-CTO was the only independent predictor of any VA [hazard ratio (HR) 3.64, P = 0.002] and fast VT/VF (HR 3.36, P = 0.008). On the contrary, CTO not associated with a prior infarction in their territory did not increase the risk of VA. Infract-related artery-CTO was also an independent predictor of cardiac mortality or heart transplantation (HR 3.46, P = 0.022). Conclusion: In ischaemic patients implanted with an ICD for primary prevention, a CTO associated with a previous infarction in its territory is an independent predictor of VA and, especially, of fast VT/VF, identifying a subgroup of patients with a very high rate of arrhythmic events at follow-up.