Early approach to LDL-related risk after acute coronary syndrome: the OPTA project.

INTRODUCTION: Hyperlipidemia is the main underlying cause of atherosclerotic cardiovascular disease. Reducing low-density lipoprotein (LDL) cholesterol to recommended targets after an acute coronary syndrome (ACS) is of utmost importance as it is associated with a reduction of mortality and further cardiovascular events. Unfortunately, there are considerable gaps between guideline recommendations and clinical practice. In addition, the approach to treatment of this population is very heterogeneous, even in specialized cardiovascular units. Some easy-to-implement strategies may help to optimize the management of these patients. AREAS COVERED: The OPTA Project was developed to identify these gaps and to provide recommendations to improve and harmonize the management of patients with ACS, with a specific focus on lipids. EXPERT OPINION: Five areas of interest were defined: 1) evaluation of cardiovascular risk at admission, 2) development of a strategy to effectively and rapidly reduce LDL cholesterol levels, 3) determining LDL cholesterol goals (<55 mg/dL or stricter) and follow-up, 4) data collection during hospitalization, and 5) standardized discharge report. Specific recommendations are given to reduce inequalities, following the targets 'the lower, the better' and 'the earlier, the better.'

Optimal surgical timing after post-infarction ventricular septal rupture.

BACKGROUND: Ventricular septal rupture (VSR) following acute myocardial infarction (AMI) is a dangerous condition. Surgical VSR closure is the definitive therapy, but there is controversy regarding the surgical timing and the bridging therapy between diagnosis and intervention. The objective of this study is to analyze the ideal time of surgical repair and to establish the contribution of mechanical circulatory support (MCS) devices on the prognosis. METHODS: We designed an observational, retrospective, multicenter study, selecting all consecutive patients with post-AMI VSR between January 1, 2008 and December 31, 2018, with non-exclusion criteria. The main objective of this study was to analyze the optimal timing for surgical repair of post-AMI VSR. Secondary endpoints were to determine which factors could influence mortality in the patients of the surgical group. RESULTS: A total of 141 patients were included. We identified lower mortality rates with an odds ratio of 0.3 (0.1-0.9) in patients operated on from day 4 compared with the surgical mortality in the first 24 hours after VSR diagnosis. The use of MCS was more frequent in patients treated with surgery, particularly for intra-aortic balloon pump (IABP; 79.6% vs. 37.8%, p < 0.001), but also for veno-arterial extracorporeal membrane oxygenation (VA-ECMO; 18.2% vs. 6.4%, p = 0.134). Total mortality was 91.5% for conservative management and 52.3% with surgical repair (p < 0.001). CONCLUSIONS: In our study, we observed that the lowest mortality rates in patients with surgical repair of post-AMI VSR were observed in patients operated on from day 4 after diagnosis of VSR, compared to earlier interventions.

#CienciaenelParlamento: la necesidad de una oficina parlamentaria de asesoramiento científico y tecnológico / #CienciaenelParlamento: the need for a parliamentary office of science and technology advice

Uno de los objetivos de la iniciativa ciudadana #CienciaenelParlamento es contribuir al establecimiento de una oficina parlamentaria de asesoramiento científico y tecnológico en las Cortes Generales. Dicha oficina estaría encargada de favorecer espacios de confluencia entre el conocimiento científico y las políticas públicas, y fomentar el debate entre políticos, expertos y la sociedad en general. En este artículo se revisan los principales mecanismos parlamentarios de asesoramiento científico, con especial atención a uno de ellos: las oficinas parlamentarias de asesoramiento científico y tecnológico. Estas oficinas existen en 22 parlamentos en todo el mundo, pero en España no. En segundo lugar, se describe la acción realizada por #CienciaenelParlamento en su colaboración con el Congreso de los Diputados durante la XII Legislatura, que culminó con unas jornadas en noviembre de 2018 en las que más de 200 científicos y casi 100 diputados debatieron sobre 12 temas de actualidad con el conocimiento científico más actualizado. Gracias a esta colaboración, el Congreso ha dado los primeros pasos para el establecimiento oficial de una oficina de asesoramiento científico. Por último, se exponen algunos ejemplos de cómo la acción de estas oficinas parlamentarias de asesoramiento científico y tecnológico en otros países se imbrica con la de otros agentes para un mayor debate público y la tramitación de mejores políticas públicas en temas de salud y otras áreas. Como conclusión, desde #CienciaenelParlamento creemos que una oficina asesora ayudaría a enriquecer el ecosistema ciencia-política en España. (AU)

One of the aims of the citizen's initiative #CienciaenelParlamento is helping to establishing a parliamentary office of scientific and technological advice in the Spanish parliament. Said office would be in charge of fostering networking spaces between scientific knowledge and public policies and of triggering public debate between policy-makers, experts and the general public. In this article, we first review the main parliamentary mechanisms of scientific advice, with special attention to one in particular: parliamentary offices of scientific and technological advice. These offices exist in 22 parliaments worldwide, but there are none in Spain. Second, we describe the activity undertaken by #CienciaenelParlamento in its collaboration with the Congress of Deputies during the 12th Spanish Legislature. This collaboration reached its peak with a two-day networking event in November 2018 with over 200 scientists and almost 100 deputies, who all debated twelve topics of social interest and the most up-to-date scientific knowledge. Thanks to this collaboration, the Congress has taken the first steps towards officially establishing a parliamentary science advice office. Lastly, we enumerate some examples about how these parliamentary offices in other countries have contributed with other stakeholders to better public debate and processing of public policies in public health and other areas. To conclude, we at #CienciaenelParlamento believe that a parliamentary science advice office would help to enhance the science-policy ecosystem in Spain. (AU)

Reproductive history determines Erbb2 locus amplification, WNT signalling and tumour phenotype in a murine breast cancer model.

Understanding the mechanisms underlying tumour heterogeneity is key to the development of treatments that can target specific tumour subtypes. We have previously targeted CRE recombinase-dependent conditional deletion of the tumour suppressor genes Brca1, Brca2, p53 (also known as Trp53) and/or Pten to basal or luminal oestrogen receptor-negative (ER-) cells of the mouse mammary epithelium. We demonstrated that both the cell-of-origin and the tumour-initiating genetic lesions cooperate to influence mammary tumour phenotype. Here, we use a CRE-activated HER2 orthologue to specifically target HER2/ERBB2 oncogenic activity to basal or luminal ER- mammary epithelial cells and perform a detailed analysis of the tumours that develop. We find that, in contrast to our previous studies, basal epithelial cells are less sensitive to transformation by the activated NeuKI allele, with mammary epithelial tumour formation largely confined to luminal ER- cells. Histologically, most tumours that developed were classified as either adenocarcinomas of no special type or as metaplastic adenosquamous tumours. The former were typically characterized by amplification of the NeuNT/Erbb2 locus; in contrast, tumours displaying squamous metaplasia were enriched in animals that had been through at least one pregnancy and typically had lower levels of NeuNT/Erbb2 locus amplification but had activated canonical WNT signalling. Squamous changes in these tumours were associated with activation of the epidermal differentiation cluster. Thus, in this model of HER2 breast cancer, cell-of-origin, reproductive history, NeuNT/Erbb2 locus amplification and the activation of specific branches of the WNT signalling pathway all interact to drive inter-tumour heterogeneity.

Initial outcomes of a multidisciplinary network for the care of patients with cardiogenic shock.

INTRODUCTION AND OBJECTIVES: Mortality remains high in cardiogenic shock (CS), especially in refractory CS involving the use of mechanical circulatory support (MCS) devices. The aim of this study was to analyze the results of a care program for patients in CS after the creation of a multidisciplinary team in our center and a regional network of hospitals in our area. METHODS: Observational and retrospective study of patients attended in this program from September 2014 to January 2019. We included patients in refractory CS who required MCS and those who, because of their age and absence of comorbidities, were candidates for advanced therapies. The primary endpoint was survival to discharge. RESULTS: A total of 130 patients were included (69 local and 61 transferred patients). The mean age was 52±15 years (72% men). The most frequent causes of CS were acute decompensated heart failure (29%), acute myocardial infarction (26%), and postcardiotomy CS (25%). MCS was used in 105 patients (81%), mostly extracorporeal membrane oxygenation (58%). Survival to discharge was 57% (74 of 130 patients). The most frequent destinations were myocardial recovery and heart transplant. Independent predictors of in-hospital mortality were SAPS II score, lactate level, acute myocardial infarction etiology, and vasoactive-inotropic score. CONCLUSIONS: The creation of multidisciplinary teams for patients with mainly refractory CS and a regional network is feasible and allows survival to discharge in more than a half of attended patients with CS.

[#CienciaenelParlamento: the need for a parliamentary office of science and technology advice]. / #CienciaenelParlamento: la necesidad de una oficina parlamentaria de asesoramiento científico y tecnológico.

One of the aims of the citizen's initiative #CienciaenelParlamento is helping to establishing a parliamentary office of scientific and technological advice in the Spanish parliament. Said office would be in charge of fostering networking spaces between scientific knowledge and public policies and of triggering public debate between policy-makers, experts and the general public. In this article, we first review the main parliamentary mechanisms of scientific advice, with special attention to one in particular: parliamentary offices of scientific and technological advice. These offices exist in 22 parliaments worldwide, but there are none in Spain. Second, we describe the activity undertaken by #CienciaenelParlamento in its collaboration with the Congress of Deputies during the 12th Spanish Legislature. This collaboration reached its peak with a two-day networking event in November 2018 with over 200 scientists and almost 100 deputies, who all debated twelve topics of social interest and the most up-to-date scientific knowledge. Thanks to this collaboration, the Congress has taken the first steps towards officially establishing a parliamentary science advice office. Lastly, we enumerate some examples about how these parliamentary offices in other countries have contributed with other stakeholders to better public debate and processing of public policies in public health and other areas. To conclude, we at #CienciaenelParlamento believe that a parliamentary science advice office would help to enhance the science-policy ecosystem in Spain.

Temporal trends in postinfarction ventricular septal rupture: the CIVIAM Registry.

INTRODUCTION AND OBJECTIVES: Postinfarction ventricular septal rupture is a rare but severe complication of myocardial infarction with high mortality rates. Our goal was to analyze which factors could have an impact on mortality due to this entity over the past decade, including those related to mechanical circulatory support. METHODS: The CIVIAM registry is an observational, retrospective, multicenter study carried out in Spain. We designed a comparative analysis, focused on description of in-hospital management and in-hospital and 1-year total mortality as the primary endpoints, dividing the total observation time into 2 equal temporal periods (January 2008 to June2013 and July 2013 to December 2018). RESULTS: We included 120 consecutive patients. Total mortality during this period was 61.7% at 1-year follow-up. Patients in the second period were younger. One-year mortality was significantly reduced in the second period (75.6% vs 52.7%, P=.01), and this result was confirmed after adjustment by confounding factors (OR, 0.40; 95%CI, 0.17-0.98). Surgical repair was attempted in 58.7% vs 70.3%, (P=.194), and percutaneous closure in 8.7% and 6.8%, respectively (P=.476). Heart transplant was performed in 1 vs 5 patients (2.2% vs 6.8%, P=.405). The main difference in the clinical management between the 2 periods was the greater use of venoarterial extracorporeal membrane oxygenatiom in the second half of the study period (4.4% vs 27%; P=.001). CONCLUSIONS: Postinfarction ventricular septal rupture still carries a very high mortality risk. There has been a progressive trend to increased support with venoarterial extracorporeal membrane oxygenatiom and greater access to available corrective treatments, with higher survival rates.

The Role of Anxiety in Patients With Persistent Atrial Fibrillation Undergoing Elective Cardioversion: An Observational Study.

OBJECTIVE: Anxiety is often present among patients with atrial fibrillation (AF). This condition has been associated with greater symptom severity and worse quality of life in these patients. However, the influence of anxiety on the risk of AF recurrence is not well known. We aimed to define the level of anxiety in patients with persistent AF undergoing elective cardioversion (EC) and determine whether there is an association between anxiety and the risk of early AF recurrence after EC. METHODS: Anxiety was measured before EC using the State-Trait Anxiety Inventory. Early AF recurrence was assessed with a control electrocardiogram at 30-day follow-up. RESULTS: We included 107 patients undergoing effective EC. Early AF recurrence was diagnosed in 40 patients (37.4%). Compared with those who remained in sinus rhythm, individuals with early AF recurrence had significantly higher levels of trait anxiety (23.1 [10.4] versus 17.9 [9.5]; p = .013) and larger left atrial volume index (45.8 [12.3] versus 37.9 [13.3] ml/m; p = .004). Both variables remained independently associated with early AF recurrence after multivariate analysis. A predictive model including trait anxiety score >20 and left atrial volume index >41 ml/m showed acceptable accuracy for the diagnosis of early AF recurrence (area under the curve = 0.733; 95% confidence interval = 0.634-0.832; p < .001). CONCLUSIONS: Our study shows that trait anxiety is an independent risk factor for early AF recurrence after EC. Further studies are warranted to assess the beneficial role of anxiety-reducing strategies on the outcomes of patients with AF.

Evolución e impacto bibliométrico de las becas de la Sociedad Española de Cardiología/Fundación Española del Corazón en el periodo 2007-2012 / Trends and bibliometric impact of research grants of the Spanish Society of Cardiology/Spanish Heart Foundation (2007-2012)

Introducción y objetivos: La Sociedad Española de Cardiología/Fundación Española del Corazón (SEC/FEC) realiza convocatorias anuales de becas para proyectos de investigación cardiovascular. El objetivo es analizar la evolución de estas inversiones y la producción científica derivada en el periodo 2007-2012. Métodos: Se ha realizado una búsqueda de las publicaciones financiadas por SEC/FEC, según los siguientes criterios de inclusión: publicación en revista indexada en MEDLINE o EMBASE, fecha de publicación posterior a la de la ayuda, estar firmadas por el investigador principal de la ayuda y reconocer la financiación SEC/FEC. Se analizó el factor impacto y las citas posteriores de los artículos (Web of Science). Resultados: Se han otorgado 235 becas (39/año) con una dotación de 3.854.300 euros (642.383 euros/año), el 37% a mujeres. Hay 122 publicaciones derivadas de 88 proyectos (37%) de investigación financiados SEC/FEC. Estas publicaciones han recibido hasta octubre de 2017 un total de 2.258 citas en estudios posteriores en la Web of Science, con una media de 18,5 y una mediana de 8 citas/estudio. Conclusiones: Las becas concedidas por la SEC/FEC han crecido en número y cuantía media en el periodo analizado, a pesar de la crisis económica. Las mujeres acceden a ellas en igualdad de condiciones que los varones. El impacto bibliométrico de los proyectos financiados es aceptable, aunque deben hacerse esfuerzos para mejorarlo

Introduction and objectives: The Spanish Society of Cardiology/Spanish Heart Foundation (SEC/FEC) annually awards grants for cardiovascular research projects. Our objective was to analyze the trend in these investments and their resulting scientific production from 2007 to 2012. Methods: A search of the publications funded by the SEC/FEC was carried out, according to the following inclusion criteria: publication in a journal indexed in MEDLINE or EMBASE, publication date after the grant, authorship by the principal investigator of the grant, and acknowledgment of SEC/FEC funding. The impact factor and subsequent citations of the articles were analyzed (Web of Science). Results: A total of 235 grants were awarded (39/y) with an allocation of €3 854 300 (€642 383/y), 37% of them to women. In all, 122 publications resulted from 88 research projects (37%) funded by the SEC/FEC. Up to October 2017, these publications had received 2258 citations in subsequent studies in the Web of Science, with a mean of 18.5 and a median of 8 citations/study. Conclusions: Despite the economic crisis, the mean number and size of the grants awarded by the SEC/FEC increased in the period analyzed. Grants were awarded on an equal opportunity basis to men and women. The bibliometric impact of the funded projects is acceptable, although efforts should be made to improve it

El Cardiólogo y la Cardiología del Futuro: visión y propuestas de la Sociedad Española de Cardiología para la cardiología del siglo XXI / Cardiologists and the cardiology of the future. Vision and proposals of the Spanish Society of Cardiology for the cardiology of the 21st Century

«La Cardiología del Futuro» es un proyecto de la Sociedad Española de Cardiología (SEC) que tiene como objetivos definir hacia dónde, desde la posición actual, deben dirigirse las políticas de acción de la SEC, analizar las tendencias y los cambios del entorno que influirán en la práctica de la cardiología en España, definir el perfil de los cardiólogos necesarios en el futuro, proponer las políticas para alcanzar los objetivos que se deriven de las necesidades identificadas, y establecer el papel que ha de desempeñar la SEC en el desarrollo y la implantación de esas políticas. En este artículo se presentan la metodología y los hallazgos más relevantes del informe final de este proyecto y las líneas estratégicas de actuación de la SEC en el futuro inmediato, derivadas del análisis realizado

The Cardiology of the Future is a project of the Spanish Society of Cardiology (SEC) whose objectives are as follows: to define the action policies of the SEC; to analyze the trends and changes in the environment that will influence the practice of cardiology in Spain; to define the profile of the cardiologists needed in the future; to propose policies to achieve the objectives resulting from the identified needs; and to identify the role of the SEC in the development and implementation of these policies. This article describes the methodology and the most relevant findings of the final report of this project and the strategic lines to be developed by the SEC in the immediate future, resulting from the analysis performed

Cardiologists and the Cardiology of the Future. Vision and proposals of the Spanish Society of Cardiology for the Cardiology of the 21st Century.

The Cardiology of the Future is a project of the Spanish Society of Cardiology (SEC) whose objectives are as follows: to define the action policies of the SEC; to analyze the trends and changes in the environment that will influence the practice of cardiology in Spain; to define the profile of the cardiologists needed in the future; to propose policies to achieve the objectives resulting from the identified needs; and to identify the role of the SEC in the development and implementation of these policies. This article describes the methodology and the most relevant findings of the final report of this project and the strategic lines to be developed by the SEC in the immediate future, resulting from the analysis performed.

Trends and Bibliometric Impact of Research Grants of the Spanish Society of Cardiology/Spanish Heart Foundation (2007-2012).

INTRODUCTION AND OBJECTIVES: The Spanish Society of Cardiology/Spanish Heart Foundation (SEC/FEC) annually awards grants for cardiovascular research projects. Our objective was to analyze the trend in these investments and their resulting scientific production from 2007 to 2012. METHODS: A search of the publications funded by the SEC/FEC was carried out, according to the following inclusion criteria: publication in a journal indexed in MEDLINE or EMBASE, publication date after the grant, authorship by the principal investigator of the grant, and acknowledgment of SEC/FEC funding. The impact factor and subsequent citations of the articles were analyzed (Web of Science). RESULTS: A total of 235 grants were awarded (39/y) with an allocation of €3 854 300 (€642 383/y), 37% of them to women. In all, 122 publications resulted from 88 research projects (37%) funded by the SEC/FEC. Up to October 2017, these publications had received 2258 citations in subsequent studies in the Web of Science, with a mean of 18.5 and a median of 8 citations/study. CONCLUSIONS: Despite the economic crisis, the mean number and size of the grants awarded by the SEC/FEC increased in the period analyzed. Grants were awarded on an equal opportunity basis to men and women. The bibliometric impact of the funded projects is acceptable, although efforts should be made to improve it.

Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients.

The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include maximizing response and the use of maintenance therapy. We used whole exome sequencing to study the genetics of paired samples taken at presentation and at relapse from 56 newly diagnosed patients, following induction therapy, randomized to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomization. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterized by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumor suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response, the evolutionary features were predominantly stable with a similar mutational and structural profile seen at both time points. There were no significant differences between patients relapsing after lenalidomide maintenance versus observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse. This trial is registered at clinicaltrials.gov identifier: 01554852.

Cumulative advantages and social capabilities in scientific mobility in the Health Sciences: The Spanish case.

BACKGROUND: The big problem in global public health, arising from the international migration of physicians from less-developed to more-developed countries, increases if this migration also affects scientists dedicated to health areas. This article analyzes critical variables in the processes of Spanish scientific mobility in Health Sciences to articulate effective management policies for the benefit of national public health services and the balance between local and global science. METHODS: This study develops a survey to measure and analyze the following crucial variables: research career, training, funding, working with a world-class team, institutional prestige, wages, facilities/infrastructure, working conditions in the organization of the destination country, fringe benefits in the organization of the destination country and social responsibility in the organization of the departure country. A total of 811 researchers have participated in the survey, of which 293 were from the health sector: Spanish scientists abroad (114), scientists that have returned to Spain (32) and young researchers in Spain (147). RESULTS: The most crucial variables for Spanish scientists and young researchers in Spain in Health Sciences moving abroad are the cumulative advantages (research career, training, funding and institutional prestige) plus wages. On the other hand, the return of Spanish scientists in the Health Sciences is influenced by cumulative variables (working with a world-class team, research career and institutional prestige) and also by other variables related to social factors, such as working conditions and fringe benefits in the destination country. Permanent positions are rare for these groups and their decisions regarding mobility depend to a large extent on job opportunities. CONCLUSIONS: Spanish health organizations can influence researchers to return, since these decisions mainly depend on job opportunities. These organizations can complement the cumulative advantages offered by the wealthier countries with the intensification of social factors.

Impacto de la circulación colateral en el pronóstico a largo plazo de los pacientes tratados con angioplastia primaria / Impact of coronary collaterals on long-term prognosis in patients treated with primary angioplasty

Introducción y objetivos: El efecto beneficioso de la circulación colateral (CC) coronaria en pacientes con infarto agudo de miocardio con elevación del segmento ST es controvertido. Se investigó su impacto antes de la reperfusión con angioplastia primaria (AP) en el pronóstico a largo plazo de estos pacientes. Métodos: Estudio observacional retrospectivo de una cohorte de 947 pacientes tratados con AP y flujo de grado TIMI ≤ 1 en un centro entre 2005 y 2013. Tras emparejar por puntuación de propensión, se obtuvieron 2 grupos de 175 pacientes emparejados por el grado de CC (Rentrop 0-1 frente a 2-3). En la cohorte emparejada se determinó el impacto de la CC en la mortalidad total, la mortalidad cardiovascular y un combinado de eventos cardiovasculares tras una mediana de seguimiento de 864 [intervalo intercuartílico, 396-1.271] días. Resultados: Del total de 947 pacientes incluidos, 735 (78%) tenían Rentrop 0-1 y 212 (22%), Rentrop 2-3. Durante el seguimiento, 105 fallecieron, 71 de causa cardiovascular. En la cohorte emparejada, la tasa de mortalidad total fue similar entre los grupos (Rentrop 0-1 [8,8%] frente a Rentrop 2-3 [6,3%]; HR = 1,22; IC95%, 0,50-2,94; p = 0,654). Tampoco hubo diferencias en la mortalidad cardiovascular (Rentrop 0-1, [4,6%] frente a Rentrop 2-3 [2,3%]; sub-HR = 0,49; IC95%, 0,14-1,62; p = 0,244) ni en el combinado de eventos muerte cardiovascular, reinfarto, revascularización del vaso diana y cirugía de revascularización coronaria (Rentrop 0-1 [18,8%] frente a Rentrop 2-3 [13,1%]; sub-HR = 0,68; IC95%, 0,40-1,15; p = 0,157). Conclusiones: En esta serie contemporánea, la presencia de buena CC antes de la AP no se asoció a mejor pronóstico de los pacientes en cuanto a eventos clínicos a largo plaz (AU)

Introduction and objectives: The beneficial effect of coronary collateral circulation (CC) in patients with ST-segment elevation myocardial infarction is controversial. The aim of this study was to evaluate the impact of CC before reperfusion with primary angioplasty (PA) on the long-term prognosis of these patients. Methods: Retrospective observational study of a cohort of 947 patients treated with PA and TIMI grade ≤ 1 flow in a single center from 2005 to 2013. Propensity score matching was used to create 2 groups of 175 patients each, matched by the degree of CC (Rentrop 0-1 vs Rentrop 2-3). In the matched cohort, we determined the impact of CC on total mortality, cardiovascular mortality, and a combined adverse cardiovascular event endpoint for a median follow-up of 864 (interquartile range, 396-1271) days. Results: Of a total of 947 patients included, 735 (78%) had Rentrop 0 to 1 and 212 (22%) had Rentrop 2 to 3. During follow-up, 105 patients died, 71 from cardiovascular causes. In the matched cohort, the total mortality rate was similar between the 2 groups (Rentrop 0-1 [8.8%] vs Rentrop 2-3 [6.3%]; HR = 1.22; 95%CI, 0.50-2.94; P = .654). There were no differences in cardiovascular mortality (Rentrop 0-1 [4.6%] vs Rentrop 2-3 [2.3%]; sHR = 0.49; 95%CI, 0.14-1.62; P = .244) or the composite endpoint including cardiovascular death, reinfarction, target vessel revascularization, and coronary artery bypass surgery (Rentrop 0-1 [18.8%] vs Rentrop 2-3 [13.1%]; sHR = 0.68; 95%CI, 0.40-1.15; P = .157). Conclusions: In this contemporary series, the presence of good CC before PA was not associated with better long-term clinical outcomes (AU)

Impact of Coronary Collaterals on Long-term Prognosis in Patients Treated With Primary Angioplasty.

INTRODUCTION AND OBJECTIVES: The beneficial effect of coronary collateral circulation (CC) in patients with ST-segment elevation myocardial infarction is controversial. The aim of this study was to evaluate the impact of CC before reperfusion with primary angioplasty (PA) on the long-term prognosis of these patients. METHODS: Retrospective observational study of a cohort of 947 patients treated with PA and TIMI grade ≤ 1 flow in a single center from 2005 to 2013. Propensity score matching was used to create 2 groups of 175 patients each, matched by the degree of CC (Rentrop 0-1 vs Rentrop 2-3). In the matched cohort, we determined the impact of CC on total mortality, cardiovascular mortality, and a combined adverse cardiovascular event endpoint for a median follow-up of 864 (interquartile range, 396-1271) days. RESULTS: Of a total of 947 patients included, 735 (78%) had Rentrop 0 to 1 and 212 (22%) had Rentrop 2 to 3. During follow-up, 105 patients died, 71 from cardiovascular causes. In the matched cohort, the total mortality rate was similar between the 2 groups (Rentrop 0-1 [8.8%] vs Rentrop 2-3 [6.3%]; HR = 1.22; 95%CI, 0.50-2.94; P = .654). There were no differences in cardiovascular mortality (Rentrop 0-1 [4.6%] vs Rentrop 2-3 [2.3%]; sHR = 0.49; 95%CI, 0.14-1.62; P = .244) or the composite endpoint including cardiovascular death, reinfarction, target vessel revascularization, and coronary artery bypass surgery (Rentrop 0-1 [18.8%] vs Rentrop 2-3 [13.1%]; sHR = 0.68; 95%CI, 0.40-1.15; P = .157). CONCLUSIONS: In this contemporary series, the presence of good CC before PA was not associated with better long-term clinical outcomes.

Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids.

The development of in vitro culture systems quantitatively and qualitatively recapitulating normal breast biology is key to the understanding of mammary gland biology. Current three-dimensional mammary culture systems have not demonstrated concurrent proliferation and functional differentiation ex vivo in any system for longer than 2 weeks. Here, we identify conditions including Neuregulin1 and R-spondin 1, allowing maintenance and expansion of mammary organoids for 2.5 months in culture. The organoids comprise distinct basal and luminal compartments complete with functional steroid receptors and stem/progenitor cells able to reconstitute a complete mammary gland in vivo. Alternative conditions are also described that promote enrichment of basal cells organized into multiple layers surrounding a keratinous core, reminiscent of structures observed in MMTV-Wnt1 tumours. These conditions comprise a unique tool that should further understanding of normal mammary gland development, the molecular mechanism of hormone action and signalling events whose deregulation leads to breast tumourigenesis.

The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma.

PURPOSE: Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison. EXPERIMENTAL DESIGN: Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease. RESULTS: In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers. CONCLUSIONS: Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 22(23); 5783-94. ©2016 AACR.

Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma.

PURPOSE: At the molecular level, myeloma is characterized by copy number abnormalities and recurrent translocations into the immunoglobulin heavy chain locus. Novel methods, such as massively parallel sequencing, have begun to describe the pattern of tumor-acquired mutations, but their clinical relevance has yet to be established. METHODS: We performed whole-exome sequencing for 463 patients who presented with myeloma and were enrolled onto the National Cancer Research Institute Myeloma XI trial, for whom complete molecular cytogenetic and clinical outcome data were available. RESULTS: We identified 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3. The mutational spectrum is dominated by mutations in the RAS (43%) and nuclear factor-κB (17%) pathways, but although they are prognostically neutral, they could be targeted therapeutically. Mutations in CCND1 and DNA repair pathway alterations (TP53, ATM, ATR, and ZNFHX4 mutations) are associated with a negative impact on survival. In contrast, those in IRF4 and EGR1 are associated with a favorable overall survival. We combined these novel mutation risk factors with the recurrent molecular adverse features and international staging system to generate an international staging system mutation score that can identify a high-risk population of patients who experience relapse and die prematurely. CONCLUSION: We have refined our understanding of genetic events in myeloma and identified clinically relevant mutations that may be used to better stratify patients at presentation.