Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

¿Prótesis aórticas biológicas o mecánicas? Un análisis de supervivencia a largo plazo en pacientes de 50 a 69 años

Resumen: Introducción: Actualmente existe una gran controversia sobre el uso de prótesis biológicas o mecánicas en posición aórtica para pacientes de mediana edad. Objetivos: Analizar la supervivencia a largo plazo de los pacientes entre 50 y 69 años según el tipo de prótesis implantada. Métodos y materiales: Revisión retrospectiva de pacientes con sustitución valvular aórtica convencional, con o sin revascularización miocárdica con edad entre 50 y 69 años. Análisis y comparación de supervivencia. Predictores del evento primario mediante análisis de riesgos proporcionales de Cox. Análisis con muestra ajustada mediante propensity score. Resultados: Media de seguimiento 5,3 años (±3,7). Doscientos noventa (52,5%) recibieron prótesis biológica y 262 (44,4%) una mecánica. Supervivencia a 7 años de 85 vs. 88% (p = 0,26) respectivamente. No identificamos el tipo de prótesis como factor predictor o de riesgo para el evento primario (HR1,5; 95% CI: 0,91-2,6). Supervivencia en la muestra ajustada: 86 vs. 90%(= 0,89) respectivamente. Conclusiones: Tanto en la cohorte total como en la ajustada, no existen diferencias significativas en la supervivencia a largo plazo según el tipo de prótesis utilizada. Abstract: Introduction: There continues to be controversy on the use of biological or mechanical prosthesis for aortic valve replacement in the middle aged population. Objectives: To analyse and compare long-term survival in patients aged from 50-69 years, according to the type of valve replacement. Methods and materials: A retrospective review was conducted on of patients aged 50-69 years with aortic valve replacement, with or without adjunct coronary artery surgery. The long-term survival was analysed and compared. A proportional hazard risks model was also performed for the primary outcome. This primary outcome was then analysed in a propensity score-matched cohort. Results: The mean follow-up was 5.3 years (±3.7). A total of 290 (52.5%) patients received a bioprosthesis, and 262 (44%) a mechanical one. The 7- year survival was 85 vs. 88% (P = .26), respectively. Valve replacement type was not associated with the primary outcome (HR1,5; 95%CI: 0.91-2.6). Survival on the adjusted cohort was 86% vs. 90% (P = .89), respectively. Conclusions: In the total cohort studied, as well as in the adjusted cohort, there was no difference in long-term survival between middle aged patients with a biological or mechanical aortic valve. Palabras clave: Sustitución valvular aórtica, Prótesis biológica, Prótesis mecánica, Edad media, Keywords: Aortic valve replacement, Surgical aortic valve replacement, Mechanical prosthesis, Biologic prosthesis, Middle age

Endarterectomía coronaria y cirugía de revascularización

Resumen: Introducción: La ateromatosis coronaria difusa actualmente es un reto para el cirujano cardiaco. La endarterectomía coronaria es un procedimiento útil para el tratamiento de esta enfermedad en conjunto con la cirugía de revascularización. Actualmente existe poca evidencia del impacto de la endarterectomía coronaria en la supervivencia a largo plazo de la cirugía de revascularización miocárdica. Objetivos: Analizar y comparar supervivencia y eventos adversos cardiovasculares mayores de la endarterectomía en la cirugía coronaria a corto y largo plazo. Material y métodos: Revisión retrospectiva de los pacientes sometidos a cirugía coronaria aislada, comparando endarterecomías vs revascularización aislada. Comparación de supervivencia a largo plazo en la cohorte total y análisis de riesgos proporcionados de Cox para la supervivencia. Comparación de eventos adversos cardiovasculares en una muestra ajustada mediante propensity score. Resultados: Media de seguimiento: 5,9 años (±3,9). Ciento siete pacientes sometidos a endarterectomía y 1.936 a revascularización aislada, a 10 años. La supervivencia fue del 62% y del 70% (p = 0,044) para el grupo de endarterectomía y revascularización aislada, respectivamente. La endarterectomía fue un factor de riesgo independiente para mortalidad (HR: 1,6; IC 95%: 1,1-2,3). En la muestra ajustada observamos una mayor incidencia de eventos adversos cardiovasculares perioperatorios (23,8% vs 10,4%; p < 0,000) y a largo plazo (35% vs 54%; p = 0,015). Conclusiones: La endarterectomía se asocia a mayor incidencia de eventos adversos cardiovasculares perioperatorios, principalmente debido a infarto agudo de miocardio. A largo plazo, la endarterectomía es un factor de riesgo independiente para mortalidad. Abstract: Introduction: Diffuse coronary artery disease is a challenge for the Cardiac Surgeon. Coronary endarterectomy is a useful procedure for the management of this condition as an adjunct to coronary artery bypass grafting. Currently, there's limited evidence about long term outcomes after coronary endarterectomy as an adjunct to coronary artery revascularization. Objectives: Analyze and compare major adverse cardiovascular events in coronary endarterectomy. Material and methods: Retrospective review of patients who underwent coronary artery surgery, comparing patients with an endarterectomy and those with isolated coronary surgery. We compared long term survival in the total cohort and performed a proportional hazard risks analysis for survival. Also, we compared adverse cardiovascular events in a propensity score matched cohort. Results: Mean follow-up: 5,9 years (±3,9). 107 patients underwent endarterectomy, 1936 isolated coronary surgery. 10-year survival were 62% vs 70% (p = 0,044) respectively. Coronary endarterectomy was identified as an independent risk factor for this event (HR: 1,6; 95% CI: 1,1-2,3). On the adjusted cohort, we observed a higher incidence of perioperative (23,8% vs 10,4%; P < .000) and long term (35% vs 54%; P = .015) major adverse cardiovascular events for the endarterectomy group. Conclusions: Coronary endarterectomy is associated to a higher incidence of perioperative major adverse cardiovascular events, mainly because of a higher incidence of myocardial infarction. At long term, coronary endarterectomy was identified as an independent risk factor for mortality. Palabras clave: Endarterectomía coronaria, Revascularización sin bomba, Cirugía sin bomba, Revascularizacion miocárdica, Keywords: Coronary endarterectomy, Off-pump revascularization, Off-pump coronary artery bypass graft, Coronary revascularizatio

SYNTAX Score is associated with worse outcomes after off-pump coronary artery bypass grafting surgery for three-vessel or left main complex coronary disease

ObjectiveThe SYNergy between percutaneous intervention with TAXus drug eluting stents and cardiac surgery (SYNTAX) Score is a tool for risk stratification of patients according to the complexity of coronary lesions developed during the SYNTAX trial. We examined the influence of the SYNTAX Score on the incidence of major adverse cardiac and cerebrovascular events.MethodsAll patients with de novo left main or 3-vessel disease undergoing coronary artery bypass grafting from January 2005 to December 2008 at our institution (Hospital Clínico San Carlos, Madrid, Spain) were retrospectively assessed, and their SYNTAX Score was calculated. The influence of the SYNTAX Score on postprocedural and follow-up mortality and combined major adverse cardiac and cerebrovascular events (including death, myocardial infarction, cerebrovascular accident, and repeat revascularization) was identified by multivariate analysis. Balancing score analysis was performed to eliminate the effect of potential confounders.ResultsA total of 716 patients were enrolled. Mean SYNTAX Score was 34.5 (standard deviation, 6.7; range, 11.5–76). Three groups of patients were identified according to the score terciles: low (≤33), intermediate (33–37), and high (>37). These terciles scores differed greatly from those reported by the SYNTAX trial investigators. The multivariate analysis identified that the SYNTAX Score was associated with follow-up mortality (hazard ratio = 1.046, P = .015) and combined early and follow-up major adverse cardiac and cerebrovascular events (odds ratio = 1.079, P < .001; and hazard ratio = 1.034, P = .026, respectively). Balancing score-adjusted analyses demonstrated that the SYNTAX Score was independently associated with early and late major adverse cardiac and cerebrovascular events (odds ratio = 1.65, P < .001; and hazard ratio = 1.034, P = .027, respectively).ConclusionsSYNTAX Score was remarkably high among patients undergoing surgical off-pump myocardial revascularization at our institution. In this subset of patients, a higher SYNTAX Score was associated with a higher incidence of in-hospital and follow-up major adverse cardiac and cerebrovascular events after coronary artery bypass grafting, but not with early or late mortality

Resultados de la cirugía coronaria sin circulación extracorpórea en el contexto del infarto agudo de miocardio

Introducción y objetivos: La evidencia actual señala que existe una relación inversamente proporcional entre la mortalidad quirúrgica y el tiempo de evolución del infarto agudo de miocardio. El objetivo de este estudio es evaluar los resultados a corto y largo plazo de los pacientes sometidos a cirugía coronaria sin circulación extracorpórea en el contexto del infarto agudo de miocardio. Métodos: Se incluyó en el estudio a todos los pacientes intervenidos de cirugía coronaria sin circulación extracorpórea en el contexto del infarto agudo de miocardio en las primeras 72 h. Se analizaron los resultados a corto plazo, así como la mortalidad en el seguimiento y el evento combinado de muerte, accidente cerebrovascular, infarto agudo de miocardio y reintervención coronaria. Resultados: Se incluyó a 26 pacientes entre septiembre del 2003 y enero del 2016. La edad media fue 62,5 años (58,6-66,3) y fueron fundamentalmente varones (89%). El pico de troponina i preoperatoria medio fue 35,6 ng/ml (20,1-51,1) ng/ml. La enfermedad grave del tronco coronario izquierdo fue muy prevalente (73%). El Euroscore I logístico medio fue 24,5% (17,4-31,8) %. La mortalidad quirúrgica fue del 7,7%, con una mortalidad ajustada de 0,31. Respecto al seguimiento a largo plazo, la supervivencia acumulada a los 5 y 10 años fue del 61% (34%-80%) y el 48% (0,20%-73%), respectivamente. Conclusiones: La cirugía coronaria sin circulación extracorpórea en el contexto del infarto agudo de miocardio es un procedimiento seguro, con resultados favorables a corto plazo y aceptables a largo plazo