Lurbinectedin, a selective inhibitor of oncogenic transcription, in patients with pretreated germline BRCA1/2 metastatic breast cancer: results from a phase II basket study

Breast cancer; Lurbinectedin; Response rateCáncer de mama; Lurbinectedina; Tasa de respuestaCàncer de mama; Lurbinectedina; Taxa de respostaBackground Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer. Patients and methods This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results Confirmed partial response (PR) was observed in six patients [ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2%] who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%)]. Clinical benefit rate (PR + SD ≥ 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia). Conclusions This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted.This work was supported by PharmaMar S.A, including partial funding by grants from the Centro para el Desarrollo Tecnológico IndustrialCentro para el Desarrollo Tecnológico Industrial (CDTI) during the conduct of the study (grant number IDI-20150006). VS is supported by NIH [grant number R01CA242845]. MD Anderson Cancer Center Department of Investigational Cancer Therapeutics is supported by the Cancer Prevention and Research Institute of Texas [grant number RP1100584], the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy [grant number 1U01 CA180964], NCATS [grant number UL1 TR000371] (Center for Clinical and Translational Sciences) and the MD Anderson Cancer Center Support [grant number P30 CA016672]

Factors influencing the progression of primary angular closure following Laser peripheral iridotomy

Introducción: los efectos de la iridotomía periférica láser están demostrados, sin embargo, no siempre logra controlar la presión intraocular ni la progresión de la enfermedad por cierre angular primario.Objetivo: analizar los factores que influyen en la progresión de la enfermedad por cierre angular primario de pacientes pinareños tratados con iridotomía periférica láser.Método: se realizó un estudio analítico de cohorte retrospectivo en el servicio de Oftalmología del Hospital General Docente Abel Santamaría, de Pinar del Río, durante el año 2019. El universo estuvo constituido por pacientes con diagnóstico de enfermedad por cierre angular primario tratados con iridotomía periférica láser. La muestra final quedó integrada por 223 ojos de 123 pacientes. El análisis estadístico se realizó con el programa SPSS.Resultados: el 20,6 % de la muestra experimentó progresión de la enfermedad, lo que se relacionó de forma significativa con la forma clínica (p<0,001), la edad (p=0,012), la amplitud de la cámara anterior (p<0,001), el cierre angular residual (p<0,001), la presión intraocular (p<0,001) y la medicación hipotensora (p<0,001). No arrojó diferencias significativas el sexo (p=0,427), el color de la piel (p=0,741) y la longitud axial (p=0,549).Conclusión: los factores que influyen en la progresión de la enfermedad por cierre angular primario de los pacientes pinareños tratados con iridotomía periférica láser estudiados fueron la forma clínica, menor amplitud de la cámara anterior, presencia de cierre angular residual y presión intraocular superior a 18 mmHg con uso de mayor número de colirios hipotensores oculares.ABSTRACTIntroduction: the effects of Laser peripheral iridotomy have been demonstrated; however it does not always manage to control intraocular pressure or the progression of the disease by primary angular closure.Objective: to analyze the factors influencing the disease progression by primary angular closure in Pinar del Rio patients treated with Laser peripheral iridotomy.Methods: a retrospective analytical cohort study was carried out in the Ophthalmology Service at Abel Santamaria Cuadrado General Teaching Hospital in Pinar del Río, during 2019. The target group comprised the patients diagnosed with primary angular closure disease treated with Laser peripheral iridotomy and the final sample consisted of 223 eyes from 123 patients. The statistical analysis was performed with the SPSS program.Results: of the sample (20.6%) experienced disease progression, which was significantly related to the clinical form (p<0.001), age (p=0.012), anterior chamber amplitude (p<0.001), residual angular closure (p<0.001), intraocular pressure (p<0.001) and hypotensive medication (p<0.001). Sex (p=0.427), skin color (p=0.741) and axial length (p=0.549) did not show significant differences.Conclusions: factors influencing on the progression of the disease by primary angular closure in Pinar del Rio patients who were treated with Laser peripheral iridotomy were: the clinical form, lower anterior chamber amplitude, presence of residual angular closure and intraocular pressure higher than 18 mmHg with the use of more ocular hypotensive eye drops.

Consideraciones quirúrgicas de la facoemulsificación del cristalino en pacientes con cierre angular primario

Introducción: la cirugía del cristalino se considera uno de los métodos quirúrgicos más seguros a nivel mundial.Objetivo: describir las consideraciones quirúrgicas a tener en cuenta para lograr el éxito de la facoemulsificación del cristalino en pacientes con cierre angular primario en el Hospital General Docente “Abel Santamaría Cuadrado” de Pinar del Río.Métodos: se realizó una búsqueda de los principales artículos científicos de los últimos años, así como de la literatura impresa que incluye el tema, siendo seleccionados los contenidos más relevantes para la confección del informe final.Desarrollo: la extracción del cristalino constituye un reto quirúrgico en pacientes con cierre angular primario por las peculiaridades anatómicas, variaciones de la presión intraocular y alteraciones del segmento anterior asociadas.Conclusiones: un detallado examen preoperatorio, una adecuada técnica quirúrgica realizada por un cirujano hábil puede reducir el índice de complicaciones y lograr total éxito

¿Podemos mejorar la comunicación interna en atención primaria?

A pesar de la importancia de la comunicación interna en las organizaciones, tanto en hospitales, como en la atención primaria, se han puesto de manifiesto en diversas publicaciones serios problemas de comunicación entre los gestores y los profesionales. En la Dirección de Atención Primaria (DAP) Costa de Ponent se elaboró en 2006 un plan para mejorar la comunicación interna. El primer paso fue una encuesta a todos los profesionales y posteriormente un estudio mediante grupos focales y un análisis DAFO5. El objetivo del trabajo es conocer, mediante una encuesta a los 2 años, el efecto que el plan había tenido en la comunicación interna de la organización. El ámbito del estudio fue la DAP Costa de Ponent del Institut Català de la Salut que cuenta con 3.675 profesionales en 110 centros de salud. Se diseñó un estudio de intervención antes-después. La intervención consistió en la implementación de un plan de comunicación que comprendía elaborar un boletín electrónico, potenciar Intranet y el correo electrónico y hacer sesiones explicativas entre otras acciones

Total oxidation of VOCs on mesoporous iron oxide catalysts: soft chemistry route versus hard template method

[EN] A comparative study on the total oxidation of volatile organic compounds, VOCs, on mesoporous iron oxide catalysts prepared by soft chemistry route versus those achieved by hard template methodThe authors would like to acknowledge the DGICYT in Spain (CTQ2012-37925-C03-1, CTQ2012-37925-C03-2, CTQ2012-37925-C03-3 and CTQ2012-37984-C02-01) and FEDER for financial support. We also thank the University of Valencia and SCSIE-UV for assistance.Solsona Espriu, BE.; Garcia, T.; Sanchis Martinez, R.; Soriano Rodríguez, MD.; Moreno, M.; Rodríguez-Castellon, E.; Agouram, S.... (2016). Total oxidation of VOCs on mesoporous iron oxide catalysts: soft chemistry route versus hard template method. The Chemical Engineering Journal and the Biochemical Engineering Journal. 290:273-281. https://doi.org/10.1016/j.cej.2015.12.109S27328129

The relevance of EGFR, ErbB receptors and neuregulins in human adipocytes and adipose tissue in obesity

Objective: To investigate the potential role of EGFR, ErbBs receptors and neuregulins in human adipose tissue physiology in obesity. Methods: Gene expression analysis in human subcutaneous (SAT) and visceral (VAT) adipose tissue in three independent cohorts [two cross-sectional (N = 150, N = 87) and one longitudinal (n = 25)], and in vitro gene knockdown and overexpression experiments were performed. Results: While both SAT and VAT ERBB2 and ERBB4 mRNA increased in obesity, SAT EGFR mRNA was negatively correlated with insulin resistance, but did not change in obesity. Of note, both SAT and VAT EGFR mRNA were significantly associated with adipogenesis and increased during human adipocyte differentiation. In vitro experiments revealed that EGFR, but not ERBB2 and ERBB4, gene knockdown in preadipocytes and in fully differentiated human adipocytes resulted in decreased expression of adipogenic-related genes. ERBB2 gene knockdown also reduced gene expression of fatty acid synthase in fully differentiated adipocytes. In addition, neuregulin 2 (NRG2) mRNA was associated with expression of adipogenic genes in human adipose tissue and adipocytes, and its overexpression increased expression of EGFR and relevant adipogenic genes. Conclusions: This study demonstrates the association between adipose tissue ERBB2 and obesity, confirms the relevance of EGFR on human adipogenesis, and suggests a possible adipogenic role of NRG2

Band Depopulation of Graphene Nanoribbons Induced by Chemical Gating with Amino Groups

Altres ajuts: Xunta de Galicia (ED431G/09); Gobierno Vasco (IT1246-19, IT-1255-19); Diputación Foral de Gipuzkoa (RED 2019-096); CERCA Program/Generalitat de Catalunya; Program Interreg V-A España-Francia-Andorra (194/16 TNI)The electronic properties of graphene nanoribbons (GNRs) can be precisely tuned by chemical doping. Here we demonstrate that amino (NH) functional groups attached at the edges of chiral GNRs (chGNRs) can efficiently gate the chGNRs and lead to the valence band (VB) depopulation on a metallic surface. The NH-doped chGNRs are grown by on-surface synthesis on Au(111) using functionalized bianthracene precursors. Scanning tunneling spectroscopy resolves that the NH groups significantly upshift the bands of chGNRs, causing the Fermi level crossing of the VB onset of chGNRs. Through density functional theory simulations we confirm that the hole-doping behavior is due to an upward shift of the bands induced by the edge NH groups

Transplantation of mesenchymal stem cells exerts a greater long-term effect than bone marrow mononuclear cells in a chronic myocardial infarction model in rat

The aim of this study is to assess the long-term effect of mesenchymal stem cells (MSC) transplantation in a rat model of chronic myocardial infarction (MI) in comparison with the effect of bone marrow mononuclear cells (BM-MNC) transplant. Five weeks after induction of MI, rats were allocated to receive intramyocardial injection of 106 GFP-expressing cells (BM-MNC or MSC) or medium as control. Heart function (echocardiography and 18F-FDG-microPET) and histological studies were performed 3 months after transplantation and cell fate was analyzed along the experiment (1 and 2 weeks and 1 and 3 months). The main findings of this study were that both BM-derived populations, BM-MNC and MSC, induced a long-lasting (3 months) improvement in LVEF (BM-MNC: 26.61 ± 2.01% to 46.61 ± 3.7%, p < 0.05; MSC: 27.5 ± 1.28% to 38.8 ± 3.2%, p < 0.05) but remarkably, only MSC improved tissue metabolism quantified by 18FFDG uptake (71.15 ± 1.27 to 76.31 ± 1.11, p < 0.01), which was thereby associated with a smaller infarct size and scar collagen content and also with a higher revascularization degree. Altogether, results show that MSC provides a long-term superior benefit than whole BM-MNC transplantation in a rat model of chronic MI

First-in-Human, First-in-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients with Advanced Tumors

We present here the results of a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus. Celyvir was manufactured from a bone marrow aspirate and then given intravenously. Patients received weekly infusions for 6 weeks at a dose of 2 × 106 cells/kg (children) or 0.5-1 × 106 cells/kg (adults), 2 × 104 viral particles per cell. Fifteen pediatric and 19 adult patients were recruited, but 18 were screen failures, mainly because rapid disease progression before Celyvir was available. No grade 2-5 toxicities were reported. Adenoviral replication detected by PCR was found in all but 2 pediatric patient and in none of the adult ones. Absolute numbers of circulating leukocytes suffered minor changes along therapy, but some subsets showed differences comparing the pediatric versus the adult cohorts. Two patients with neuroblastoma showed disease stabilization, and one of them continued on treatment for up to 6 additional weeks. Celyvir, the combination of MSCs and oncolytic adenovirus, is safe and warrants further evaluation in a phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections.The trial was sponsored by Fundación de Investigacion Biomedica del Hospital Nino Jesus (EudraCT 2008-000364-16; NCT01844661). This work was funded by grants EC11/061, EC08/00094, and EC07/90591 from Instituto de Salud Carlos III and Fondos FEDER. M.R is supported by Asociación Pablo Ugarte, Asociación NEN, and Fundación Neuroblastoma.S