Cabazitaxel for metastatic castration-resistant prostate cancer: safety data from the Spanish expanded access program

[Abstract] BACKGROUND: Based on the TROPIC study results, cabazitaxel was approved for the management of metastatic castration-resistant prostate cancer (mCRPC) progressing on or after docetaxel. METHODS: This multi-centre program provided early access to cabazitaxel to patients with mCRPC before its commercialization. Safety data from 153 Spanish patients receiving cabazitaxel 25 mg/m(2) i.v. Q3W, plus oral prednisone/prednisolone 10 mg daily, are reported. RESULTS: Median age of patients was 70 years (26.8% ≥ 75 years), 94.1 and 26.8% had bone and visceral metastasis, respectively. Most had an Eastern Cooperative Oncology Group ≤ 1 (88.9%) and had received a median of 8.0 cycles of last docetaxel treatment. The median of cabazitaxel cycles and cumulative dose were 6.0 (Interquartile range [IQR]: 4.0; 8.0) and 148.9 (IQR: 98.2; 201.4) mg/m(2), respectively. Adverse events (AEs) possibly related to cabazitaxel occurred in 143 (93.5%) patients. The most frequent grade ≥ 3 AEs were neutropenia (n = 25, 16.3%) and asthenia (n = 17, 11.1%). Febrile neutropenia and grade ≥ 3 diarrhea occurred in 5.2% of the patients each. There were five (3.3%) possibly treatment-related deaths, mainly infection-related. G-CSFs were used in 114 (74.5%) patients, generally as prophylaxis (n = 107; 69.9%). Grade ≥ 3 peripheral neuropathy and nail disorders were uncommon. CONCLUSIONS: Cabazitaxel administration, in a real-world setting, is tolerated by Spanish patients with mCRPC, and the AEs are manageable

HIF pathway and c-Myc as biomarkers for response to sunitinib in metastatic clear-cell renal cell carcinoma

Clear-cell renal cell carcinoma (ccRCC) is a heterogeneous disease with a different clinical behavior and response to targeted therapies. Differences in hypoxia-inducible factor (HIF) expression have been used to classify von Hippel-Lindau gene (VHL)-deficient ccRCC tumors. c-Myc may be driving proliferation in HIF-2α-expressing tumors in a growth factor-independent manner. To explore the HIF-1α, HIF-2α and c-Myc baseline expression as potential predictors of sunitinib outcome as well as the effectiveness and safety with sunitinib in patients with metastatic ccRCC in routine clinical practice. This was an observational and prospective study involving 10 Spanish hospitals. Formalin-fixed, paraffin-embedded primary tumor samples from metastatic ccRCC patients who received sunitinib as first-line treatment were analyzed. Association between biomarker expression and sunitinib treatment outcomes was evaluated. Kaplan-Meier method was applied to measure progression-free survival (PFS) and overall survival. Eighty-one patients were included: median PFS was 10.8 months (95% CI: 7.4-13.5 months), median overall survival was 21.8 months (95% CI: 14.7-29.8 months) and objective response rate was 40.7%, with 7.4% of patients achieving a complete response. Molecular marker staining was performed in the 69 available tumor samples. Significant association with lower PFS was identified for double c-Myc/HIF-2α-positive staining tumors (median 4.3 vs 11.5 months, hazard ratio =2.64, 95% CI: 1.03-6.80, P =0.036). A trend toward a lower PFS was found in positive c-Myc tumors (median 5.9 vs 10.9 months, P =0.263). HIF-1α and HIF-2α expression levels were not associated with clinical outcome. These preliminary results suggest that predictive subgroups might be defined based on biomarkers such as c-Myc/HIF-2α. Further validation with more patients will be needed in order to confirm it. Outcomes with sunitinib in metastatic ccRCC in daily clinical practice resemble those obtained in clinical trials

La Comisión de Mujeres y Ciencia del CSIC: diez años promoviendo la igualdad de oportunidades y la excelencia en el organismo

The Women and Science Committee was set up in 2002 as an advisory unit on gender issues to the Presidency of the Spanish National Research Council (CSIC). During these ten years of existence, the committee has helped to improve the scientific careers of women in the CSIC and at the same time promoted the visibility of their scientific contributions. The history, objectives and activities of the Women and Science Committee during these years are reported here. The main gender policies and legal-framework changes at European and Spanish levels are recapped. Specifically, the sex distribution of permanent staff scientists in 2003 and 2012 are analysed and compared. The sex-disaggregated data by fields of knowledge show an improvement on the number and rank of female researchers in recent years, although they are still far from balanced. There is a bigger shortage of women in certain fields and at the top of the professional ladder. The implementation and monitoring of gender equality policies is still needed in order to approach a gender-balanced situation. This, in turn, will contribute to the excellence of the results of the CSIC´s research activities.La Comisión Mujeres y Ciencia del Consejo Superior de Investigaciones Científicas (CSIC) fue creada en 2002 como comisión asesora de la Presidencia para temas de género. En sus diez años de funcionamiento, la comisión ha contribuido a mejorar la carrera científica de las mujeres investigadoras del CSIC y a aumentar la visibilidad de los resultados de sus investigaciones. En este trabajo se resumen los orígenes y objetivos de esta comisión, así como las actividades realizadas desde 2002, y se analiza la historia de la plantilla investigadora en ese periodo. Se recogen, también, los cambios producidos desde 2005 en la legislación española y europea en materia de igualdad de género. Al analizar específicamente los datos de la situación de las mujeres en 2003 y en 2012 desagregados por áreas de conocimiento, se muestra un avance en la proporción de mujeres en casi todas las áreas pero se está aún lejos del objetivo de paridad. El déficit en la presencia de mujeres es mayor en ciertas áreas y en el nivel profesional más alto, por lo que siguen siendo necesarias medidas activas para promover la igualdad, lo que a su vez contribuirá a la excelencia en las actividades científicas del CSIC

Plataforma online de investigación y prácticas docentes para alumnos de Comunicación Audiovisual, Publicidad y Relaciones Públicas, e Historia del Arte

El proyecto busca la creación de una plataforma online en la que los alumnos de los grados y máster de Comunicación Audiovisual, Publicidad y Relaciones Publicas, e Historia del Arte puedan presentar y divulgar los resultados de los trabajos y prácticas docentes elaboradas en el aula. Igualmente, se pretende construir un espacio en el que se puedan difundir sus primeras aproximaciones al mundo de la investigación (Trabajos de Fin de Grado y de Fin de Máster, TFG, TFM) y al laboral (entrevistas a profesionales de los diferentes sectores implicados, reseñas de eventos profesionales, exposiciones, etc.). La plataforma digital se plantea como necesario complemento al Campus Virtual en el que los alumnos vienen desarrollando algunas de las prácticas, ampliando sus posibilidades y difusión. A través de la plataforma aquellos alumnos que lo deseen podrán difundir los trabajos realizados e inicialmente planteados a través de esta intranet, facilitando su conocimiento y difusión, con las implicaciones positivas que esto tiene tanto en el ámbito académico/investigador como laboral

Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma

Background: several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation. Patients and methods: multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)≥22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS. Results: 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found. Conclusions: certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p could be potentially used as biomarkers of sunitinib response

Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma

Background: Several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation. Patients and methods: Multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)=22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS. Results: 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found. Conclusions: Certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR- 628-5p could be potentially used as biomarkers of sunitinib response

Artesãos, cartografia e império. A produção social de um instrumento náutico no mundo ibérico, 1500-1650

Explicar cómo y en qué condiciones fueron construidos algunos de los instrumentos científicos más emblemáticos del mundo moderno sigue siendo un desafío para los historiadores de la ciencia y de la tecnología. Este principio afecta también a los instrumentos náuticos. Así, el objetivo del presente artículo es considerar el “cómo” y el “en qué condiciones”, en un sentido amplio, analizando uno de estos artefactos: las cartas náuticas construidas durante la expansión marítima europea. Originalidad: La originalidad del texto no reside únicamente en llevar a cabo una reconstrucción de este instrumento en Portugal y España que aporte nuevos datos sobre su proceso de fabricación y sus fabricantes, sino también en arrojar luz sobre antiguos debates historiográficos que subyacen a la génesis de la ciencia moderna, tales como la difícil colaboración entre hombres prácticos y hombres teóricos; la aportación de comunidades de artesanos al mundo del conocimiento; el papel que los saberes prácticos tuvieron en el establecimiento de nuevas formas de estandarización en ciencia; la adopción de una metodología empírica para el dominio del mundo o la construcción de grandes imperios globales cimentados sobre la base del trabajo manual. Metodología: El análisis de estos debates requiere una aproximación metodológica que atienda a las categorías y los conceptos principales puestos en circulación tanto por la historia como por la filosofía de la ciencia más reciente. En definitiva, se trata de atender a las condiciones que permitieron el establecimiento de acuerdos (y también de controversias) epistemológicos entre diferentes comunidades de conocimiento tomando un instrumento náutico como “mediador”. Conclusiones: El artículo concluye que la consideración de las culturas empíricas del conocimiento y sus realizaciones materiales son una condición sine qua non para entender la génesis de la modernidad científica europea y la construcción de un mundo globalExplaining how and under what conditions some of the most emblematic scientific instruments of the modern world were built remains a challenge for historians of science and technology. This principle also affects nautical instruments. Thus, the objective of this article is to consider the “how” and the “under what conditions”, in a broad sense, by examining one of these devices: the nautical charts developed during the European maritime expansion. Originality: The originality of this article lies not only in the reconstruction of this instrument in Portugal and Spain, providing new information about its development process and its manufacturers, but also in shedding light on old historiographical debates that underlie the genesis of modern science, such as the difficult collaboration between practical men and theoretical men; the contribution of artisan communities to the world of knowledge; the role that practical knowledge played in the establishment of new forms of standardization in science; the adoption of an empirical methodology for achieving mastery of the world or the construction of large global empires founded upon manual labor. Methodology: Analyzing these debates requires a methodological approach that addresses the main categories and concepts put into circulation by the most recent history and philosophy of science. In short, unveiling the conditions that enabled the establishment of epistemological agreements (and also disputes) between different knowledge communities by taking a nautical instrument as “mediator.” Conclusions: The article concludes that examining empirical knowledge cultures and their material achievements are a sine qua non condition to understand the genesis of European scientific modernity and the construction of a global worldExplicar como e em que condições foram construídos alguns dos instrumentos científicos mais emblemáticos do mundo moderno continua sendo um desafio para os historiadores da ciência e da tecnologia. Esse princípio afeta também os instrumentos náuticos. Assim, o objetivo do presente artigo é considerar o “como” e o “em que condições”, em um sentido amplo, e analisar um desses artefatos: as cartas náuticas construídas durante a expansão marítima europeia. Originalidade: A originalidade do texto não reside unicamente na realização de uma reconstrução desse instrumento em Portugal e na Espanha de forma que traga novos dados sobre seu processo de fabricação e de seus fabricantes, mas também em lançar luz sobre antigos debates historiográficos que subjazem à gênese da ciência moderna, tais como a difícil colaboração entre homens práticos e homens teóricos, a contribuição de comunidades de artesãos ao mundo do conhecimento; o papel que os saberes práticos tiveram no estabelecimento de novas formas de padronização na ciência, a adoção de uma metodologia empírica para o domínio do mundo ou a construção de grandes impérios globais cimentados sobre a base do trabalho manual. Metodologia: A análise desses debates requer uma aproximação metodológica que atenda às categorias e aos principais conceitos colocados em circulação tanto pela história quanto pela filosofia da ciência mais recente. Definitivamente, trata-se de atender às condições que permitiram o estabelecimento de acordos (e também de controvérsias) epistemológicos entre diferentes comunidades de conhecimento tomando o instrumento náutico como “mediador”. Conclusões: O artigo conclui que a consideração das culturas empíricas do conhecimento e suas realizações materiais são uma condição sine qua non para entender a gênese da modernidade científica europeia e a construção de um mundo globa

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

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Site index model for natural stands of rebollo oak (<i>Quercus pyrenaica</i> Willd.) in Galicia, NW Iberian Peninsula.

<p>Data from stem analysis of 56 dominant trees of <em>Quercus pyrenaica</em> Willd., in natural stands in Galicia (NW Iberian Peninsula), were used to evaluate four dynamic site equations derived with the Generalized Algebraic Difference Approach (GADA). All the equations are base-age invariant and directly estimate height and site index from any height and age. The fittings were made using a data structure involving all possible growth intervals. The GADA formulation derived on the basis of the Bertalanffy-Richards model by considering the asymptote and the initial pattern parameters as related to site productivity. It is therefore recommended for height growth prediction and site classification for natural stands of rebollo oak in Galicia. The autocorrelation was analyzed with a test of residuals using Durbin's t-test without reaching a manifest result of autocorrelation between managed data.</p