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Expert recommendations on the management of patients with metastatic castration-resistant prostate cancer who progress after CHAARTED or LATITUDE
No full textObjective: Our aim was to provide practical recommendations on the management of patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel plus androgen-deprivation therapy (ADT) or abiraterone plus ADT. Methods: Systematic literature review (SLR), nominal group meeting, and Delphi process. A panel of 12 experts was established who defined the scope, users, and sections of the document. We performed an SLR in order to assess the efficacy and safety of available drugs in patients with mCRPC. Abstracts from the American Society of Oncology and European Society for Medical Oncology meetings were also examined. The results were discussed during an expert meeting in which 14 recommendations were generated. The level of agreement with the recommendations was also tested by 13 additional experts following the Delphi process. Recommendations were voted by means of scores ranging from 0 (total disagreement) to 10 (total agreement). We defined agreement when at least 70% of the experts voted 7. Next, we assigned a level of evidence and grade to the recommendation using the Oxford Centre for Evidence-based Medicine Levels of Evidence, following which the final document was drafted. Results: The literature search did not find any articles meeting the inclusion criteria. Finally, 13 out of 14 recommendations were accepted after two Delphi rounds (two were modified after the first round). They pertain to general and individual case-based treatment recommendations. Conclusions: In mCRPC patients who have progressed after docetaxel or abiraterone plus ADT in the metastatic hormone-sensitive prostate cancer setting, these recommendations may support treatment decision-making, due to the lack of evidence or other globally accepted sequencing algorithms
Recomendaciones nacionales sobre donación pediátrica
Get PDFDespite being an international reference in donation and transplantation, Spain needs to improve pediatric donation, including donation after the circulatory determination of death. The present article, a summary of the consensus report prepared by the Organizacion Nacional de Trasplantes and the Spanish Pediatrics Association, intends the facilitation of donation procedures in newborns and children and the analysis of associated ethical dilemma. The ethical basis for donation in children, the principles of clinical assessment of possible donors, the criteria for the determination of death in children, intensive care management of donors, basic concepts of donation after the circulatory determination of death and the procedures for donation in newborns with severe nervous system's malformation incompatible with life, as well as in children receiving palliative care are commented. Systematically considering the donation of organs and tissues when a child dies in conditions consistent with donation is an ethical imperative and must become an ethical standard, not only because of the need of organs for transplantation, but also to ensure family centered care.A pesar de ser una referencia internacional en donación y trasplante, España precisa mejorar los procesos de donación en niños, en particular la donación tras la determinación de la muerte por criterios circulatorios (donación en asistolia). El presente artículo, resumen del documento de consenso elaborado por la Organización Nacional de Trasplantes y la Asociación Española de Pediatría, pretende facilitar los procesos de donación en niños y neonatos y analizar los conflictos éticos que plantea. Se comentan los fundamentos éticos de la donación pediátrica, los principios de la evaluación clínica de los posibles donantes, los criterios diagnósticos de muerte encefálica en niños, los cuidados intensivos para el mantenimiento de los donantes, los conceptos básicos de la donación en asistolia y los procesos de donación en neonatos con malformaciones muy graves del sistema nervioso incompatibles con la vida y en niños en cuidados paliativos. Considerar sistemáticamente la donación de órganos y tejidos cuando un niño fallece en condiciones de ser donante es un imperativo ético y ha de constituir un estándar profesional, tanto por la necesidad de órganos para trasplante, como por asegurar un cuidado integral centrado en la familia
Improved classification of rheumatoid arthritis with a score including anti-acetylated ornithine antibodies
Get PDFThe presence of rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) autoantibodies contributes to the current rheumatoid arthritis (RA) classification criteria. These criteria involve stratification on antibody levels, which limits reproducibility, and underperform in the RA patients without RF and anti-CCP. Here, we have explored if two anti-acetylated peptide antibodies (AAPA), anti-acetylated lysine (AcLys) and anti-acetylated ornithine (AcOrn), could improve the performance of the current criteria. The analysis was done in 1062 prospectively-followed early arthritis (EA) patients. The anti-AcOrn were more informative than the anti-AcLys, the conventional RA antibodies and the anti-carbamylated protein antibodies. The anti-AcOrn produced a classification that did not require antibody levels and showed improved specificity (77.6% vs. 72.6%, p = 0.003) and accuracy (79.0% vs. 75.8%, p = 0.002) over the current criteria. These improvements were obtained with a scoring system that values concordance between anti-AcOrn, RF and anti-CCP. No significant gain was obtained in sensitivity (80.2% vs. 78.8%, p = 0.25) or in improving the classification of the RA patients lacking RF and anti-CCP, although the anti-AcOrn ranked first among the analysed new antibodies. Therefore, the anti-AcOrn antibodies could contribute to the improvement of RA classification criteria by exploiting antibody concordance
Pathway towards an ideal and sustainable framework agreement for the public procurement of vaccines in Spain: a multi-criteria decision analysis
Get PDFObjective: To advance the development of an ideal and sustainable framework agreement for the public procurement of vaccines in Spain, and to agree on the desirable award criteria and their relative weight. Methods: A multidisciplinary committee of seven health-care professionals and managers developed a partial multi-criteria decision analysis to determine the award criteria that should be considered and their specific weights for the public procurement of routine vaccines and seasonal influenza vaccines, considering their legal viability. A re-test of the results was carried out. The current situation was analyzed through 118 tender specifications and compared to the ideal framework. Results: Price is the prevailing award criterion for the public procurement of both routine (weighting of 60% versus 40% for all other criteria) and influenza (36% versus 64%) vaccines. Ideally, 22 criteria should be considered for routine vaccines, grouped and weighted into five domains: efficacy (weighting of 29%), economic aspects (27%), vaccine characteristics (22%), presentation form and packaging (13%), and others (9%). Per criteria set, price was the most important criterion (22%), followed by effectiveness (9%), and composition/formulation (7%). Regarding influenza vaccines, 20 criteria were selected, grouped, and weighted: efficacy (29%), economic aspects (25%), vaccine characteristics (20%), presentation form and packaging (16%), and others (11%). Per criteria set, price was also the most relevant criterion (19%), followed by composition/formulation (8%), and effectiveness (8%). Conclusions: Contrary to the current approach, technical award criteria should prevail over economic criteria in an ideal and sustainable framework agreement for the public procurement of vaccines
Information Needs in COPD After an Educational Programme: Influence in Exacerbations and Admissions
Get PDFIntroduction: Improving patients' information needs (IN) may contribute to better control in COPD. This study analyses IN using Lung Information Needs Questionnaire (LINQ) following an educational intervention, evaluates how clinical characteristics modify IN, and studies high IN as a prognostic factor for COPD exacerbations and hospital admissions. Methods: Cohort of 143 patients with initial diagnosis of COPD included in a structured educational program. Two months after completing the program, IN was assessed using LINQ. Correlations between IN and clinical variables of COPD and distribution of IN in different clinical groups were analyzed. Univariate and multivariate analysis was performed to determine influence of IN on exacerbations and COPD admissions over the following year. Results: LINQ scored 6.3+/-2.9. There were no differences in LINQ scoring between different clinical groups, but LINQ score positively correlated with age (r=0.184, p=0.029). High IN was a predictor of COPD hospitalizations (HR 2.3 [95% CI 1.1-5.1] (p=0.029)) but not of less severe exacerbations (p=0.334). Conclusion: IN was not associated with any clinical variables, but it correlated with age. High IN proved to be an independent predictor of admissions
A Meta-Analysis of Multiple Whole Blood Gene Expression Data Unveils a Diagnostic Host-Response Transcript Signature for Respiratory Syncytial Virus
Get PDFRespiratory syncytial virus (RSV) is one of the major causes of acute lower respiratory tract infection worldwide. The absence of a commercial vaccine and the limited success of current therapeutic strategies against RSV make further research necessary. We used a multi-cohort analysis approach to investigate host transcriptomic biomarkers and shed further light on the molecular mechanism underlying RSV-host interactions. We meta-analyzed seven transcriptome microarray studies from the public Gene Expression Omnibus (GEO) repository containing a total of 922 samples, including RSV, healthy controls, coronaviruses, enteroviruses, influenzas, rhinoviruses, and coinfections, from both adult and pediatric patients. We identified > 1500 genes differentially expressed when comparing the transcriptomes of RSV-infected patients against healthy controls. Functional enrichment analysis showed several pathways significantly altered, including immunologic response mediated by RSV infection, pattern recognition receptors, cell cycle, and olfactory signaling. In addition, we identified a minimal 17-transcript host signature specific for RSV infection by comparing transcriptomic profiles against other respiratory viruses. These multi-genic signatures might help to investigate future drug targets against RSV infection
The Value of PD-L1 Expression as Predictive Biomarker in Metastatic Renal Cell Carcinoma Patients: A Meta-Analysis of Randomized Clinical Trials
No full textImmune checkpoint inhibitors (ICIs) are soluble antibodies that have dramatically changed the outcomes including overall survival in a subset of kidney tumors, specifically in renal cell carcinoma (RCC). To date, there is no a single predictive biomarker approved to be used to select the patients that achieve benefit from ICIs targeting. It seems reasonable to analyze whether the programmed death-ligand 1 (PD-L1) expression could be useful. To assess the role of PD-L1 expression as a potential predictive biomarker for benefit of ICIs in RCC patients, we performed a search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care in metastatic RCC patients according to PRISMA guidelines. Trials must have included subgroup analyses evaluating the selected outcomes (progression-free survival (PFS) and overall survival (OS)) in different subsets of patients according to PD-L1 expression on tumor samples. Hazard ratios with confidence intervals were used as the measure of efficacy between groups. A total of 4635 patients (six studies) were included (ICIs arm: 2367 patients; standard of care arm: 2268 patients). Globally, PFS and OS results favored ICIs. Differential expression of PD-L1 on tumor samples could select a subset of patients who could benefit more in terms of PFS (those with higher levels; p-value for difference between subgroups: <0.0001) but it did not seem to impact in OS results (p-value for difference: 0.63). As different methods to assess PD-L1 positivity were used among trials, this heterogeneity could have an influence on the results. PD-L1 could represent a biomarker to test PFS in clinical trials but its value for OS is less clear. In this meta-analysis, the usefulness of PD-L1 expression as a predictive biomarker to select treatment in metastatic RCC patients was not clearly shown
Inflammatory and lipid regulation by cholinergic activity in epicardial stromal cells from patients who underwent open-heart surgery
No full textThe modulation of acetylcholine (ACh) release by botulinum toxin injection into epicardial fat diminishes atrial fibrillation (AF) recurrence. These results suggest an interaction between autonomic imbalance and epicardial fat as risk factors of AF. Our aim was to study the inflammatory, lipidic and fibroblastic profile of epicardial stroma from patients who underwent open-heart surgery, their regulation by cholinergic activity and its association with AF. We performed in vitro and ex vivo assays from paired subcutaneous and epicardial stromal cells or explants from 33 patients. Acute ACh effects in inflammation and lipid-related genes were analysed by qPCR, in intracellular calcium mobilization were performed by Fluo-4 AM staining and in neutrophil migration by trans-well assays. Chronic ACh effects on lipid accumulation were visualized by AdipoRed. Plasma protein regulation by parasympathetic denervation was studied in vagotomized rats. Our results showed a higher pro-inflammatory profile in epicardial regarding subcutaneous stromal cells. Acute ACh treatment up-regulated monocyte chemoattractant protein 1 levels. Chronic ACh treatment improved lipid accumulation within epicardial stromal cells (60.50% [22.82-85.13] vs 13.85% [6.17-23.16], P < .001). Additionally, patients with AF had higher levels of fatty acid-binding protein 4 (1.54 +/- 0.01 vs 1.47 +/- 0.01, P = .005). Its plasma levels were pronouncedly declined in vagotomized rats (2.02 +/- 0.21 ng/mL vs 0.65 +/- 0.23 ng/mL, P < .001). Our findings support the characterization of acute or chronic cholinergic activity on epicardial stroma and its association with AF
Test-Retest Repeatability of F-18 MC225-PET in Rodents: A Tracer for Imaging of P-gp Function
Get PDFIn longitudinal PET studies, animals are repeatedly anesthetized which may affect the repeatability of PET measurements. The aim of this study was to assess the effect of anesthesia on the P-gp function as well as the reproducibility of [(18)F]MC225 PET scans. Thus, dynamic PET scans with blood sampling were conducted in 13 Wistar rats. Seven animals were exposed to isoflurane anesthesia 1 week before the PET scan ("Anesthesia-exposed" PET). A second group of six animals was used to evaluate the reproducibility of measurements of P-gp function at the blood-brain barrier (BBB) with [(18)F]MC225. In this group, two PET scans were made with a 1 week interval ("Test" and "Retest" PET). Pharmacokinetic parameters were calculated using compartmental models and metabolite-corrected plasma as an input function. "Anesthesia-exposed" animals showed a 28% decrease in whole-brain volume of distribution (VT) (p < 0.001) compared to "Test", where the animals were not previously anesthetized. The VT at "Retest" also decreased (19%) compared to "Test" (p < 0.001). The k2 values in whole-brain were significantly increased by 18% in "Anesthesia-exposed" (p = 0.005) and by 15% in "Retest" (p = 0.008) compared to "Test". However, no significant differences were found in the influx rate constant K1, which is considered as the best parameter to measure the P-gp function. Moreover, Western Blot analysis did not find significant differences in the P-gp expression of animals not pre-exposed to anesthesia ("Test") or pre-exposed animals ("Retest"). To conclude, anesthesia may affect the brain distribution of [(18)F]MC225 but it does not affect the P-gp expression or function