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Majadahonda, Spain

Bouza C.,Health Care Technology Assessment Agency | Lopez-Cuadrado T.,Carlos III Health Institute | Almendro N.,Health Care Technology Assessment Agency | Amate J.M.,Health Care Technology Assessment Agency
European Spine Journal | Year: 2015

Purpose: The study aims to evaluate the safety of balloon kyphoplasty in the treatment of painful osteoporotic vertebral compression fractures in Europe. Methods: Systematic review of the literature, until September 2013, and meta-analysis of randomized controlled trials performed in Europe assessing the safety of balloon kyphoplasty in patients with symptomatic osteoporotic vertebral fractures. Outcomes sought include cement leaks, serious clinical complications and new vertebral fractures. Results: Six randomized controlled trials fulfilled the inclusion criteria. These studies included data on 525 treated levels in 424 patients. Cement leakages were detected in 18.3 % (95 % CI 11.6, 23.0) of fractures intervened. In about 0.5 % (95 % CI 0.1, 1.1) of fractures leakages proved to be symptomatic. Serious clinical complications were recorded in 11.5 % (95 % CI 1.1, 21.7) of patients treated with balloon kyphoplasty with several of these cases requiring intensive treatment or postoperative surgery. New vertebral fractures were detected in 20.7 % (95 % CI 0.4, 40.9) of patients treated but rates showed an upward pattern when the follow-up period increased. In 54 % of such cases, the fractures were located in regions adjacent to the treated level. Conclusions: The safety profile and associated complications of balloon kyphoplasty shown in this analysis, based on the evidence provided by existing randomized controlled trials, can be of help to the practicing clinician who must contrast them with the potential benefits of the technique. These data represent an important step towards a balanced evaluation of the intervention though, a better reporting and more reliable data on long-term assessment of potential sequelae are needed. © 2014, Springer-Verlag Berlin Heidelberg.

Echevarria J.M.,Carlos III Health Institute | Gonzalez J.E.,National Institute of Infectious Diseases | Lewis-Ximenez L.L.,Instituto Oswaldo Cruz | Dos Santos D.R.L.,Federal Rural University of Rio de Janeiro | And 4 more authors.
Journal of Medical Virology | Year: 2013

Data reported during recent years reveal the complex picture of the epidemiology of hepatitis E virus (HEV) infection in Latin America. Whereas in countries like Argentina and Brazil is almost identical to the characteristic of most countries from North America and Europe, HEV in the Caribbean and Mexico involves the water-borne, non-zoonotic viral genotypes responsible for epidemics in Asia and Africa. Nevertheless, Latin America has been considered a highly endemic region for hepatitis E in the scientific literature, a generalization that ignores the above complexity. In addition, reports from isolated Amerindian communities, which display well known, important and very specific epidemiological features for hepatitis B and D virus infections are neither taken into account when considering the epidemiology of hepatitis E in the region. This review updates compilation of the available information for the HEV infection, both among humans and other mammals, in Latin America, discusses the strengths and the weaknesses of our current knowledge, and identifies future areas of research. © 2013 Wiley Periodicals, Inc.

Hu-Lieskovan S.,University of California at Los Angeles | Robert L.,University of California at Los Angeles | Moreno B.H.,University of California at Los Angeles | Moreno B.H.,Carlos III Health Institute | Ribas A.,University of California at Los Angeles
Journal of Clinical Oncology | Year: 2014

Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non-BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials. © 2014 by American Society of Clinical Oncology.

Hu-Lieskovan S.,University of California at Los Angeles | Mok S.,University of California at Los Angeles | Homet Moreno B.,University of California at Los Angeles | Homet Moreno B.,Carlos III Health Institute | And 9 more authors.
Science Translational Medicine | Year: 2015

Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAFV600E-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAFV600E mutant metastatic melanoma. © 2015, American Association for the Advancement of Science. All rights reserved.

Prados-Torres A.,University of Zaragoza | Prados-Torres A.,Carlos III Health Institute | Prados-Torres A.,Aragon Health science Institute IACS | Calderon-Larranaga A.,University of Zaragoza | And 7 more authors.
Journal of Clinical Epidemiology | Year: 2014

Objectives The aim of this review was to identify studies on patterns of associative multimorbidity, defined as the nonrandom association between diseases, focusing on the main methodological features of the studies and the similarities among the detected patterns. Study Design and Setting Studies were identified through MEDLINE and EMBASE electronic database searches from their inception to June 2012 and bibliographies. Results The final 14 articles exhibited methodological heterogeneity in terms of the sample size, age and recruitment of study participants, the data source, the number of baseline diseases considered, and the statistical procedure used. A total of 97 patterns composed of two or more diseases were identified. Among these, 63 patterns were composed of three or more diseases. Despite the methodological variability among studies, this review demonstrated relevant similarities for three groups of patterns. The first one comprised a combination of cardiovascular and metabolic diseases, the second one was related with mental health problems, and the third one with musculoskeletal disorders. Conclusion The existence of associations beyond chance among the different diseases that comprise these patterns should be considered with the aim of directing future lines of research that measure their intensity, clarify their nature, and highlight the possible causal underlying mechanisms. © 2014 Elsevier Inc. All rights reserved.

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