Terapia anticipada de Aspergilosis Invasora en pacientes oncohematológicos de alto riesgo mediante el uso de PCR para la detección precoz de Aspergillus. Estudio de los polimorfismos genéticos de la vía NFKB y su implicación en las Arpergilosis Invasora

[ES] La aspergilosis invasora (AI) es un problema fundamental en el manejo de muchos pacientes hematológicos, por lo que es esencial un diagnóstico precoz que permita instaurar un tratamiento adecuado lo antes posible con el fin de disminuir la morbimortalidad de esta complicación. Nuestra hipótesis es que la asociación del galactomanano con una técnica de detección del ADN de aspergillus, como es la PCR de aspergillus, podría reducir la incidencia de AI probable o probada según los criterios de la EORTC/MSG 2008. Para ello se pone en marcha el estudio TERAPIA ANTICIPADA DE ASPERGILOSIS INVASORA EN PACIENTES ONCOHEMATOLÓGICOS DE ALTO RIESGO MEDIANTE LA DETECCIÓN PRECOZ DE PCR DE ASPERGILLUS (PCRAGA). Se trata de un estudio multicéntrico, randomizado y prospectivo en 13 Servicios de Hematología y Hemoterapia en España llevado a cabo entre Febrero de 2011 y Julio de 2012. Se incluyeron 224 pacientes, que fueron randomizados en dos grupos; uno caracterizado por el seguimiento por PCR y Galactomanano, y otro cuyo seguimiento se realizó sólo con galactomanano. Se extraían 2 muestras semanales y, en el caso de positivizar alguna de ellas, se iniciaba un tratamiento antifúngico. 203 pacientes fueron válidos para el análisis. El numero de aspergilosis probables o probadas fue significativamente menor en el grupo de combinación de ambas técnicas; es decir, la estrategia de combinación de las dos técnicas consiguió una reducción global de aspergilosis invasoras probables o probadas de un 8,9%. El 69% de las aspergilosis del grupo de combinación de las dos técnicas fueron posibles, probablemente por un diagnóstico más precoz de la infección gracias a la PCR. Además el uso de tratamiento antifúngico empírico y, lo más importante, la necesidad de iniciar un tratamiento antifúngico dirigido, fue menor en el grupo de combinación de ambas técnicas. Aunque no se pudieron establecer diferencias significativas con respecto a la mortalidad, la mortalidad atribuible a aspergilosis invasora parece ser menor en el grupo de combinación de las dos técnicas. En una segunda parte del trabajo , se estudió si existían ciertos polimorfismos genéticos de la vía de señalización NFKB que podían aumentar o reducir el riesgo de desarrollar una aspergilosis invasora. La población de estudio estaba constituida por 822 pacientes de alto riesgo del consorcio aspBIOmics, población del estudio PCRAGA, muestras de los hospitales general del Valencia, Universitario de Salamanca y Universidad de Perugia (Italia). El genotipado de los SNPs seleccionados se realizó mediante técnicas basadas en PCR y de acuerdo a los protocolos establecidos por las respectivas casas comerciales. Se observó que la variante rs11574851 del gen NFKB2 aumenta por 2 el riesgo de desarrollar una aspergilosis invasora, la variante rs12203592 del gen IRF4 aumenta casi por 4 el riesgo de desarrollar una aspergilosis invasora. Por el contrario la variante rs2288918 parece ser un factor protector de aspergilosis invasora. Además, si seleccionamos una población de 173 pacientes sometidos a trasplante, observamos que la variante rs12203592 del gen IRF4 aumenta casi 6 veces el riesgo de desarrollar una aspergilosis invasora

Micafungin as antifungal prophylaxis in non-transplanted haemotological patients

Introduction. Fungal infections are a major cause of morbidity and mortality in the haematological patients. These infections are mainly due to Candida spp. and Aspergillus spp. Mortality by these infections is high, but rates have descended in the latest series due to better antifungal agents. Echinocandins are, in vitro, very active against Candida and Aspergillus spp. The objective of the study is to analyse the efficacy and safety of micafungin in the antifungal prophylaxis of haematological patients on chemotherapy. Material and methods. A multicentre, observational retrospective study was performed in 7 Haematology Departments in Spain. Patients admitted to these departments with chemotherapy or immunosuppressive treatment, and who had received antifungal prophylaxis with micafungin between 1 January 2009 and 31 December 2014 were included. Results. There were 5 cases of probable or proven fungal infection (4.8%) according to the 2008 EORTC criteria: 2 proven, 3 probable. The types of fungal infection were 3 aspergillosis and 2 candidiasis. There were no drop-outs from the prophylaxis with micafungin due to toxicity. Conclusion. Micafungin is an antifungal agent which, used in prophylaxis, has demonstrated good efficacy and an excellent toxicity profile, making it an apparently interesting option in patients requiring antifungal prophylaxis during their hospitalisation episode

Endocannabinoid regulation of amyloid-induced neuroinflammation

The modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer’s disease (AD). We aimed to evaluate the effect of the pharmacological and genetic inhibiton of anandamide (AEA)-degrading enzyme in a mouse model of AD (5xFAD). Pharmacological inhibition of the fatty acid amide hydrolase (FAAH) had little impact on the expression of key enzymes and cytokines as well as on the cognitive impairment and plaque deposition and gliosis in 5xFAD mice. CB1 blockade exacerbated inflammation in this transgenic mouse model of AD. The genetic inactivation of FAAH led to increases in the expression of inflammatory cytokines. At the same time, FAAH-null 5xFAD mice exhibited a behavioral improvement in spatial memory that was independent of the level of anxiety and was not CB1-mediated. Finally, mice lacking FAAH showed diminished soluble amyloid levels, neuritic plaques and gliosis. These data reinforce the notion of a role for the endocannabinoid system in neuroinflammation and open new perspectives on the relevance of modulating endocannabinoid levels in the inflammed brain.pre-print687 K

Safety of switching from intravenous to subcutaneous rituximab during first-line treatment of patients with non-Hodgkin lymphoma: the Spanish population of the MabRella study

Rituximab is a standard treatment for non-Hodgkin diffuse large B-cell (DLBCL) and follicular (FL) lymphomas. A subcutaneous formulation was developed to improve the resource use of intravenous rituximab, with comparable efficacy and safety profiles except for increased administration-related reactions (ARRs). MabRella was a phase IIIb trial to assess the safety of switching from intravenous to subcutaneous administration of rituximab during first-line induction/maintenance for DLBCL or FL, focusing on ARRs. Efficacy, satisfaction and quality of life were also assessed. Patients received subcutaneous rituximab plus standard induction chemotherapy for DLBCL or FL for 4–7 cycles, and/or every 2 months maintenance monotherapy for FL for 6–12 cycles. The study included 140 patients: DLBCL, n = 29; FL, n = 111. Ninety-five percent of patients experienced adverse events, reaching grade ≥3 in 38 6% and were serious in 30 0%. AARs occurred in 48 6%, mostly (84 9%) at the injection site, with only 2 1% of patients reaching grade 3. The end-of-induction complete/unconfirmed complete response rate was 69 6%. After a median follow-up of 33 5 months, median disease-/event-/progression-free and overall survivals were not attained. The Rituximab Administration Satisfaction Questionnaire showed improvements in overall satisfaction and the EuroQoL-5D a good quality-of-life perception at induction/maintenance end. Therefore, switching to subcutaneous rituximab showed no new safety issues and maintained efficacy with improved satisfaction and quality of life

Peripheral T-cell lymphoma: Molecular profiling recognizes subclasses and identifies prognostic markers

Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of approximately 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform (NanoString Technologies, Seattle, WA) that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways, and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma [AITL]; PTCL with T follicular helper [TFH] phenotype; PTCL not otherwise specified [NOS]) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers, and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells, and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH, and PTCL-NOS. The main differences among the 3 nodal PTCL classes involved the RHOAG17V mutations (P < .0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these 3 categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

Estudio ecográfico del carcinoma epidermoide. Indicaciones pronosticas

Objetivo: El objetivo es evaluar el grado de concordancia entre la valoración ecográfica e histopatológica del carcinoma epidermoide cutáneo, debido a las repercusiones diagnósticas y pronosticas que tiene la profundidad tumoral en dicha patología. De manera secundaria se estudia el valor pronóstico de la ecografía cutánea para diferenciar los tumores de un grosor mayor de 2 mm y los menores de 2 milímetros, ya que es un claro factor pronóstico que permite diferenciar los carcinomas epidermoides de alto riesgo. Material y métodos: Estudio prospectivo de una serie consecutiva de pacientes que presentaban carcinoma epidermoide cutáneo comprobado histológicamente mediante biopsia cutánea tipo punch, durante un periodo de seguimiento de 4 años, desde 2010 a 2014, realizado en el servicio de Dermatología del Complejo Hospitalario Universitario de Albacete. Se comparó la profundidad tumoral expresada en milímetros medida mediante ecografía cutánea respecto a la obtenida histopatológicamente. Se incluyeron un total de 44 lesiones de 40 pacientes. Resultados: Se obtuvo una media de la medición ecográfica 3,7 mm con una Desv. Típica =3,2mm y una mediana de 2,1mm; y una media de la medición histológica 3,4 mm con una Desv. Típica 2,9 mm con una mediana de 2,1mm. Existe una diferencia significativa entre la medida que obtenemos ecográficamente respecto a la medición histopatológica. Esta diferencia es de 0,3 mm, superior en la ecografía, con un intervalo de confianza de 95% entre 0,08 y 0,5 mm (p=0.008). El diagrama de Pearson o análisis de correlación simple muestra un grado de cercanía alto de la relación entre las dos variables. Tomando como referencia para el diagnóstico los valores histológicos por encima y debajo de 2 (milímetros) que es el valor de referencia y uno de los parámetros que permite clasificar al carcinoma epidermoide de alto riesgo; se obtuvo una sensibilidad de 95,.65%, especificidad de 80.95%, un valor predictivo positivo de 84,.62% y un valor predictivo negativo de 94.44%. Conclusiones: La ecografía sobreestima el grosor de los carcinomas epidermoides de manera estadísticamente significativa en todas las localizaciones estudiadas en la muestra estudiada salvo en el labio. Por otro lado, la ecografía permite diferenciar con gran fiabilidad, los carcinomas epidermoides de grosor mayor de 2 mm de los menores de 2 mm, factor que está claramente vinculado a una mayor agresividad biológica

Estudio del Ager Aesonensis (Isona i Conca Dellà, Pallars Jussà, Lleida)

A systematic prospection survey in the territory of iberan and roman town of Eso/Aeso allowed the discovering of a relatively dense netof rural settlements. We proceed to analyse morphometrically the landscape. Apart from some medieval and modern age interventions, we found at least two kinds of ancient age (re)ordinations of rural landscape. Besides the relics of a centuriated parcellation, we found traces of a coherent parcellation system, in which structures keep a coherent orientation and follow some kind of metrical rhythm in spite of lacking the rigorous orthogonallity of a centuriation. At last, the data acquired during systematic prospection and those obtained by photointerpretation were merged using a GIS. Some environmental variables werecrossed with the former data to confirm hypothesis a suggest new ones relative to chronology and functionality of both ancient parcellationLa prospección sistemática de una muestra del territorio de la ciudad ibérica y romana de Eso/Aeso permitió descubrir la existencia de una red relativamente densa de núcleos rurales en las inmediaciones de la ciudad. Se realizó un análisis morfométrico del parcelario de la zona, detectándose, junto a operaciones de época medieval y moderna, al menos dos (re)ordenaciones del paisaje rural adscribibles a época antigua: vestigios de un parcelario centuriado, y un sistema parcelario coherente -sus estructuras mantienen una orientación coherente, con cierto ritmo métrico, aunque sin la rigurosaortogonalidad de una centuriación. Se pusieron en relación los datos de la prospección sistemática con los de la fotointerpretación, median te un SIG. Cruzando dichos datos con variables ambien- tales, se confirmaron y plantearon hipótesis sobre la cronología y funcionalidad de los parcelarios antiguos