Gaston Roustan

Host Genetic Factors in Susceptibility to Herpes Simplex Type 1 Virus Infection: Contribution of Polymorphic Genes at the Interface of Innate and Adaptive Immunity

HSV-1 establishes life-long latency that can result in clinical relapses or in asymptomatic virus shedding. Although virtually all adults have been exposed to HSV-1, the clinical course varies remarkably. Genetic host variability could be related to this clinical diversity. In this study, we analyzed the contribution of gene families in chromosomes 1, 6, 12, and 19, which encode key regulators of the innate and adaptive immunity, in a cohort of 302 individuals. Class I and class II alleles of the HLA system, the copy-number variation of NK cell receptor genes (KIR and NKG2C), the combinations of killer cell Ig-like receptor and their HLA ligands, and CD16A and CD32A allotypes of variable affinity for IgG subclasses were all studied. Although no major susceptibility locus for HSV-1 was identified, our results show that the risk of suffering clinical HSV-1 infection is modified by MHC class I allotypes (B*18, C*15, and the group of alleles encoding A19), the high-affinity receptor/ligand pair KIR2DL2/HLA-C1, and the CD16A-158V/F dimorphism. Conversely, HLA class II and CD32A polymorphisms and NKG2C deletion did not seem to influence the clinical course of herpetic infection. Collectively, these findings support an important role in host defense against herpetic infection for several polymorphic genes implicated in adaptive immunity and in surveillance of its subversion. They confirm the crucial role of cytotoxic cells (CTL and NK) and the contribution of genetic diversity to the clinical course of HSV-1 infection.

Guidelines for Performing Dermatologic Ultrasound Examinations by the DERMUS Group.

To support standardization for performing dermatologic ultrasound examinations.

Ultrasound Evaluation as a Complementary Test in Hidradenitis Suppurativa: Proposal of a Standarized Report

BACKGROUND Staging and monitoring of patients with hidradenitis suppurativa (HS) have been traditionally based on clinical findings. However, the physical examination may show important limitations because of its poor sensitivity for differentiating between different lesion subtypes, and its low sensitivity to define the diseases activity. OBJECTIVE To develop a consensus ultrasound (US) report that could summarize the relevant anatomical characteristics and staging of patients considering the experience of radiologists and dermatologists working on imaging of HS. METHODS A questionnaire on different aspects related to US examination in HS was performed. A working group, called DERMUS, composed of doctors from 9 countries who have been working in dermatologic US applied in patients with HS on a regular basis were included to evaluate the different items provided. RESULTS A consensus US report to evaluate HS patients was established. CONCLUSION The authors present the first attempt to define a HS standardized sonographic report. This model would be the first effort to include this imaging technique as the first elective medical test for staging and monitoring patients, which can support therapeutic decisions by providing earlier, objective, deeper, anatomical, and comparative evaluations in this difficult to treat disease.

High-Frequency Color Doppler Sonography of Bullous Pemphigoid Correlation With Histologic Findings

Bullous pemphigoid is the most frequent autoimmune‐mediated blistering skin disease, belonging to the group of subepidermal bullae. We performed high‐frequency color Doppler sonography in 3 cases of bullous pemphigoid, in bullous and adjacent non‐bullous skin, which showed homogeneous sonographic findings. Subepidermal cystic structures with dermal hypoechogenicity were observed in bullous skin. In nonbullous skin, the dermis showed hypoechogenicity compared to normal skin. Color Doppler signals were increased in both areas. These findings correlate histologically with subepidermal bullae and dermal inflammatory infiltrates.

Aparición de nódulos subcutáneos después de aplicación de mesoterapia

Servicio de Medicina Interna, Unidad de Infecciosas, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, Majadahonda, ed Espanola para la Investigacion de la Patologia Infecciosa, Madrid, Espana Servicio de Dermatologia, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, Majadahonda, Madrid, Espana Servicio de Cirugia General y Aparato Digestivo, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, Majadahonda, Madrid, Espana Servicio de Microbiologia, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, Majadahonda, Madrid, Espana

Erupción vesiculosa aguda en tronco

Se trataba de un paciente varon de 36 anos de edad, diagnosticado de enfermedad de Darier, que, sin haber recibido tratamientos previos, presento una erupcion cutanea vesiculosa en el tronco de 2 dias de evolucion acompanada de dolor local intenso y malestar general. En la exploracion fisica se observaron numerosas lesiones vesiculosas pequenas, de contenido claro, muchas de ellas umbilicadas en su centro, que se distribuian por la parte central y superior del torax (fig. 1). Algunas vesiculas se habian roto formando costras. No tenia lesiones similares en ninguna otra localizacion. Presentaba tambien lesiones cutaneas cronicas caracteristicas de la enfermedad de Darier en otras partes del tronco y en extremidades. Las exploraciones complementarias realizadas fueron todas normales. Se practico biopsia cutanea y se tomo una muestra para cultivo microbiologico (bacterias, virus, hongos) mediante puncion.

Leuconiquia: pigmentación blanquecina de la lámina ungueal

Presentamos el caso de un paciente de sexo masculino de 45 anos de edad, diagnosticado de mastocitosis cutanea desde el primer ano de vida y de liquen plano erosivo de mucosas y hepatitis C cronica en el ano 1990. Preciso tratamiento en los ultimos anos con corticoides orales, azatioprina, interferon y ribavirina. En la actualidad estaba en tratamiento con cloroquina. Acudio a la consulta de Dermatologia por notar la aparicion, un mes antes, de una macula blanquecina en la superficie de la una del dedo gordo del pie derecho. La mancha se habia extendido hasta afectar toda la superficie ungueal y era totalmente asintomatica. A la exploracion se observaba una lamina ungueal blanco-amarillenta homogenea y de superficie lisa (fig. 1). No presentaba signos de paroniquia asociada. Se procedio a la toma de una muestra para cultivo micologico. Al raspar la una, la superficie ungueal se desmenuzo, arrastrandose la parte afectada de la una hasta casi eliminarla (fig.2). Se efectuo cultivo del material obtenido en agar glucosado de Sabouraud con y sin actidiona. En la placa sin actidiona crecieron colonias blancas algodonosas, mientras que en la placa con actidiona no hubo crecimiento. Se realizo subcultivo en agar glucosado con patata donde desarrollo una coloracion violeta (fig. 3). En la observacion microscopica con azul de lactofenol por el metodo de la cinta adhesiva se apreciaron microconidias ovaladas y macroconidias multicelulares en forma de platano.

Ex Vivo High-Frequency Ultrasound for Assessment of Basal Cell Carcinoma: Ex Vivo High-Frequency Ultrasound for Basal Cell Carcinoma

The use of Mohs micrographic surgery for poorly defined cutaneous tumors is present in a few departments in Spain. Reintervention is occasionally necessary when the margins of the surgical specimen are invaded by the tumor. We propose the use of ultrasound to assess these margins by imaging the surgical specimen once excised.

Abstract 51: Activating PLCG1 mutations in cutaneous T-cell lymphomas.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of diseases characterized by clonal expansion of malignant T-cells in the skin. The two predominant clinical forms of CTCL are mycosis fungoides (MF) and Sezary syndrome (SS). Tumor-stage MF has an unfavorable prognosis with a 10-year survival of approximately 40%. Despite the molecular pathogenesis of CTCL is still basically unknown, some data including Gene expression profiling (GEP) studies have shown that increased signaling from the T-cell receptor (TCR) can be considered a driving force of CTCL and that the neoplastic T-cells can acquire Treg and Th17 phenotypes. However, the molecular mechanisms responsible for this activation have not been fully clarified. Based on the hypothesis that deregulated TCR activity may depend, at least in part, on somatic mutations, we have studied the coding exons of a selection of genes with known biological relevance in T-cells, including TCR and MAPK signaling, cytokine activity and survival/apoptosis regulators. By means of deep sequencing we analyzed paired (non tumoral vs. tumoral) genomic DNA from 11 CTCL patients. Under these premises, we first prepared enriched libraries for exons and regulatory regions for 524 genes belonging to the aforementioned pathways, and then proceeded to sequence with a Genome Analyzer GA2 (Illumina). The sequencing data was checked by FastQC and aligned to the human reference genome (GRCh37) and somatic variants were identified using GATK. Candidate variants were manually reviewed and validated by capillary sequencing. Our results showed multiple somatic mutations in essential genes implicated in the biology of T cells. Strikingly, we found recurrent mutations in PLCG1 affecting 3/11 patients (two of them sharing the same mutation) in our cohort. This protein can be considered a mayor effector of TRC signaling as well as to play a central role in the differentiation processes of T-cells towards the acquisition of a Treg/Th17 phenotype. Using a combination of PLCG1-targeted DNA sequencing and immune-staining in FFPE patient samples, we corroborated that up to 20% of a new cohort of 60 patients harbored the recurrent PLCG1 mutation. Moreover we found a correlation between the presence of this mutation and the nuclear accumulation of activated NFAT, a well-known PLCG1downstream effector, suggesting that these mutations may confer a gain of function activity to this enzyme. We corroborated this observation by comparing the activity of exogenous expression of WT and mutant PLCG1 proteins towards the activation of NFAT using a luciferase reporter gene assay. Moreover we also found that the resultant activity from these mutants was highly sensitive to the specific inhibition of CaN and PLC in our system which may suggest that the finding of these mutations in CTCL patients might be used as an indicative for targeted therapy. Citation Format: Jose P. Vaque, Gonzalo Gomez-Lopez, Veronica Monsalvez, Sagrario Gomez de Benito, Ignacio Varela, Nerea Martinez, Laura Cereceda, Soraya Curiel, Osvaldo Grana, Maria S. Rodriguez-Pinilla, Carmen M. Gonzalez-Vela, Jose L. Rodriguez-Peralto, Miriam Rubio-Camanillo, Esperanza Martin, Miriam Mendez, Jose A. Garcia-Marco, Mariano Provencio, Gaston Roustan, Mercedes Hospital, Dolores Suarez, Orlando Dominguez, Pablo Ortiz-Romero, Miguel A. Piris, Margarita Sanchez-Beato. Activating PLCG1 mutations in cutaneous T-cell lymphomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 51. doi:10.1158/1538-7445.AM2013-51

Empeoramiento de lesiones de lepra en un paciente filipino

Varon de 36 anos natural de Filipinas y residente en Espana desde hacia 3 anos. Habia sido diagnosticado hacia 10 anos de enfermedad de Hansen, caracterizada por lesiones dermicas nodulares y en placas en la cara y las extremidades, y fue tratado durante 3 meses con una medicacion que no recordaba. En agosto de 2006 fue remitido por su medico a la consulta de dermatologia por aumento de sus lesiones dermicas. El paciente presentaba maculas, nodulos y placas cutaneas eritematosas en cara, tronco y extremidades (fig. 1). Tambien tenia la mano derecha en garra con atrofia de eminencia hipotenar, anquilosis del cuarto y quinto dedos y anestesia en territorio cubital derecho de unos 8 anos de evolucion (fig. 2). Asimismo, presentaba enrojecimiento leve de ambas conjuntivas sin dolor ni disminucion de la agudeza visual. No referia congestion nasal. Una de la lesiones del brazo fue biopsiada, y se observo un infiltrado granulomatoso con macrofagos, que contenian bacilos acido-alcohol resistentes y escasas celulas gigantes de localizacion dermica y subdermica, y un infiltrado granulomatoso y linfocitario con infiltracion de los nervios cutaneos que era concordante con lepra dimorfa (borderline borderline, fig. 3). Tras confirmar el diagnostico de lepra multibacilar se instauro tratamiento con rifampicina 600 mg y dapsona 100 mg al dia por via oral. Tres semanas despues acudio porque llevaba una semana con fiebre de predominio noc-