Juan, M. (Manel)

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2015 - 20182

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    Recurrent Invasive Pneumococcal Disease in Children: Underlying Clinical Conditions, and Immunological and Microbiological Characteristics
    (Public Library of Science (PLOS), 2015) de Sevilla, M.F. (Mariona F.); de Paz, H.D. (Héctor D.); Alsina, L. (Laia); Juan, M. (Manel); Basteiro, M.G. (María G.); Muñoz-Almagro, C. (Carmen); Iñigo, M. (Melania); Triviño, M. (Miriam)
    Purpose Clinical, immunological and microbiological characteristics of recurrent invasive pneumo- coccal disease (IPD) in children were evaluated, differentiating relapse from reinfection, in order to identify specific risk factors for both conditions. Methods All patients <18 years-old with recurrent IPD admitted to a tertiary-care pediatric center from January 2004 to December 2011 were evaluated. An episode of IPD was defined as the presence of clinical findings of infection together with isolation and/or pneumococcal DNA detection by Real-Time PCR in any sterile body fluid. Recurrent IPD was defined as 2 or more episodes in the same individual at least 1 month apart. Among recurrent IPD, we differentiated relapse (same pneumococcal isolate) from reinfection. Results 593 patients were diagnosed with IPD and 10 patients died. Among survivors, 23 episodes of recurrent IPD were identified in 10 patients (1.7%). Meningitis was the most frequent form of recurrent IPD (10 episodes/4 children) followed by recurrent empyema (8 episodes/4 chil- dren). Three patients with recurrent empyema caused by the same pneumococcal clone ST306 were considered relapses and showed high bacterial load in their first episode. In contrast, all other episodes of recurrent IPD were considered reinfections. Overall, the rate of relapse of IPD was 0.5% and the rate of reinfection 1.2%. Five out of 7 patients with rein- fection had an underlying risk factor: cerebrospinal fluid leak (n = 3), chemotherapytreatment (n = 1) and a homozygous mutation in MyD88 gene (n = 1). No predisposing risk factors were found in the remainder. Conclusions recurrent IPD in children is a rare condition associated with an identifiable risk factor in case of reinfection in almost 80% of cases. In contrast, recurrent IPD with pleuropneumonia is usually a relapse of infection.
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    Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types
    (Elsevier BV, 2018) Adamo, B. (B.); Prat, A. (A.); Font, C. (C.); Rodríguez, A. (A.); Garcia-Corbacho, J. (J.); Viñolas, N. (N.); Mellado, B. (B.); Gaba, L. (L.); Seguí, E. (E.); Gonzalez-Cao, M. (María); Perez-Ruiz, E. (Elisabeth); Martin-Algarra, S. (Salvador); Ruiz, G. (G.); Paré, L. (L.); González, B. (B.); Arance, A. (Ana); Galván, P. (P.); Torné, A. (A.); Juan, M. (Manel); Llovet, J.M. (J. M.); Pineda, E. (E.); Teixidó, C. (Cristina); Victoria, I. (I.); Vidal, M. (M.); Cuatrecasas, M. (M.); Reig, Ó. (Ó.); Maurel, J. (J.); Reguart, N. (Noemi); Crespo, G. (Guillermo); Viladot, M. (M.); Muñoz, M. (M.); Pascual, T. (T.); Molina-Vila, M.A. (Miguel Angel)
    Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%–84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r ¼ 0.91) with the ORR following antiPD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low ¼ 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.