Hospital Universitario Marque Valdecilla

Santander, Spain

Hospital Universitario Marque Valdecilla

Santander, Spain
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Rodriguez-Pinilla S.M.,CNIO Lymphoma Group | Ortiz-Romero P.L.,Hospital Universitario 12 Of Octubre | Monsalvez V.,Hospital Universitario 12 Of Octubre | Tomas I.E.,Hospital Of Torrejo N Of Ardoz | And 18 more authors.
American Journal of Surgical Pathology | Year: 2013

Primary cutaneous γδ T-cell lymphomas (PCGD-TCLs) are considered a subgroup of aggressive cytotoxic T-cell lymphomas (CTCLs). We have taken advantage of a new, commercially available antibody that recognizes the T-cell receptor-γ (TCR-γ) subunit of the TCR in paraffin-embedded tissue. We have analyzed a series of 146 primary cutaneous T-cell lymphomas received for consultation or a second opinion in the CNIO Pathology Department. Cases were classified according to the World Health Organization 2008 classification as mycosis fungoides (MF; n=96), PCGD-TCLs (n=5), pagetoid reticulosis (n=6), CD30 primary cutaneous anaplastic large cell lymphomas (n=5), primary cutaneous CD8 aggressive epidermotropic CTCLs (n=3), primary cutaneous CTCL, not otherwise specified (n=4), and extranodal nasal-type NK/T-cell lymphomas primarily affecting the skin or subcutaneous tissue (n=11). Sixteen cases of the newly named lymphomatoid papulosis type D (LyP-D; n=16) were also included. In those cases positive for TCR-γ, a further panel of 13 antibodies was used for analysis, including TIA-1, granzyme B, and perforin. Clinical and follow-up data were recorded in all cases. Twelve cases (8.2%) were positive for TCR-γ, including 5 PCGD-TCLs, 2 MFs, and 5 LyP-Ds. All 5 PCGD-TCL patients and 1 MF patient died of the disease, whereas the other MF patient and all those with LyP-D were alive. All cases expressed cytotoxic markers, were frequently CD3/CD8, and tended to lose CD5 and CD7 expressions. Eight of 12 and 5 of 11 cases were CD30 and CD56, respectively. Interestingly, 5/12 TCR-γ-positive cases also expressed TCR-BF1. All cases analyzed were negative for Epstein-Barr virus-encoded RNA. In conclusion, TCR-γ expression seems to be rare and is confined to cytotoxic primary cutaneous TCLs. Nevertheless, its expression is not exclusive to PCGD-TCLs, as TCR-γ protein can be found in other CTCLs. Moreover, its expression does not seem to be associated with bad prognosis by itself, as it can be found in cases with good and bad outcomes. Copyright © 2013 by Lippincott Williams & Wilkins.

Martin-Sanchez E.,Spanish National Cancer Research Center | Martin-Sanchez E.,Hospital Universitario Marque Valdecilla | Odqvist L.,Spanish National Cancer Research Center | Rodriguez-Pinilla S.M.,Fundacio N Jime Nez Diaz | And 22 more authors.
PLoS ONE | Year: 2014

Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs) and pharmacologically (mainly with the pan-PIM inhibitor (PIMi) ETP-39010) in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL) cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL. © 2014 Martín-Sánchez et al.

Menezes J.,Molecular Cytogenetics Group | Acquadro F.,Molecular Cytogenetics Group | Wiseman M.,NIMGenetics | Gomez-Lopez G.,Bioinformatic Unit | And 15 more authors.
Leukemia | Year: 2014

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment. © 2014 Macmillan Publishers Limited.

Castellanos-Ortega A.,Hospital Universitario Marque Valdecilla | Suberviola B.,Hospital Universitario Marque Valdecilla | Garcia-Astudillo L.A.,Institute Formacio N E Investigacio N Marque S Of Valdecilla | Holanda M.S.,Hospital Universitario Marque Valdecilla | And 3 more authors.
Critical Care Medicine | Year: 2010

Objectives: To describe the effectiveness of the Surviving Sepsis Campaign bundles with regard to both implementation and outcome in patients with septic shock and to determine the contribution of the various elements of the bundles to the outcome. Design: Quasi-experimental study with a historical comparison group. Setting: The three medical-surgical intensive care units of an academic tertiary care center. Patients: A total of 384 adult patients in septic shock were enrolled after the educational intervention (September 2005-August 2008) and 96 patients in the historical group (June 2004-May 2005). Intervention: A hospital-wide quality improvement program based on the implementation of the Surviving Sepsis Campaign guidelines performed between June 2005 and August 2005. Measurements and Results: In-hospital mortality was reduced from 57.3% in the historical group to 37.5% in the intervention group (p =.001). This difference remained significant after controlling for confounding factors (odds ratio, 0.50; 95% confidence interval, 0.28-0.89). The intervention group had also lower length of stay for survivors in the hospital (36.2 ± 34.8 days vs. 41.0 ± 26.3 days; p =.043) and in the intensive care units (8.4 ± 9.8 days vs. 11.0 ± 9.5 days; p =.004). Improvements in survival were related to the number of bundle interventions completed (p for trend <.001). Compliance with six or more interventions of the 6-hr resuscitation bundle was an independent predictor of survival (adjusted odds ratio, 0.30; 95% confidence interval, 0.17-0.53; p <.001). The only single intervention with impact on mortality was the achievement of ScvO2 ≥70% (adjusted odds ratio, 0.62; 95% confidence interval, 0.38-0.99; p =.048). Conclusions: The implementation of the Surviving Sepsis Campaign guidelines was associated with a significant decrease in mortality. The benefits depend on the number of interventions accomplished within the time limits. The 6-hr resuscitation bundle showed greater compliance and effectiveness than the 24-hr management bundle. © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

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