Showing papers by "Luis M. Montuenga published in 2015"

Improving Selection Criteria for Lung Cancer Screening. The Potential Role of Emphysema

Abstract: Rationale: Lung cancer (LC) screening using low-dose chest computed tomography is now recommended in several guidelines using the National Lung Screening Trial (NLST) entry criteria (age, 55–74; ≥30 pack-years; tobacco cessation within the previous 15 yr for former smokers). Concerns exist about their lack of sensitivity.Objectives: To evaluate the performance of NLST criteria in two different LC screening studies from Europe and the United States, and to explore the effect of using emphysema as a complementary criterion.Methods: Participants from the Pamplona International Early Lung Action Detection Program (P-IELCAP; n = 3,061) and the Pittsburgh Lung Screening Study (PLuSS; n = 3,638) were considered. LC cumulative frequencies, incidence densities, and annual detection rates were calculated in three hypothetical cohorts, including subjects who met NLST criteria alone, those with computed tomography–detected emphysema, and those who met NLST criteria and/or had emphysema.Measurements and Main Results: ...

Expression of Sirtuin 1 and 2 Is Associated with Poor Prognosis in Non-Small Cell Lung Cancer Patients

Abstract: Background Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are NAD+-dependent protein deacetylases involved in the regulation of key cancer-associated genes. In this study we evaluated the relevance of these deacetylases in lung cancer biology.

Lung cancer screening: fourteen year experience of the Pamplona early detection program (P-IELCAP).

Abstract: Introduction and objectives European experience regarding lung cancer screening using low-dose chest CT (LDCT) is available. However, there is limited data on the Spanish experience in this matter. Our aim is to present the results from the longest ongoing screening program in Spain. Methodology The Pamplona International Early Lung Cancer Detection Program (P-IELCAP) is actively screening participants for lung cancer using LDCT since the year 2000 following the IELCAP protocol, including spirometric assessments. Men and women, ≥40 years of age, current or former smokers with a tobacco history of ≥10 pack-years are included. Results are compared to those from other European trials. Results A total of 2989 participants were screened until March 2014 (73% male). A median of 2 (IQR 1–3) annual screening rounds were performed. Sixty lung cancers were detected in 53 participants (73% in Stage I). Adenocarcinoma was the most frequent. The lung cancer prevalence and incidence proportion was 1.0% and 1.4%, respectively, with an annual detection rate of 0.41. The estimated 10-year survival rate among individuals with lung cancer was 70%. Chronic obstructive pulmonary disease and emphysema are important lung cancer predictors. Conclusions The experience in Spain's longest lung cancer screening program is comparable to what has been described in the rest of Europe, and confirms the feasibility and efficacy of lung cancer screening using LDCT.

Cribado de cáncer de pulmón: catorce años de experiencia del Programa Internacional de Detección Precoz de Cáncer de Pulmón con TBDR de Pamplona (P-IELCAP)

Abstract: Resumen Introduccion y objetivos La experiencia europea en relacion con el cribado de cancer de pulmon con tomografia de baja dosis de radiacion (TBDR) es amplia. Sin embargo, la evidencia sobre la experiencia en Espana es limitada. Nuestro objetivo es presentar los resultados del programa de cribado de cancer de pulmon mas largo de Espana. Metodos El Programa Internacional de Deteccion Precoz de Cancer de Pulmon con TBDR de Pamplona (P-IELCAP) viene reclutando individuos de manera activa desde el ano 2000 siguiendo el protocolo IELCAP. Se incluyen individuos ≥ 40 anos de edad, fumadores o ex fumadores (consumo acumulado ≥ 10 paquetes-ano). Los resultados se comparan con los de otros estudios europeos. Resultados Un total de 2.989 participantes fueron reclutados hasta marzo de 2014 (73% varones), realizando una mediana de 2 (IQR 1-3) rondas de cribado por individuo. Se detectaron 60 canceres de pulmon en 53 participantes (73% en estadio i ). Adenocarcinoma fue el tipo histologico mas frecuente. La proporcion de prevalencia e incidencia de cancer de pulmon fue del 1,0 y del 1,4%, respectivamente, con una tasa de deteccion anual de 0,41. La tasa de supervivencia a 10 anos de los pacientes con cancer de pulmon fue del 70%. La enfermedad pulmonar obstructiva cronica y el enfisema son importantes factores de riesgo para desarrollar cancer de pulmon. Conclusiones La experiencia del programa de cribado de cancer de pulmon mas largo de Espana es comparable con lo descrito en el resto de Europa y confirma la viabilidad y la eficacia del cribado mediante TBDR.

Complement activation product C4d in oral and oropharyngeal squamous cell carcinoma

Abstract: We thank Amaya Lavin for technical assistance. This work was supported by Foundation for Applied Medical Research (FIMA), Red Tematica de Investigacion Cooperativa en Cancer (RD12/0036/0015, RD12/0036/0025, and RD12/0036/0040), and Fondo de Investigacion Sanitaria-Fondo Europeo de Desarrollo Regional (FEDER, PI11/00618, PI13/00806, PI11/00929, and PI14/01686).

Elevated levels of the complement activation product c4d in bronchial fluids for the diagnosis of lung cancer

Abstract: Molecular markers in bronchial fluids may contribute to the diagnosis of lung cancer. We previously observed a significant increase of C4d-containing complement degradation fragments in bronchoalveolar lavage (BAL) supernatants from lung cancer patients in a cohort of 50 cases and 22 controls (CUN cohort). The present study was designed to determine the diagnostic performance of these complement fragments (hereinafter jointly referred as C4d) in bronchial fluids. C4d levels were determined in BAL supernatants from two independent cohorts: the CU cohort (25 cases and 26 controls) and the HUVR cohort (60 cases and 98 controls). A series of spontaneous sputum samples from 68 patients with lung cancer and 10 controls was also used (LCCCIO cohort). Total protein content, complement C4, complement C5a, and CYFRA 21-1 were also measured in all cohorts. C4d levels were significantly increased in BAL samples from lung cancer patients. The area under the ROC curve was 0.82 (95%CI = 0.71–0.94) and 0.67 (95%CI = 0.58–0.76) for the CU and HUVR cohorts, respectively. In addition, unlike the other markers, C4d levels in BAL samples were highly consistent across the CUN, CU and HUVR cohorts. Interestingly, C4d test markedly increased the sensitivity of bronchoscopy in the two cohorts in which cytological data were available (CUN and HUVR cohorts). Finally, in the LCCCIO cohort, C4d levels were higher in sputum supernatants from patients with lung cancer (area under the ROC curve: 0.7; 95%CI = 0.56–0.83). In conclusion, C4d is consistently elevated in bronchial fluids from lung cancer patients and may be used to improve the diagnosis of the disease.

Combined clinical and genomic signatures for the prognosis of early stage non-small cell lung cancer based on gene copy number alterations

Abstract: The development of a more refined prognostic methodology for early non-small cell lung cancer (NSCLC) is an unmet clinical need. An accurate prognostic tool might help to select patients at early stages for adjuvant therapies. A new integrated bioinformatics searching strategy, that combines gene copy number alterations and expression, together with clinical parameters was applied to derive two prognostic genomic signatures. The proposed methodology combines data from patients with and without clinical data with a priori information on the ability of a gene to be a prognostic marker. Two initial candidate sets of 513 and 150 genes for lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), respectively, were generated by identifying genes which have both: a) significant correlation between copy number and gene expression, and b) significant prognostic value at the gene expression level in external databases. From these candidates, two panels of 7 (ADC) and 5 (SCC) genes were further identified via semi-supervised learning. These panels, together with clinical data (stage, age and sex), were used to construct the ADC and SCC hazard scores combining clinical and genomic data. The signatures were validated in two independent datasets (n = 73 for ADC, n = 97 for SCC), confirming that the prognostic value of both clinical-genomic models is robust, statistically significant (P = 0.008 for ADC and P = 0.019 for SCC) and outperforms both the clinical models (P = 0.060 for ADC and P = 0.121 for SCC) and the genomic models applied separately (P = 0.350 for ADC and P = 0.269 for SCC). The present work provides a methodology to generate a robust signature using copy number data that can be potentially used to any cancer. Using it, we found new prognostic scores based on tumor DNA that, jointly with clinical information, are able to predict overall survival (OS) in patients with early-stage ADC and SCC.

Biological Marker Analysis as Part of the CIBERES-RTIC Cancer-SEPAR Strategic Project on Lung Cancer.

Abstract: The aim of the Clinical and Molecular Staging of Stage I-IIp Lung Cancer Project is to identify molecular variables that improve the prognostic and predictive accuracy of TMN classification in stage I/IIp non-small cell lung cancer (NSCLC). Clinical data and lung tissue, tumor and blood samples will be collected from 3 patient cohorts created for this purpose. The prognostic protein signature will be validated from these samples, and micro-RNA, ALK, Ros1, Pdl-1, and TKT, TKTL1 y G6PD expression will be analyzed. Tissue inflammatory markers and stromal cell markers will also be analyzed. Methylation of p16, DAPK, RASSF1a, APC and CDH13 genes in the tissue samples will be determined, and inflammatory markers in peripheral blood will also be analyzed. Variables that improve the prognostic and predictive accuracy of TNM in NSCLC by molecular staging may be identified from this extensive analytical panel.

Sphere-derived tumor cells exhibit impaired metastasis by a host-mediated quiescent phenotype

Abstract: // Anne-Marie Bleau 1 , Carolina Zandueta 1 , Miriam Redrado 1 , Susana Martinez-Canarias 1 , Leyre Larzabal 1 , Luis M. Montuenga 1, 2, 3 , Alfonso Calvo 1, 2, 3, * , Fernando Lecanda 1, 2, 3, * 1 Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain 2 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain 3 IdiSNA, Navarra Institute for Health Research, Pamplona, Spain * These authors have contributed equally to this work Correspondence to: Fernando Lecanda, e-mail: flecanda@unav.es Keywords: stem cell, dormancy, p27, osteolysis, p38 Abbreviations: TSC, tumor sphere cultures; AC, adherent cultures; BLI, bioluminescence imaging; i.c., intracardiac; i.t., intratibial Received: November 04, 2014 Accepted: July 27, 2015 Published: August 07, 2015 ABSTRACT The spread of lung cancer cells to distant sites represents a common event associated with poor prognosis. A fraction of tumor cells named cancer stem cells (CSCs) have the ability to overcome therapeutic stress and remain quiescent. However, whether these CSCs have also the capacity to initiate and sustain metastasis remains unclear. Here, we used tumor sphere cultures (TSC) isolated from mouse and human lung cancer models to enrich for CSCs, and assessed their metastatic potential as compared to non-CSCs. As expected, TSC overexpressed a variety of stem cell markers and displayed chemoresistance. The CSC phenotype of TSC was confirmed by their higher growth ability in soft agar and tumorigenic potential in vivo , despite their reduced in vitro cell growth kinetics. Surprisingly, the appearance of spontaneous lung metastases was strongly delayed in mice injected with TSC as compared to non-TSC cells. Similarly, this finding was confirmed in several other models of metastasis, an effect associated with a retarded colonization activity. Interestingly, such delay correlated with a quiescent phenotype whose underlined mechanisms included an increase in p27 protein and lower phospho-ERK1/2 levels. Thus, these data suggest that cells enriched for CSC properties display an impaired metastatic activity, a finding with potential clinical implications.

Análisis de marcadores biológicos en el Proyecto Estratégico de Cáncer de Pulmón CIBERES-RTIC Cáncer-SEPAR

Abstract: The aim of the Clinical and Molecular Staging of Stage I-IIp Lung Cancer Project is to identify molecular variables that improve the prognostic and predictive accuracy of TMN classification in stage I/IIp non-small cell lung cancer (NSCLC). Clinical data and lung tissue, tumor and blood samples will be collected from 3 patient cohorts created for this purpose. The prognostic protein signature will be validated from these samples, and micro-RNA, ALK, Ros1, Pdl-1, and TKT, TKTL1 y G6PD expression will be analyzed. Tissue inflammatory markers and stromal cell markers will also be analyzed. Methylation of p16, DAPK, RASSF1a, APC and CDH13 genes in the tissue samples will be determined, and inflammatory markers in peripheral blood will also be analyzed. Variables that improve the prognostic and predictive accuracy of TNM in NSCLC by molecular staging may be identified from this extensive analytical panel.