Impact of Tumor LINE-1 Methylation Level and Neoadjuvant Treatment and Its Association with Colorectal Cancer Survival

Recent studies suggest that long-interspersed nucleotide element-1 (LINE-1) hypomethylation is commonly found in colorectal cancer (CRC), and is associated with worse prognosis. However, the utility of LINE-1 methylation on the prognosis of CRC is still controversial, and may be due to the fact that some clinical and pathological features may affect LINE-1 methylation. Thus, the aim of this study was to assess the prognostic value of tumor LINE-1 methylation in CRC, through their association with the CRC clinical and pathological characteristics. Survival of sixty-seven CRC patients was evaluated according to the median of tumor LINE-1 methylation, as well as pathological and oncological variables. We also studied the association between LINE-1 methylation and pathological features, and finally, we assessed the overall and disease-free survival of LINE1 methylation, stratified by neoadjuvant treatment and further checked by multivariate Cox regression to assess the statistical interactions. LINE-1 was hypomethylated in the CRC tumor with respect to the tumor adjacent-free area (p < 0.05), without association with any other clinical and oncological features, nor with overall and disease-free survival rates for CRC. Relevantly, in neoadjuvant treatment, LINE-1 methylation was associated with survival rates. Thus, disease-free and overall survival rates of treated CRC patients were worse in the hypomethylated LINE-1 tumors than those with normal LINE-1 methylation (p = 0.004 and 0.0049, respectively). Indeed, LINE-1 was hypermethylated more in the treated patients than in the non-treated patients (p < 0.05). The present study showed that tumor LINE-1 hypomethylation was associated with worse survival rates in only treated patients. Our data suggest an interactive effect of neoadjuvant treatment and tumor LINE-1 methylation, which could be a specific-tissue biomarker to predict survival of the treated patients, and help to personalize treatment in CRC

Diagnostic yield of electromagnetic navigation bronchoscopy is highly dependent on the presence of a Bronchus sign on CT imaging: results from a prospective study

Electromagnetic navigation bronchoscopy (ENB) has been developed as a novel ancillary tool for the bronchoscopic diagnosis of pulmonary nodules. Despite successful navigation in 90% of patients, ENB diagnostic yield does not generally exceed 70%. We sought to determine whether the presence of a bronchus sign on CT imaging conditions diagnostic yield of ENB and might account for the discrepancy between successful navigation and diagnostic yield. METHODS: We conducted a prospective, single-center study of ENB in 51 consecutive patients with pulmonary nodules. ENB was chosen as the least invasive diagnostic technique in patients with a high surgical risk, suspected metastatic disease, or advanced-stage disease, or in those who demanded a preoperative diagnosis prior to undergoing curative resection. We studied patient and technical variables that might condition diagnostic yield, including size, cause, location, distance to the pleural surface, and fluorodeoxyglucose uptake of a given nodule; the presence of a bronchus sign on CT imaging; registration point divergence; and the minimum distance from the tip of the locatable guide to the nodule measured during the procedure. RESULTS: The diagnostic yield of ENB was 67% (34/51). The sensitivity and specificity of ENB for malignancy in this study were 71% and 100%, respectively. ENB was diagnostic in 79% (30/38) patients with a bronchus sign on CT imaging but only in 4/13 (31%) with no discernible bronchus sign. Univariate analysis identified the bronchus sign (P = .005) and nodule size (P = .04) as statistically significant variables conditioning yield, but on multivariate analysis, only the bronchus sign remained significant (OR, 7.6; 95% CI, 1.8-31.7). No procedure-related complications were observed. CONCLUSIONS: ENB diagnostic yield is highly dependent on the presence of a bronchus sign on CT imaging

Emphysema presence, severity, and distribution has little impact on the clinical presentation of a cohort of patients with mild to moderate COPD

Phenotypic characterization of patients with COPD may have potential prognostic and therapeutic implications. Available information on the relationship between emphysema and the clinical presentation in patients with COPD is limited to advanced stages of the disease. The objective of this study was to describe emphysema presence, severity, and distribution and its impact on clinical presentation of patients with mild to moderate COPD. METHODS: One hundred fifteen patients with COPD underwent clinical and chest CT scan evaluation for the presence, severity, and distribution of emphysema. Patients with and without emphysema and with different forms of emphysema distribution (upper/lower/core/peel) were compared. The impact of emphysema severity and distribution on clinical presentation was determined. RESULTS: Fifty percent of the patients had mild homogeneously distributed emphysema (1.84; 0.76%-4.77%). Upper and core zones had the more severe degree of emphysema. Patients with emphysema were older, more frequently men, and had lower FEV(1)%, higher total lung capacity percentage, and lower diffusing capacity of the lung for carbon monoxide. No differences were found between the clinical or physiologic parameters of the different emphysema distributions. CONCLUSIONS: In patients with mild to moderate COPD, although the presence of emphysema has an impact on physiologic presentation, its severity and distribution seem to have little impact on clinical presentation

Effect of a specific supplement enriched with n-3 polyunsaturated fatty acids on markers of inflammation, oxidative stress and metabolic status of ear, nose and throat cancer patients.

Journal Article; Research Support, Non-U.S. Gov't;Malnutrition affects 40-50% of patients with ear, nose and throat (ENT) cancer. The aim of this study was to assess changes induced by a specific nutritional supplement enriched with n-3 polyunsaturated fatty acids, fiber and greater amounts of proteins and electrolytes, as compared with a standard nutritional supplement, on markers of inflammation, oxidative stress and metabolic status of ENT cancer patients undergoing radiotherapy (RT). Fourteen days after starting RT, 26 patients were randomly allocated to one of two groups, 13 supplemented with Prosure, an oncologic formula enriched with n-3 polyunsaturated fatty acids, fiber and greater amounts of proteins and electrolytes (specific supplement), and 13 supplemented with Standard-Isosource (standard supplement). Patients were evaluated before RT, and 14, 28 and 90 days after starting RT. The results showed that there were no significant differences between the groups, but greater changes were observed in the standard supplement group, such as a decline in body mass index (BMI), reductions in hematocrit, erythrocyte, eosinophil and albumin levels, and a rise in creatinine and urea levels. We concluded that metabolic, inflammatory and oxidative stress parameters were altered during RT, and began to normalize at the end of the study. Patients supplemented with Prosure showed an earlier normalization of these parameters, with more favorable changes in oxidative stress markers and a more balanced evolution, although the difference was not significant.This study was supported in part by grants from the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovación, EC07/90285). F. Cardona is a recipient of CP07/0095 grant. M.M. Roca-Rodríguez is supported by fellowship Rio Hortega CM11/00030 Program from the Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness. Trial registration, EudraCT Number 2008-000330-50.Ye

Trabecular bone score in active or former smokers with and without COPD

Background Smoking is a recognized risk factor for osteoporosis. Trabecular bone score (TBS) is a novel texture parameter to evaluate bone microarchitecture. TBS and their main determinants are unknown in active and former smokers. Objective To assess TBS in a population of active or former smokers with and without Chronic Obstructive Pulmonary Disease (COPD) and to determine its predictive factors. Methods Active and former smokers from a pulmonary clinic were invited to participate. Clinical features were recorded and bone turnover markers (BTMs) measured. Lung function, low dose chest Computed Tomography scans (LDCT), dual energy absorptiometry (DXA) scans were performed and TBS measured. Logistic regression analysis explored the relationship between measured parameters and TBS. Results One hundred and forty five patients were included in the analysis, 97 (67.8%) with COPD. TBS was lower in COPD patients (median 1.323; IQR: 0.13 vs 1.48; IQR: 0.16, p = 0.003). Regression analysis showed that a higher body mass index (BMI), younger age, less number of exacerbations and a higher forced expiratory volume-one second (FEV1%) was associated with better TBS (β = 0.005, 95% CI:0.000–0.011, p = 0.032; β = -0.003, 95% CI:-0.007(-)-0.000, p = 0.008; β = -0.019, 95% CI:-0.034(-)-0.004, p = 0.015; β = 0.001, 95% CI:0.000–0.002, p = 0.012 respectively). The same factors with similar results were found in COPD patients. Conclusions A significant proportion of active and former smokers with and without COPD have an affected TBS. BMI, age, number of exacerbations and the degree of airway obstruction predicts TBS values in smokers with and without COPD. This important information should be considered when evaluating smokers at risk of osteoporosis

Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest.

Identification of risk factors for lung cancer can help in selecting patients who may benefit the most from smoking cessation interventions, early detection, or chemoprevention. OBJECTIVE: To evaluate whether the presence of emphysema on low-radiation-dose CT (LDCT) of the chest is an independent risk factor for lung cancer. METHODS: The study used data from a prospective cohort of 1,166 former and current smokers participating in a lung cancer screening study. All individuals underwent a baseline LDCT and spirometry followed by yearly repeat LDCT studies. The incidence density of lung cancer among patients with and without emphysema on LDCT was estimated. Stratified and multiple regression analyses were used to assess whether emphysema is an independent risk factor for lung cancer after adjusting for age, gender, smoking history, and the presence of airway obstruction on spirometry. RESULTS: On univariate analysis, the incidence density of lung cancer among individuals with and without emphysema on LDCT was 25.0 per 1,000 person-years and 7.5 per 1,000 person-years, respectively (risk ratio [RR], 3.33; 95% confidence interval [CI], 1.41 to 7.85). Emphysema was also associated with increased risk of lung cancer when the analysis was limited to individuals without airway obstruction on spirometry (RR, 4.33; 95% CI, 1.04 to 18.16). Multivariate analysis showed that the presence of emphysema (RR, 2.51; 95% CI, 1.01 to 6.23) on LDCT but not airway obstruction (RR, 2.10; 95% CI, 0.79 to 5.58) was associated with increased risk of lung cancer after adjusting for potential cofounders. CONCLUSIONS: Results suggest that the presence of emphysema on LDCT is an independent risk factor for lung cancer

Regulation of Endothelial Cell Adhesion Molecule Expression by Mast Cells, Macrophages, and Neutrophils

Leukocyte adhesion to the vascular endothelium and subsequent transendothelial migration play essential roles in the pathogenesis of cardiovascular diseases such as atherosclerosis. The leukocyte adhesion is mediated by localized activation of the endothelium through the action of inflammatory cytokines. The exact proinflammatory factors, however, that activate the endothelium and their cellular sources remain incompletely defined.Using bone marrow-derived mast cells from wild-type, Tnf(-/-), Ifng(-/-), Il6(-/-) mice, we demonstrated that all three of these pro-inflammatory cytokines from mast cells induced the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin in murine heart endothelial cells (MHEC) at both mRNA and protein levels. Compared with TNF-α and IL6, IFN-γ appeared weaker in the induction of the mRNA levels, but at protein levels, both IL6 and IFN-γ were weaker inducers than TNF-α. Under physiological shear flow conditions, mast cell-derived TNF-α and IL6 were more potent than IFN-γ in activating MHEC and in promoting neutrophil adhesion. Similar observations were made when neutrophils or macrophages were used. Neutrophils and macrophages produced the same sets of pro-inflammatory cytokines as did mast cells to induce MHEC adhesion molecule expression, with the exception that macrophage-derived IFN-γ showed negligible effect in inducing VCAM-1 expression in MHEC.Mast cells, neutrophils, and macrophages release pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL6 that induce expression of adhesion molecules in endothelium and recruit of leukocytes, which is essential to the pathogenesis of vascular inflammatory diseases

Smokers with CT detected emphysema and no airway obstruction have decreased plasma levels of EGF, IL-15, IL-8 and IL-1ra

Current or former smokers expressing a well-defined disease characteristic such as emphysema, has a specific plasma cytokine profile. This includes a decrease of cytokines mainly implicated in activation of apoptosis or decrease of immunosurveillance. This information should be taken into account when evaluated patients with tobacco respiratory diseases