High Levels of IL-1ß, TNF-α and MIP-1α One Month after the Onset of the Acute SARS-CoV-2 Infection, Predictors of Post COVID-19 in Hospitalized Patients.

The pandemic caused by SARS-CoV-2 infection has left behind a new symptomatology called post COVID-19, or "long COVID". The pathophysiological mechanisms still remain controversial; however, a link between persistent inflammation and these sequelae has been suggested. Herein, we longitudinally assessed up- and downstream molecules of the NLRP3 inflammasome's pathway in three study groups: healthy donors (HC, n = 14) and donors with a confirmed SARS-CoV-2 infection who had been hospitalized, the latter divided into post COVID-19 (PC, n = 27) and non-post COVID-19 patients (nPC, n = 27) based on the presence or absence of symptomatology at month 6, respectively. Plasma cytokines (IL-1ß, IL-3, IL-6, IL-8, IL-18, IP-10, MIG, TNF-α, IFN-γ, MIP-1α and MIP-1ß) and total peroxide (TPX) levels were quantified at baseline and at months 1 and 6 after the onset of the infection. Baseline values were the highest for both TPX and cytokines that progressively decreased thereafter the acute infection. IL-1ß, MIP-1α and TNF-α at month 1 were the only cytokines that showed a significant difference between nPC and PC. These findings suggest that a persistent inflammatory state one month after the onset of SARS-CoV-2 infection related to specific cytokines (IL-1ß, MIP-1α, and TNF-α) might guide to predicting post COVID-19 symptomatology.

Is the diagnostic yield of mediastinal lymph node cryobiopsy (cryoEBUS) better for diagnosing mediastinal node involvement compared to endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)? A systematic review.

INTRODUCTION: New tools such as cryobiopsy of mediastinal lymph nodes (cryoEBUS) have been described to improve the diagnostic usefulness of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The literature suggests that this novel procedure could be associated with greater diagnostic usefulness than conventional EBUS-TBNA. METHODS: To develop a systematic analysis and meta-analysis on the diagnostic diagnostic yield and safety of cryobiopsy of hilar and mediastinal adenopathies compared to EBUS-TBNA. RESULTS: Seven studies that had included a total of 555 patients were considered in this review, with 365 (65.7%) of these patients having an etiology of malignant lymph node involvement. The overall diagnostic usefulness of cryoEBUS was higher compared to EBUS-TBNA (92% vs. 80%). However, when the results were analysed according to the specific aetiologies of the adenopathies, cryoEBUS was especially useful in cases of lymphomas or non-pulmonary carcinomas (83% vs. 42%) and in cases that were benign (87% vs. 60.1%), with no significant differences being found in specific cases of lung cancer. For lymphoma, cryoEBUS was diagnostic in 87% of cases compared to 12% for EBUS-TBNA and in addition, also allowed the characterisation of every lymphoma subtype. Genetic studies and immunohistochemical determination of PD-L1 was possible in almost all (97%) of the samples obtained by cryoEBUS, while this was only possible in 79% of those obtained by EBUS-TBNA. The most frequent complication was light bleeding, which was described in up to 85% of cases in some series. CONCLUSION: CryoEBUS could represent a promising technique in the diagnostic algorithm used for mediastinal and hilar involvement. Although cryoEBUS did not significantly improve the diagnosis of lung cancer compared to EBUS-TBNA, the results were significantly better in patients with benign pathologies and other tumour types, including lymphomas. In addition, it seems that the samples obtained by cryoEBUS better defined the histological subtypes of lymphoma and allowed complete molecular characterisation in cases of lung cancer. The technique has proven to be safe and no serious complications were described after the procedure.

Biological Biomarkers in Respiratory Diseases. / Biomarcadores biológicos en las enfermedades respiratorias.

In recent years, personalized or precision medicine has made effective inroads into the management of diseases, including respiratory diseases. The route to implementing this approach must invariably start with the identification and validation of biological biomarkers that are closely related to the diagnosis, treatment, and prognosis of respiratory patients. In this respect, biological biomarkers of greater or lesser reliability have been identified for most respiratory diseases and disease classes, and a large number of studies are being conducted in the search for new indicators. The aim of this review is to update the reader and to analyze the existing scientific literature on the existence and diagnostic, therapeutic, and prognostic validity of the most important biological biomarkers in the main respiratory diseases, and to identify future challenges in this area.

Different Faces of Idiopathic Pulmonary Fibrosis With Preserved Forced Vital Capacity.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is progressive and irreversible. Some discrepancies about IPF staging exists, especially in mild phases. Forced vital capacity (FVC) higher than 80% has been considered early or mild IPF even for the design of clinical trials. METHODS: Spanish multicentre, observational, retrospective study of IPF patients diagnosed between 2012 and 2016, based on the ATS/ERS criteria, which presented FVC greater or equal 80% at diagnosis. Clinical and demographic characteristics, lung function, radiological pattern, treatment, and follow-up were analyzed. RESULTS: 225 IPF patients were included, 72.9% were men. The mean age was 69.5 years. The predominant high-resolution computed tomography (HRCT) pattern was consistent usual interstitial pneumonia (UIP) (51.6%). 84.7% of patients presented respiratory symptoms (exertional dyspnea and/or cough) and 33.33% showed oxygen desaturation below 90% in the 6min walking test (6MWT). Anti-fibrotic treatment was initiated at diagnosis in 55.11% of patients. Median FVC was 89.6% (IQR 17) and 58.7% of patients had a decrease of diffusion lung capacity for carbon monoxide (DLCO) below 60% of theoretical value; most of them presented functional progression (61.4%) and higher mortality at 3 years (20.45%). A statistically significant correlation with the 3-years mortality was observed between DLCO <60% and consistent UIP radiological pattern. CONCLUSIONS: Patients with preserved FVC but presenting UIP radiological pattern and moderate-severe DLCO decrease at diagnosis associate an increased risk of progression, death or lung transplantation. Therefore, in these cases, preserved FVC would not be representative of early or mild IPF.

Mediastinal staging for non-small cell lung cancer.

The staging of mediastinal lymph nodes for lung cancer is crucial for planning treatments or reinterventions. In potentially curable patients the aim of mediastinal staging is to exclude the presence of malignancy in mediastinal lymph nodes with a high level of accuracy while also considering clinical factors and the balance of the benefits and risks of tissue sampling techniques. Mediastinal staging is based on computed tomography (CT) and positron emission tomography (PET) and can be sufficient when no mediastinal abnormalities are present and the probability of unforeseen N2 disease is low. In the case of bulky lymph nodes with a high probability of malignancy in PET-CT, tissue confirmation is not normally required. If mediastinal sampling is needed it can be achieved by endosonographic techniques, including endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) or a combination of the two. Positive results do not need further confirmation. In the case of negative results, surgical techniques still play a role in the selected cases discussed by multidisciplinary lung cancer committees. New mediastinal surgical techniques including video-assisted cervical mediastinoscopy (VACM), video-assisted mediastinoscopic lymphadenectomy (VAMLA), and transcervical extended mediastinal lymphadenectomy (TEMLA) have been shown to be useful in selected patients. Final pathological staging is based on lymph node removal during surgery and can be achieved by taking one of two approaches: lymph node sampling or systematic lymph node sampling. The accuracy of PET-CT and mediastinal endosonography is lower for mediastinal restaging than it is for surgical techniques; their false positive and false negative (FN) rate is high and so, they require histological confirmation. Here we explain and revise the results from the most recent studies and current international guidelines.

Cost Effectiveness of Malignant Pleural Effusion with Indwelling Catheter: Systematic Review.

Background: The current cost of treatment of malignant pleural effusion (MPE) with an indwelling pleural catheter (IPC) is unclear. Objective: We propose a review of the scientific evidence on the cost and effectiveness of this therapeutic option. Methods: Systematic review of the literature on the cost and effectiveness of the treatment of MPE by IPC, according to the PRISMA methodology and quality according to the scientific guidelines. Results: A total of 4 articles, 152 patients, and 159 IPCs were included. The use of IPC was associated with improvement in symptoms and quality of life. The most common complications were infections (empyema in 20.9% of patients and cellulitis in 17.3%); 9% of cases were hospitalized due to complications, and <2% required subsequent procedures. The average cost of IPC (set/drainage bottles) ranged from €2,025.6 to €1,200.5 if it was placed on an outpatient basis, €1,100 if survival was <6 weeks, and €4,028 in patients with mesothelioma. Complications increased the cost, and taking into account follow-up visits, additional tests, and days of admission for complications, the cost was >€5,000. Compared with pleurodesis, the cost of IPC was significantly lower when patient survival was <14 weeks, but not when survival was longer or home care was required. Conclusions: The use of IPC is associated with good control of MPE and seldom requires many subsequent procedures; however, it is also associated with a certain rate of complications, which may increase costs. However, ambulatory management may help reduce costs, which are directly related to the type of tumor, the duration of survival, and the need for specialized treatment.

Comparison of Bisulfite Pyrosequencing and Methylation-Specific qPCR for Methylation Assessment.

Different methodological approaches are available to assess DNA methylation biomarkers. In this study, we evaluated two sodium bisulfite conversion-dependent methods, namely pyrosequencing and methylation-specific qPCR (MS-qPCR), with the aim of measuring the closeness of agreement of methylation values between these two methods and its effect when setting a cut-off. Methylation of tumor suppressor gene p16/INK4A was evaluated in 80 lung cancer patients from which cytological lymph node samples were obtained. Cluster analyses were used to establish methylated and unmethylated groups for each method. Agreement and concordance between pyrosequencing and MS-qPCR was evaluated with Pearson's correlation, Bland-Altman, Cohen's kappa index and ROC curve analyses. Based on these analyses, cut-offs were derived for MS-qPCR. An acceptable correlation (Pearson's R2 = 0.738) was found between pyrosequencing (PYRmean) and MS-qPCR (NMP; normalized methylation percentage), providing similar clinical results when categorizing data as binary using cluster analysis. Compared to pyrosequencing, MS-qPCR tended to underestimate methylation for values between 0 and 15%, while for methylation >30% overestimation was observed. The estimated cut-off for MS-qPCR data based on cluster analysis, kappa-index agreement and ROC curve analysis were much lower than that derived from pyrosequencing. In conclusion, our results indicate that independently of the approach used for estimating the cut-off, the methylation percentage obtained through MS-qPCR is lower than that calculated for pyrosequencing. These differences in data and therefore in the cut-off should be examined when using methylation biomarkers in the clinical practice.

Lung cancer risk and do-it-yourself activities. A neglected risk factor for lung cancer.

BACKGROUND: The aim of this study was to assess the relationship between do-it-yourself activities entailing the exposure to carcinogenic substances and the risk of lung cancer. METHODS: We pooled individual data from different case-control studies conducted in Northwestern Spain which investigated residential radon and lung cancer. Cases had an anatomopathologically confirmed primary lung cancer and controls were selected at the pre-surgery unit with uncomplicated surgeries. Both cases and controls were older than 30 years with no previous cancer history. All participants were interviewed face-to-face using a specific questionnaire. Painting, model building, furniture refinishing and woodworking or home carpentry were the do-it-yourself activities considered risky due to exposure to carcinogenic agents. RESULTS: We included 1528 cases and 1457 controls. Practicing do-it-yourself risk activities was more frequent among cases: 16.0% were exposed to carcinogenic exposures during leisure time, compared to 11.8% for controls. The overall adjusted OR for lung cancer risk among individuals who practiced do-it-yourself risk activities, was 1.77 (95% CI: 1.36-2.31); this was 2.17 (95% CI: 1.51-3.11) when the analysis was restricted to individuals who performed these activities for at least 10 years. These risks were greater when the analyses were carried out exclusively among never-smokers, with the respective ORs being 2.04 (95% CI: 1.38-3.01) and 3.10 (95% CI: 1.78-5.40). CONCLUSION: These results support the hypothesis that do-it-yourself activities involving exposure to certain carcinogens are associated with an increased risk of lung cancer, both in ever and never-smokers.

Residential radon, genetic polymorphisms in DNA damage and repair-related.

OBJECTIVES: To analyze the relationship of GSTT1, GSTM1, XRCC1 (rs25487), ERCC1 (rs11615, rs3212986), ERCC2 (rs13181), XRCC3 (rs861539), OGG1 (rs1052133), and Alpha-1-Antitrypsin mutations (AAT) with the risk of lung cancer in never-smokers, and ascertain if there is an effect modification between these polymorphisms and residential radon exposure. MATERIAL AND METHODS: We designed a multicenter hospital-based case-control study in a radon-prone area. 322 cases and 338 controls, all never-smokers, were included. They were selected using a frequency sampling based on sex and age distribution of the cases. Participants donated 3 ml. of whole blood used to determine genotype for polymorphisms. They placed a radon detector to measure residential radon exposure in their dwelling. RESULTS: The OR for deleted GSTM1 patients was 3.46 (95% CI = 1.52-7.89) at residential radon exposures above 200 Bq/m3. The ERCC1 rs3212986 polymorphism was the most associated with the risk of developing lung cancer, both for low and high radon exposures. The ERCC1 rs321986 GT and TT genotypes (at radon concentrations >200 Bq/m3) were more significantly associated with higher lung cancer risk (OR = 2.40, 95% CI = 1.29-4.45; OR = 4.45, 95% CI = 1.26-15.7, respectively). CONCLUSIONS: These findings support the hypothesis that certain polymorphisms in genes involved in DNA-repair and carriers of GSTM1 deletion have an increased risk of lung cancer in never-smokers exposed to residential radon.

Predictive value of a series of inflammatory markers in COPD for lung cancer diagnosis: a case-control study.

BACKGROUND: There is a relationship between Chronic Obstructive Pulmonary Disease (COPD) and the development of lung cancer (LC). The aim of this study is to analyse several blood markers and compare their concentrations in patients with only COPD and LC + COPD. METHODS: Case-control study with cases presenting combined LC and COPD and two control groups (patients presenting only COPD and patients presenting only LC). We also included LC patients with descriptive purposes. In both groups, peripheral blood analyses of TNF-α, IL-6, IL-8, total leukocyte, lymphocyte and neutrophil counts, neutrophil-to-lymphocyte ratio, total platelet count, mean platelet volume, platelet-to-lymphocyte ratio, alpha 1-antitripsin (A1AT), IgE, C-reactive protein, fibrinogen, cholesterol and bilirubin were performed. We developed univariate and multivariate analyses of these markers, as well as a risk score variable, and we evaluated its performance through ROC curves. RESULTS: We included 280 patients, 109 cases (LC + COPD), 83 controls (COPD) and 88 LC without COPD. No differences were observed in the distribution by sex, age, BMI, smoking, occupational exposure, lung function, GOLD stage or comorbidity. Patients with LC + COPD had significantly higher levels of neutrophils [OR 1.00 (95%CI 1.00-1.00), p = 0.03] and A1AT [OR 1.02 (95%CI 1.01-1.03), p = 0.003] and lower cholesterol levels [OR 0.98 (95%CI 0.97-0.99), p = 0.009] than COPD controls. We developed a risk score variable combining neutrophils, A1AT and cholesterol, achieving a sensitivity of 80%, a negative predictive value of 90.7% and an area under the curve of 0.78 (95%CI 0.71-0.86). CONCLUSIONS: COPD patients who also have LC have higher levels of neutrophils and A1AT and lower of cholesterol. These parameters could be potentially predicting biomarkers of LC in COPD patients.

Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes.

BACKGROUND: Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients. METHODS: This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes. RESULTS: Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening. CONCLUSION: Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed.

Lung cancer and residential radon in never-smokers: A pooling study in the Northwest of Spain.

BACKGROUND: Using a pooled case-control study design, including only never-smokers, we have assessed the association of residential radon exposure with the subsequent occurrence of lung cancer. We also investigated whether residential radon poses a different risk specifically for adenocarcinoma. METHODS: We pooled individual data from different case-control studies conducted in recent years in Northwestern Spain which investigated residential radon and lung cancer. All participants were never-smokers. Cases had a confirmed biopsy of primary lung cancer. Hospital controls were selected at pre-surgery units, presenting for non-complex surgical procedures. They were interviewed using a standardized instrument. Residential radon was measured using alpha track detectors at the Galician Radon Laboratory at the University of Santiago de Compostela. RESULTS: A total of 1415 individuals, 523 cases and 892 controls were included. We observed an odds ratio of 1.73 (95%CI: 1.27-2.35) for individuals exposed to ≥ 200 Bq/m3 compared with those exposed to ≤100 Bq/m3. Lung cancer risk for adenocarcinoma was 1.52 (95%CI: 1.14-2.02) using the same categories for radon exposure. CONCLUSIONS: Residential radon is a clear risk factor for lung cancer in never-smokers. Our data suggest that radon exposure is associated with all histological types of lung cancer and also with adenocarcinoma, which is currently the most frequent histological type for this disease.

Predicting delays in lung cancer diagnosis and staging.

BACKGROUND: Despite growing interest in increasing the efficiency and speed of the diagnosis, staging, and treatment of lung cancer (LC), the interval from signs and symptoms to diagnosis and treatment remains longer than recommended. The aim of this study was to analyze the factors that cause delays in the LC diagnosis/staging process and, consequently, delays in making therapeutic decisions. METHODS: We analyzed audit data from a prospective dataset of 1330 patients assessed at The Lung Cancer Rapid Diagnostic Unit from 26 June 2013 to 26 March 2016. The number and type of procedures and medical tests and the times of all procedures were recorded. Clinical and epidemiological variables and whether the diagnosis was performed on an inpatient or outpatient basis were also recorded. RESULTS: Malignancy was confirmed in 737 (55.4%) of the 1330 patients, with LC in 627 of these (85.2%). The mean interval to final diagnosis was 19.8 ± 13.9 days. Variables significantly related to a longer diagnostic time were the number of days until computed tomography (CT) was performed (odds ratio [OR], 95% confidence interval [CI] 1.347, 1.103-1.645; P = 0.003), until a histology sample was obtained (OR 1.243, 95% CI1.062-1.454; P = 0.007), and the total number of tests performed during the diagnostic and staging process (OR 1.823, 95% CI 1.046-3.177; P = 0.03). CONCLUSIONS: A greater number of tests and more days to CT and histology led to longer delay times. Optimization of these factors should reduce delays in the LC diagnosis process.

Predictive factors and prognostic effect of telomere shortening in pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: The abnormal shortening of telomeres is a mechanism linking ageing to idiopathic pulmonary fibrosis (IPF) that could be useful in the clinical setting. The objective of this study was to identify the IPF patients with higher risk for telomere shortening and to investigate the outcome implications. METHODS: Consecutive Spanish patients were included at diagnosis and followed up for 3 years. DNA blood samples from a Mexican cohort were used to validate the results found in Spanish sporadic IPF. Prior to treatment, telomere length was measured through quantitative polymerase chain reaction (qPCR) and Southern blot. Outcome was assessed according to mortality or need for lung transplantation. A multivariate regression logistic model was used for statistical analysis. RESULTS: Family aggregation, age of <60 years and the presence of non-specific immunological or haematological abnormalities were associated with a higher probability of telomere shortening. Overall, 66.6% of patients younger than 60 years with telomere shortening died or required lung transplantation, independent of functional impairment at diagnosis. By contrast, in patients older than 60 years with telomere shortening, the negative impact of telomere shortening in outcome was not significant. CONCLUSION: Our data indicate that young sporadic IPF patients (<60 years) with some non-specific immunological or haematological abnormalities had higher risk of telomere shortening, and furthermore, they presented a poorer prognosis.

Influence of the type of emphysema in the relationship between COPD and lung cancer.

INTRODUCTION: There are no studies analyzing the relationship between emphysema and lung cancer (LC). With this aim and in order to make some comparisons between different clinical variables, we carried out the present study. METHODS: This is a case-control study, patients with COPD and LC being the cases and subjects with stable COPD being the controls. Clinical and functional parameters, as well as the existence of radiological emphysema, were evaluated in a qualitative and quantitative way, using a radiological density of -950 Hounsfield units as a cutoff point in the images. The existence of several different types of emphysema (centrilobular, paraseptal, panacinar, or bullae) was analyzed, allowing patients to have more than one simultaneously. The extent to which lobes were involved was evaluated and the extension of emphysema was graduated for each type and location, following a quantitative scale. Differences between cases and controls were compared by using bivariate and multivariate analyzes with results expressed as OR and 95% CI. RESULTS: We included 169 cases and 74 controls, 84% men with a FEV1 (%) of 61.7±18.5, with 90.1% non-exacerbators. Most of them (50%) were active smokers and 47.2% were ex-smokers. Emphysema was found in 80.2% of the subjects, the most frequent type being centrilobular (34.4%). The only significantly different factor was the presence of paraseptal emphysema (alone or combined; OR =2.2 [95% CI =1.1-4.3, P = 0.03]), with adenocarcinoma being significantly more frequent in paraseptal emphysema with respect to other types (67.2% vs 32.8%, P =0.03). CONCLUSION: Patients with COPD and paraseptal emphysema could be a risk group for the development of LC, especially adenocarcinoma subtype.

Chronic Obstructive Pulmonary Disease in Lung Cancer Patients: Prevalence, Underdiagnosis, and Clinical Characterization.

BACKGROUND: Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are associated with increased morbidity and mortality. The differential clinical and functional features among LC patients with or without COPD have not been defined. OBJECTIVES: The aims of this study were to examine the prevalence and underdiagnosis rate of COPD in LC patients and to compare the clinical and functional features of LC patients with and without COPD. METHODS: We designed a multicenter hospital-based study including all LC cases diagnosed from January 2014 to August 2016. We assessed epidemiological, clinical, radiological, functional, and histological variables in all cases. RESULTS: We recruited 602 patients with LC, most of them men (77.9%), with a median age of 67 ± 15 years. The COPD prevalence among LC patients was 51.5%, with a underdiagnosis rate of 71.6%. The LC+COPD patients were older and the proportion of men was higher compared with the LC-only patients. The LC+COPD patients had more pack-years, more squamous LC, a lower monoxide transfer coefficient (KCO), and higher Charlson index scores than patients with LC only. The median survival of LC-only patients was 37% longer than that of LC+COPD patients (22 vs. 16 months), but this difference was not statistically significant. CONCLUSIONS: Among LC patients, COPD is prevalent and underdiagnosed. Patients with LC+COPD more often have squamous LC, have greater comorbidities, and have a lower KCO. More effort should be made for an early diagnosis of COPD to select patients at higher risk of developing LC.

Alcohol consumption and lung cancer risk in never smokers: a pooled analysis of case-control studies.

Background: Lung cancer is the deadliest cancer in developed countries but the etiology of lung cancer risk in never smokers (LCRINS) is largely unknown. We aim to assess the effects of alcohol consumption, in its different forms, on LCRINS. Methods: We pooled six multi-center case-control studies developed in the northwest of Spain. Cases and controls groups were composed of never smokers. We selected incident cases with anatomopathologically confirmed lung cancer diagnoses. All participants were personally interviewed. We performed two groups of statistical models, applying unconditional logistic regression with generalized additive models. One considered the effect of alcohol type consumption and the other considered the quantity of each alcoholic beverage consumed. Results: A total of 438 cases and 863 controls were included. Median age was 71 and 66, years, respectively. Adenocarcinoma was the predominant histological type, comprising 66% of all cases. We found that any type of wine consumption posed an OR of 2.20 OR 95%CI 1.12-4.35), and spirits consumption had an OR of 1.90 (95%CI 1.13-3.23). Beer consumption had an OR of 1.33 (95%CI 0.82-2.14). These results were similar when women were analyzed separately, but for men there was no apparent risk for any alcoholic beverage. The dose-response analysis for each alcoholic beverage revealed no clear pattern. Conclusions: Wine and spirits consumption might increase the risk of LCRINSs, particularly in females. These results have to be taken with caution given the limitations of the present study.

Environmental tobacco smoke exposure and EGFR and ALK alterations in never smokers' lung cancer. Results from the LCRINS study.

Environmental tobacco smoke (ETS) exposure is a main risk factor of lung cancer in never smokers. Epidermal Growth Factor Receptor (EGFR) mutations and ALK translocations are more frequent in never smokers' lung cancer than in ever-smokers. We performed a multicenter case-control study to assess if ETS exposure is associated with the presence of EGFR mutations and its types and if ALK translocations were related with ETS exposure. All patients were never smokers and had confirmed lung cancer diagnosis. ETS exposure during childhood showed a negative association on the probability of EGRF mutation though not significant. Exposure during adulthood, at home or at workplace, did not show any association with EGFR mutation. The mutation type L858R seemed the most associated with a lower probability of EGFR alterations for ETS exposure at home in adult life. There is no apparent association between ETS exposure and ALK translocation. These results might suggest that ETS exposure during childhood or at home in adult life could influence the EGFR mutations profile in lung cancer in never smokers, reducing the probability of presenting EFGR mutation.