Epidemiological studies have demonstrated a causal relationship between smoking and lung cancer. Although most lung cancer cases are linked to smoking, only a minority of heavy smokers develop lung cancer, leading to the notion that genetic factors affect individual susceptibility. The principal molecular changes in lung cancer are seen in tumor suppressor genes, proto-oncogenes, growth factors, telomerase activity, and methylation status of promoters. Well-known agents include angiogenesis-stimulating factors (such as vascular endothelial growth factor), as well as factors related to tumor cell proliferation and apoptosis (epidermal growth factor receptor, p53, K-ras, retinoblastoma and BCL-2). Several of these genetic factors have already been investigated, but no single parameter has yet presented sufficient selectivity regarding prognostic value or therapeutic efficacy. Treatment strategies to cure lung cancer should focus on these early genetic lesions in order to promote their repair or to eliminate these lung cancer cells.

Keywords: Smoking; Lung neoplasms; Genetic markers; Prognosis

Biological markers are cellular, structural and biochemical components that can define cellular as well as molecular changes in both normal and neoplastic cells. There are two types of biological markers: 1) intermediate markers that evaluate cellular and molecular alterations before malignancy occurs; and 2) diagnostic markers, present in association with malignancy. The identification and validation of biological markers for clinical use are performed in stages: initial identification in cell cultures of the tumor;
testing of the marker in tissues obtained in biopsies of patients with an established diagnosis of the tumor;
testing of biopsies of normal tissues and tissues with an inflammatory process;
sputum, blood or urine tests for validation as a non-invasive test that can be used in high-risk populations. Sorologic and histopathologic biological markers are cellular, structural and biochemical components found in both normal and neoplastic cells that can be quantitatively assessed by biochemical, immunological and molecular methods in the body fluids or tissues, respectively, and may be associated with malignancies and, possibly, with the neoplastic organ. Biological markers are studied in diverse primary neoplasms. However, few of them proved to be clinically valuable. The role of biological markers in lung cancer patients remains unclear because only a small number of markers has been properly identifiassessed. The aim of this paper is to understand the role of sorologic and histologic biological markers in the prognosis and survival of lung cancer patients based on our previous works. Furthermore, we present a future perspective of the early detection of lung cancer on the basis of the role of intermediate biological markers.

Keywords: Biologic markers. Lung cancer. Prognosis. Survival. Morphometric method.

Objective: To estimate and compare the frequency of CYP1A1*2A gene polymorphisms in a Brazilian population and determine the possible contribution of these genetic variations to lung cancer risk. Methods: The study population included 200 patients with lung cancer, and the control group consisted of 264 blood donors. Genomic DNA was obtained from peripheral blood samples. The PCR-RFLP method was used for analysis of the CYP1A1*2A gene. Results: There was no statistically significant difference between the lung cancer patients and the controls in terms of the distribution of CYP1A1*2A polymorphisms (p = 0.49). A multivariate logistic regression model analysis by ethnic group revealed that, within the lung cancer group, the CYP1A1*2A genotype CC plus TC was more common among the African-Brazilian patients than among the White patients (adjusted OR = 3.19; 95% CI: 1.53‑6.65). Conclusions: The CYP1A1*2A gene cannot be linked with lung cancer risk in Brazilian patients at this time. Larger epidemiologic studies are needed in order to establish whether the CC plus TC polymorphism increases the risk of lung cancer in African-Brazilians.

Keywords: Lung neoplasms; Polymorphism, genetic; Metabolism.

Recent advances in genetics and molecular biology lead to the identification of genes and protein products overexpressed by tumors. Such products, called tumor markers, were previously used only as diagnostic and prognostic tools, but are currently being the target of extensive research, with growing evidence that some of them may have an important role in the development of new treatment modalities, targeting the tumor cell biological cycle. In this article, the authors review the role of some of the traditionally known tumor markers (CEA, p53, NSE, K-ras), and describe the prevalence and the role of the epidermal growth factor receptor (EGFR) overexpression and its protein product, p185neu. New drugs have been developed, aiming at the blockade of the signaling process initiated by the EGFR. Among these, the authors highlight ZD1839 (Iressa), a new orally administered drug that reversibly and selectively inhibits the EGFR tyrosine-kinase activity. This drug has demonstrated good results in the treatment of non-small-cell lung cancer, as an isolated drug or in combination with other chemotherapy agents. Targeting the EGFR could represent a significant contribution to cancer therapy, mainly the non-small-cell lung cancer.

Keywords: Lung neoplasms. Tumor markers. Receptor epidermal growth factor.

Lung cancer is the leading cause of cancer-related deaths worldwide. Promising new therapies have recently emerged from the development of molecular targeted drugs; particularly promising are those blocking the signal transduction machinery of cancer cells. One of the most widely studied cell signaling pathways is that of EGFR, which leads to uncontrolled cell proliferation, increased cell angiogenesis, and greater cell invasiveness. Activating mutations in the EGFR gene (deletions in exon 19 and mutation L858R in exon 21), first described in 2004, have been detected in approximately 10% of all non-squamous non-small cell lung cancer (NSCLC) patients in Western countries and are the most important predictors of a response to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Studies of the EGFR-TKIs gefitinib, erlotinib, and afatinib, in comparison with platinum-based regimens, as first-line treatments in chemotherapy-naïve patients have shown that the EGFR-TKIs produce gains in progression-free survival and overall response rates, although only in patients whose tumors harbor activating mutations in the EGFR gene. Clinical trials have also shown EGFR-TKIs to be effective as second- and third-line therapies in advanced NSCLC. Here, we review the main aspects of EGFR pathway activation in NSCLC, underscore the importance of correctly identifying activating mutations in the EGFR gene, and discuss the main outcomes of EGFR-TKI treatment in NSCLC.

Keywords: Molecular targeted therapy; Receptor, epidermal growth factor; Lung neoplasms/drug therapy; Mutation; Oncogenes.

Objective: To correlate the postbronchodilator (post-BD) inspiratory capacity (IC), % of predicted, with other markers of severity and prognostic factors in chronic obstructive pulmonary disease (COPD). Methods: Eighty stable patients with COPD performed forced vital capacity and slow vital capacity maneuvers, as well as the 6-min walk test, prior to and after receiving albuterol spray (400 μg). Patients were divided into four groups, based on post-BD forced expiratory volume in one second. Several variables were tested to establish correlations with the post-BD distance walked, using univariate and multivariate analysis. Post-BD IC was found to correlated with Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging and with the Body mass index, airway Obstruction, Dyspnea, and Exercise capacity (BODE) index. Results: Multivariate regression analysis revealed that the distance walked, % predicted, correlated significantly with the IC post-BD, % predicted (p = 0.001), long-term oxygen use (p = 0.014), and number of medications used in the treatment (p = 0.044). IC ≤ 70% was observed in 56% patients in GOLD stages 3 or 4 vs. 20% in GOLD 1 or 2 (p < 0.001). IC ≤ 70% was observed in (60%) patients with BODE score 3 or 4 vs. (33%) BODE score 1 or 2 (p = 0.02). Conclusion: Post-BD IC% predicted is the best functional predictor of distance walked and is significantly associated with GOLD staging and BODE index. Therefore, We propose that the inspiratory capacity should be added to the routine evaluation of the COPD patients.

Keywords: Pulmonary disease, chronic obstructive; Walking; Respiratory function tests; Inspiratory capacity.

Objective: To evaluate the prevalence of anorexia and weight loss at diagnosis (pre-treatment), to identify the factors associated with pre-treatment weight loss, and to determine the prognostic role of anorexia and weight loss in the overall survival of patients with stage IV lung cancer. Methods: This was a retrospective observational cohort study. The patients were stratified by the presence/absence of anorexia and of pre-treatment weight loss, which generated a measure composed of four categories, which were the independent variables. Results: Among the 552 patients included in the study, anorexia and pre-treatment weight loss were present in 39.1% and 70.1%, respectively. After adjusting for age, male gender, and Karnofsky performance status, we found that anorexia and tumor size were significantly associated with pre-treatment weight loss. In a Cox multivariate analysis, adjusted for age, male gender and low Karnofsky performance status were found to be independent predictors of worse survival, as was concomitance of anorexia and weight loss. Conclusions: Anorexia and pre-treatment weight loss appear to be relevant problems in the follow-up of patients with advanced (stage IV) lung cancer Specific interventions are of crucial importance in individualized treatment plans, even within the context of palliative care.

Keywords: Lung neoplasms; Anorexia; Weight loss; Neoplasms/mortality.

Objective: To determine the relationships that smoking history has with inflammatory markers, metabolic markers, body composition, muscle strength, and cardiopulmonary capacity in current smokers. Methods: This was a cross-sectional study involving 65 smokers (age range: 18-60 years). On three non-consecutive days, each participant was evaluated in terms of smoking history, pre-existing comorbidities, lung function (by spirometry), peripheral muscle strength (by dynamometry), body composition (by bioelectrical impedance analysis), levels of metabolic/inflammatory markers, and maximum cardiopulmonary capacity (by treadmill exercise test). We evaluated the relationships that smoking history has with inflammatory markers, metabolic markers, body composition, muscle strength, and cardiopulmonary capacity, using logarithmic transformation of the data and calculating Pearson's correlation coefficient and for partial correlations adjusted for age, gender, body mass index (BMI), and comorbidities. To identify the influence of smoking history on pre-existing comorbidities, we used a logistic regression model adjusted for age, BMI, and duration of smoking. Results: Smoking history correlated significantly, albeit weakly, with triglyceride level (r = 0.317; p = 0.005), monocyte count (r = 0.308; p = 0.013), and waist circumference (r = 0.299; p = 0.017). However, those correlations did not retain their significance in the adjusted analysis. In the logistic regression model, smoking more than 20 cigarettes/day correlated significantly with the presence of metabolic diseases (OR = 0.31; 95% CI: 1.009-1.701; p = 0.043). Conclusions: In this sample of smokers, smoking history correlated positively with the triglyceride level, the monocyte count, and waist circumference. The prevalence of metabolic disease was highest in those who smoked more than 20 cigarettes/day.

Keywords: Tobacco; Smoking; Triglycerides; Monocytes; Waist circumference; Body composition.

Objective: Lung cancer patients often experience profound physical and psychosocial changes as a result of disease progression or treatment side effects. Fatigue, pain, dyspnea, depression, and sleep disturbances appear to be the most common symptoms in such patients. The objective of the present study was to examine the prevalence of symptoms in lung cancer patients in order to identify subgroups (clusters) of patients, grouped according to the magnitude of the symptoms, as well as to compare the quality of life among the identified subgroups. Methods: A cross-sectional study involving agglomerative hierarchical clustering. A total of 50 lung cancer patients were evaluated in terms of their demographic characteristics and their scores on three quality of life questionnaires, namely the 30-item European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30), the Functional Assessment of Cancer Therapy-Lung, and the Medical Outcomes Study 36-item Short-form Survey. The cluster analysis took into account the magnitude of the most prevalent symptoms as assessed by the EORTC QLQ-C30 symptom scale scores; those symptoms were fatigue, pain, dyspnea, and insomnia. Results: Three clusters (subgroups)_of patients were identified on the basis of the magnitude of the four most prevalent symptoms. The three subgroups of patients were as follows: patients with mild symptoms (n = 30; 60%); patients with moderate symptoms (n = 14; 28%); and patients with severe symptoms (n = 6; 12%). The subgroup of patients with severe symptoms had the worst quality of life, as assessed by the total scores and by the integrated domains of all three instruments. Conclusions: This study highlights the importance of symptom cluster assessment as an important tool to assess the quality of life of patients with chronic diseases, such as lung cancer.

The role of immunohistochemistry is to recognize antigens and, consequently, to identify and classify specific cells within a cell population whose morphology is heterogenous or apparently homogenous. The visualization of the antigen-antibody complex is made possible through the addition of either a fluorochrome conjugate or an enzyme to the antibody, which is then viewed under microscopy. Immunohistochemistry can be used in the routine diagnosis of lung cancer, in order to identify biological markers (diagnostic and prognostic). The essential immunohistochemistry panels will be discussed in this review.

Keywords: Immunohistochemistry; Tumor markers, biological; Lung neoplasms.

BACKGROUND: In agreement with other reported studies, wehad previously found a possible association between gender and prognosis in stage I non-small cell lung cancer (NSCLC), showing a higher survival rate among females. OBJECTIVES: The purpose of this study was to further clarify the role of gender as a possible prognostic factor in NSCLC. METHOD: In a retrospective cohort study, we examined the survival of 163 NSCLC patients who underwent curative surgical treatment at the Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS) Hospital between 1990 and 1997. Data was analyzed using Kaplan-Meier plots. Additionally, we used the Mann-Whitney test for comparing group survival rates and the Cox regression model to adjust for potential confounding factors. RESULTS: Were included 124 (76.07%) males and 39 (23.93%) females, whose median survival was of 32.3 and 60.6 months, respectively. The 5-year survival was 38.0% for men and 55.4% for women (P=0.030). Considering only stage I patients, survival rates were 44.4% and 81.8% for men and women, respectively (P=0.009). Effect of gender continued after adjustment for several factors (age, hemoglobin, histology, tumor size, type of surgery and postoperative complications). CONCLUSION: This study confirms our previous findings that women live longer after NSCLC surgery when compared to men. This result is only observed at an early stage and persists after adjustment of several factorsP

Keywords: Carcinoma, bronchogenic [surgery]; Carcinoma, bronchogenic [epidemiolgy]; Prognosis; Sex distribution; Disease - free survival.

Objective: To determine the demographic and clinical characteristics of patients with non-small cell lung cancer (NSCLC), as well as their disease course, by age group and gender. Methods: This was a retrospective cohort study of patients diagnosed with NSCLC from 2000 to 2012 and followed until July 2015 in a tertiary referral hospital in the city of São Paulo, Brazil. Based on the 25th and 75th percentiles of the age distribution, patients were stratified into three age groups: < 55 years; ≥ 55 and < 72 years; and ≥ 72 years. Survival time was evaluated during the follow-up period of the study. Functions of overall and gender-specific survival stratified by age groups (event: all-cause mortality) were calculated using the Kaplan-Meier method. Differences among survival curves were assessed via the log-rank test. Results: We included 790 patients with the following age distribution: < 55 years, 165 patients; ≥ 55 and < 72 years, 423; and ≥ 72 years, 202. In the entire sample, there were 493 men (62.4%). Adenocarcinoma was the most common histological pattern in the < 72-year age groups; 575 patients (73%) presented with advanced disease (stages IIIB-IV). The median 5-year survival was 12 months (95% CI: 4-46 months), with no significant differences among the age groups studied. Conclusions: NSCLC remains more common in men, although we found an increase in the proportion of the disease in women in the < 55-year age group. Adenocarcinoma predominated in women. In men, squamous cell carcinoma predominated in the ≥ 72-year age group. Most patients presented with advanced-stage disease at diagnosis. There were no statistical differences in survival between genders or among age groups.

Keywords: Lung neoplasms; Age groups, Sex; Survival.

Silica is one of the main occupational agents associated with lung cancer. It is classified by the International Agency for Research on Cancer (IARC) as a Group 1 substance, i.e., carcinogenic for humans, since 1996. The objective of this paper is to report two cases of workers previously exposed to silica who developed lung cancer, seen in an out-patient clinic, focusing on important points of the current literature on the subject.

Objective: To analyze the locations of lung carcinomas in relation to patient gender and smoking status. Methods: In order to test the hypothesis that lung carcinoma location (upper or lower lobe; left or right side) is correlated with smoking status and gender, we conducted a retrospective study of 697 patients with bronchogenic carcinoma treated at the Pulmonology-Oncology Outpatient Clinic of the Federal University of São Paulo. Results: We found that the bronchogenic carcinomas occurring in smokers were more frequently located in the upper lobes, whereas those occurring in nonsmokers were more frequently located in the lower lobes. In women, the neoplasms were more often seen in the lower lobes, especially in nonsmokers. Based on the available data, there were no differences in terms of the side affected (left or right). Conclusion: Overall, bronchogenic carcinomas are predominantly found in the upper lobes. However, in nonsmokers, they occur more frequently in the lower lobes. In females, bronchogenic carcinomas present a tendency to occur more often in the lower lobes.

Keywords: Lung neoplasms; Sex factors; Smoking

Objective: Impaired respiratory mechanics and gas exchange may contribute to sleep disturbance in patients with COPD. We aimed to assess putative associations of different domains of lung function (airflow limitation, lung volumes, and gas exchange efficiency) with polysomnography (PSG)-derived parameters of sleep quality and architecture in COPD. Methods: We retrospectively assessed data from COPD 181 patients = 40 years of age who underwent spirometry, plethysmography, and overnight PSG. Univariate and multivariate linear regression models predicted sleep efficiency (total sleep time/total recording time) and other PSG-derived parameters that reflect sleep quality. Results: The severity of COPD was widely distributed in the sample (post-bronchodilator FEV1 ranging from 25% to 128% of predicted): mild COPD (40.3%), moderate COPD (43.1%), and severe-very severe COPD (16.6%). PSG unveiled a high proportion of obstructive sleep apnea (64.1%) and significant nocturnal desaturation (mean pulse oximetry nadir = 82.2% ± 6.9%). After controlling for age, sex, BMI, apnea-hypopnea index, nocturnal desaturation, comorbidities, and psychotropic drug prescription, FEV1/FVC was associated with sleep efficiency (ß = 25.366; R2 = 14%; p < 0.001), whereas DLCO predicted sleep onset latency (ß = -0.314; R2 = 13%; p < 0.001) and rapid eye movement sleep time/total sleep time in % (ß = 0.085; R2 = 15%; p = 0.001). Conclusions: Pulmonary function variables reflecting severity of airflow and gas exchange impairment, adjusted for some potential confounders, were weakly related to PSG outcomes in COPD patients. The direct contribution of the pathophysiological hallmarks of COPD to objectively measured parameters of sleep quality seems to be less important than it was previously assumed.

Keywords: Pulmonary disease, chronic obstructive; Respiratory function tests; Sleep; Sleep apnea, obstructive; Comorbidity.